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5 - BONE DISORDERS: TRANSLATIONAL MEDICINE CASE STUDIES

Published online by Cambridge University Press:  04 April 2011

By
S. Aubrey Stoch
Edited by
Bruce H. Littman  and
Rajesh Krishna
S. Aubrey Stoch
Affiliation:
Merck Research Laboratories
Bruce H. Littman
Affiliation:
Translational Medicine Associates
Rajesh Krishna
Affiliation:
Merck Research Laboratories
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Summary

Introduction

In the United States, about 10 million Americans have osteoporosis (8 million women and 2 million men), whereas another 34 million individuals have osteopenia and are considered at risk for osteoporosis. Osteoporosis contributes to substantial disease burden with an excess of 2 million osteoporosis-related fractures in the United States in 2005. Osteoporosis is characterized by low bone mass with skeletal fragility and increased occurrence of fractures. Bone loss results from an imbalance between bone resorption and formation. The field has witnessed the emergence of an array of new treatments providing physicians and patients a much enriched range of therapeutic options. Existing agents are not without their challenges, including significant safety issues for estrogens, bisphosphonates, and the combination of bisphosphonates with parathyroid hormone (PTH). Despite a wide range of existing therapies from which to choose, most patients remain untreated.

The major current antiosteoporotic therapies include bisphosphonates (alendronate [ALN], risedronate, ibandronate, and zoledronate), estrogens, selective estrogen receptor modulators (raloxifene, bazedoxifene), and PTH. Other niche treatments include calcitonin, vitamin D derivatives, and strontium (in some countries). Except for PTH and strontium, these drugs inhibit bone resorption. In addition, the anti-RANK-ligand monoclonal antibody (denosumab) was recently recommended for approval by a U.S. Food and Drug Administration (FDA) advisory committee (August 13, 2009) and was approved on June 1, 2010, for the treatment of postmenopausal osteoporosis and for the treatment of bone loss in patients undergoing hormone ablation for prostate cancer.

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Translational Medicine and Drug Discovery , pp. 115 - 167
Publisher: Cambridge University Press
Print publication year: 2011

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References

MacLaughlin, EJ. (2010). Improving osteoporosis screening, risk assessment, diagnosis, and treatment initiation: Role of the health-system pharmacist in closing the gap. Am. J. Health Syst. Pharm. 67, S4–S8.CrossRefGoogle ScholarPubMed
Seibel, MJ, Eastell, R, Gundber, CM, Hannon, R, & Pols, HAP. (2002). Biochemical markers of bone metabolism (pp. 1543–1571). In: Principles of Bone Biology, edited by Bilezikian, JP, Raisz, LG, & Rodan, GA. San Diego: Academic.Google Scholar
Tesch, G, Amur, S, Schousboe, JT, Siegel, J, Lesko, L, & Bai, J. (2010). Success achieved and challenges ahead of translating biomarkers into clinical applications. AAPS J. 12(3), 243–253.CrossRefGoogle ScholarPubMed
Cremers, S, & Garnero, P. (2006). Biochemical markers of bone turnover in the clinical development of drugs for osteoporosis and metastatic bone disease. Drugs. 66, 2031–2058.CrossRefGoogle ScholarPubMed
Delaissé, JM, Engsig, MT, Everts, V, del Carmen Ovejero, M, Ferreras, M, Lund, L, et al. (2000). Proteinases in bone resorption: Obvious and less obvious roles. Clin. Chem. Acta. 291, 223–234.CrossRefGoogle ScholarPubMed
Everts, V, Delaissé, JM, Korper, W, Jansen, DC, Tigchelaar-Gutter, W, Saftig, P, et al. (2002). The bone lining cell: Its role in cleaning Howship's lacunae and initiating bone formation. J. Bone Miner. Res. 17, 77–90.CrossRefGoogle ScholarPubMed
Garnero, P, Borel, O, Byrjalsen, I, Ferreras, M, Drake, F, McQueney, MS, et al. (1998). The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J. Biol. Chem. 273, 32347–32352.CrossRefGoogle ScholarPubMed
Sassi, ML, Eriksen, H, Risteli, L, Niemi, S, Mansell, J, Gowen, M, et al. (2000). Immunochemical characterization of assay for carboxyterminal telopeptide of human type I collagen: Loss of antigenicity by treatment with cathepsin K. Bone. 26, 367–373.CrossRefGoogle ScholarPubMed
Eyre, D. (1992). New biomarkers of bone resorption. J. Clin. Endocrinol. Metab. 74, 470A–470C.CrossRefGoogle ScholarPubMed
Halleen, JM, Titinen, SL, Ylipahkala, H, Fagerlund, KM, & Väänänen, HK. (2006). Tartrate-resistant acid phosphatase 5b (TRACP 5b) as a marker of bone resorption. Clin. Lab. 52, 499–509.Google ScholarPubMed
Wichers, M, Schmidt, E, Bidlingmaier, F, & Klingmüller, D. (1999). Diurnal rhythm of CrossLaps in human serum. Clin. Chem. 45, 1858–1860.Google ScholarPubMed
Greenspan, SL, Parker, RA, Ferguson, L, Rosen, HN, Maitland-Ramsey, L, Karpf, DB. (1998). Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: A randomized clinical trial. J. Bone Miner. Res. 13, 1431–1438.CrossRefGoogle ScholarPubMed
Ravn, P, Hosking, D, Thompson, D, Cizza, G, Wasnich, RD, McClung, M, et al. (1999). Monitoring of alendronate treatment and prediction of effect on bone mass by biochemical markers in the Early Postmenopausal Intervention Cohort Study. J. Clin. Endocrinol. Metab. 84, 2363–2368.Google Scholar
Bauer, DC, Garnero, P, Bilezikian, JP, Greenspan, SL, Ensrud, KE, Rosen, CJ, et al. (2006). Short-term changes in bone turnover markers and bone mineral density response to parathyroid hormone in postmenopausal women with osteoporosis. J. Clin. Endocrinol. Metab. 91, 1370–1375.CrossRefGoogle ScholarPubMed
Lathia, CD, Amakye, D, Dai, W, Girman, C, Madani, S, Mayne, J, et al. (2009). The value, qualification, and regulatory use of surrogate end points in drug development. Clin. Pharmacol. Ther. 86, 32–43.CrossRefGoogle ScholarPubMed
,U.S. Food and Drug Administration. (1985). Guidelines for clinical evaluation of agents used in the treatment and prevention of osteoporosis. Rockville, MD: U.S. Food and Drug Administration.Google Scholar
,U.S. Food and Drug Administration. (1994). Guidelines for preclinical and clinical evaluation of agents in the prevention or treatment of postmenopausal osteoporosis. Rockville, MD: U.S. Food and Drug Administration.Google Scholar
Binkley, N, Kimmel, DB, & Bruner, J. (1998). Zoledronate prevents the development of absolute osteopenia following ovariectomy in adult rhesus monkeys. J. Bone Miner. Res. 13, 1775–1782.CrossRefGoogle ScholarPubMed
Lazner, F, Gowen, M, & Kola, I. (1999). An animal model of pycnodysostosis: The role of cathepsin K in bone remodeling. Mol. Med. Today. 5, 413–414.CrossRefGoogle Scholar
Stoch, SA, & Wagner, JA. (2008). Cathepsin K inhibitors: A novel target for osteoporosis therapy. Clin. Pharmacol. Ther. 83, 172–176.CrossRefGoogle ScholarPubMed
Bossard, M, Tomazek, TA, & Thompson, S. (1996). Proteolytic activity of human osteoclast cathepsin K. J. Biol. Chem. 271, 12517–12524.CrossRefGoogle ScholarPubMed
Troen, BR. (2004). The role of cathepsin K in normal bone resorption. Drug News Perspect. 70, 19–28.CrossRefGoogle Scholar
Gelb, BD, Shi, GP, Chapman, HA, & Desnick, PJ. (1996). Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science. 273, 1236–1238.CrossRefGoogle ScholarPubMed
Marquis, RW. (2004). Inhibition of the cysteine protease cathepsinK. Ann. Rev. Med. Chem. 39, 79–98.Google Scholar
Gauthier, JY, Chauret, N, Cromlish, W, Desmarais, S, Duong, LT, Falgueyret, JP, et al. (2008). The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 18, 923–928.CrossRefGoogle Scholar
Saftig, P, Hunziker, E, Wehmeyer, O, Jones, S, Boyde, A, Rommerskirch, W, et al. (1998). Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc. Natl. Acad. Sci. U. S. A. 95, 13453–13458.CrossRefGoogle ScholarPubMed
Pennypacker, B, Shea, M, Liu, Q, Masarachia, P, Saftig, P, Rodan, S, et al. (2009). Bone density, strength, and formation in adult cathepsin K (–/–) mice. Bone. 44, 199–207.CrossRefGoogle ScholarPubMed
Marquis, RW, Ru, Y, LoCastro, SM, Zeng, J, Yamashita, DS, Oh, H-J, et al. (2001). Azapernone-based inhibitors of human and rat cathepsin K. J. Med. Chem. 44, 1380–1395.CrossRefGoogle ScholarPubMed
Yasuma, T, Oi, S, Choh, N, Nomura, T, Furuyama, N, Nishimura, A, et al. (1998). Synthesis of peptide aldehyde derivatives as selective inhibitors of human cathepsin L, and their inhibitory effect on bone resorption. J. Med. Chem. 41, 4301–4308.CrossRefGoogle ScholarPubMed
Yamane, H, Sakai, A, Mori, T, Tanaka, S, Moridera, K, & Nakamura, T. (2009). The anabolic action of intermittent PTH in combination with cathepsin K inhibitor or alendronate differs depending on the remodeling status in bone in ovariectomized mice. Bone. 44, 1055–1062.CrossRefGoogle ScholarPubMed
Pennypacker, B, Duong, LT, Cusick, TE, Masarachia, P, Gentile, MA, Gauthier, J-Y, et al. (2010). Cathepsin K inhibitors prevent bone loss in estrogen-deficient rabbits. J. Bone Miner. Res. Epub ahead of print.
Fisher, JE, Caulfield, MP, Sato, M, Quartuccio, HA, Gould, RJ, Garsky, VM, et al. (2002). Inhibition of osteoclastic bone resorption in vivo by echistatin, and “arginyl-glycyl-aspartyl” (RGD)-containing protein. Endocrinology. 30, 746–753.Google Scholar
Lark, MW, Stroup, GB, James, IE, Dodds, RA, Hwang, SM, Blake, SM, et al. (2002). A potent small molecule, nonpeptide inhibitor of cathepsin K (SB 331750) prevents bone matrix resorption in the ovariectomized rat. Bone. 30, 746–753.CrossRefGoogle ScholarPubMed
Pennypacker, B, Rodan, S, Black, C, Oballa, R, Masarachia, P, Rodan, G, & Kimmel, DB. (2006). Bone effects of cathepsin K inhibitors in the growing rabbit. J. Bone Miner. Res. 21, S304.Google Scholar
Guay, J, Riendeau, D, & Mancini, JA. (1999). Cloning and expression of rhesus monkey cathepsin K. Bone. 25, 205–209.CrossRefGoogle ScholarPubMed
Palmer, JT, Bryant, C, Wang, DX, Davis, , Setti, EL, Rydzewski, RM, et al. (2005). Design and synthesis of tri-ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K. J. Med. Chem. 48, 7520–7534.CrossRefGoogle ScholarPubMed
Kumar, S, Dare, L, Vasko-Moser, J, James, IE, Blake, SM, Rickard, DJ, et al. (2007). A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys. Bone. 40, 122–131.CrossRefGoogle Scholar
Masarachia, P, Pun, S, & Kimmel, D. (2007). Bone effects of a cathepsin K inhibitor in ovariectomized rhesus monkeys. J. Bone Miner. Res. 22, S126.Google Scholar
Pennypacker, B, Wesolowski, G, Heo, J, & Duong, LT. (2009). Effects of odanacatib on central femur cortical bone in estrogen-deficient adult rhesus monkeys. J. Bone Miner. Res. 24, S52.Google Scholar
Nishi, Y, Atley, L, Eyre, , Edelson, JG, Superti-Furga, A, Yasuda, T, et al. (1999). Determination of bone markers in pycnodysostosis: Effects of cathepsin K deficiency on bone matrix degradation. J. Bone Miner. Res. 14, 1902–1908.CrossRefGoogle ScholarPubMed
Fratzl-Zelman, N, Valenta, A, Roschger, P, Nader, A, Gelb, BD, Fratzl, P, et al. (2004). Decreased bone turnover in deterioration of bone structure in two cases of pycnodysostosis. J. Clin. Endocrinol. Metab. 89, 1538–1547.CrossRefGoogle ScholarPubMed
Stoch, SA, Zajic, S, Stone, J, Miller, DL, Dyck, K, Gutierrez, MJ, et al. (2009). 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. 86, 175–182.CrossRefGoogle Scholar
Bone, HG, McClung, MR, Roux, C, Recker, RR, Eisman, JA, Verbruggen, N, et al. (2010). Odanacatib, a cathepsin-K inhibitor for osteoporosis: A two-year study in postmenopausal women with low bone density. J. Bone Miner. Res. 25, 937–949.Google ScholarPubMed
Peroni, A, Zini, A, Braga, V, Colato, C, Adami, S, & Girolomoni, G. (2008). Drug-induced morphea: Report of a case induced by balicatib and review of the literature. J. Am. Acad. Dermatol. 59, 125–129.CrossRefGoogle ScholarPubMed
Desmarais, S, Black, WC, Oballa, R, Lamontagne, S, Riendeau, D, Tawa, P, et al. (2007). Effect of cathepsin K inhibitor basicity on in vivo off-target activities. Mol. Pharmacol. 72, 147–156.CrossRefGoogle Scholar
Khalfan, HA. (1991). Study of thiol proteases of normal human skin fibroblasts. Cell Biochem. Funct. 9, 55–62.CrossRefGoogle ScholarPubMed
Bromme, D, & Lecaille, F. (2009). Cathepsin K inhibitors for osteoporosis and potential off-target effects. Expert Opin. Invest. Drugs. 18, 585–600.CrossRefGoogle ScholarPubMed
Bühling, F, Röcken, C, Brasch, F, Hartig, R, Yasuda, Y, Saftig, P, et al. (2004). Pivotal role of cathepsin K in lung fibrosis. Am. J. Pathol. 164, 125–129.CrossRefGoogle ScholarPubMed
Hou, WS, Li, Z, Gordon, RE, Chan, K, Klein, MJ, Levy, R, et al. (2001). Cathepsin K is a critical protease in synovial fibroblast-mediated collagen degradation. Am. J. Pathol. 159, 2167–2177.CrossRefGoogle ScholarPubMed
Tepel, C, Bromme, D, Herzog, V, & Brix, K. (2000). Cathepsin K in thyroid epithelial cells: Sequence, localization and possible function in extracellular proteolysis of thyroglobulin. J. Cell Sci. 113, 4487–4498.Google ScholarPubMed
Friedrichs, B, Tepel, C, Reinheckel, T, Deussing, J, Figura, K, Herzog, V, et al. (2003). Thyroid function of mouse cathepsins B, K, and L. J. Clin. Invest. 111, 1733–1745.CrossRefGoogle Scholar
Leu, C-T, Wesolowski, G, & Nagy, R. (1997). Osteoclasts have over 107 high affinity echistatin binding sites (RGD-Integrins). J. Bone Miner. Res. 12, S416.Google Scholar
Ruoslahti, E. (1991). Integrins. J. Clin. Invest. 87, 1–5.CrossRef
Wang, N, Butler, JP, & Ingber, DE. (1995). Mechanotransduction across the cell surface and through the cytoskeleton. Science. 260, 1124–1127.CrossRefGoogle Scholar
Clark, EA, & Brugge, JS. (1995). Integrins and signal transduction pathways: The road taken. Science. 268, 233–239.CrossRefGoogle ScholarPubMed
Ruoslahti, E, Noble, NA, Kagami, S, & Border, WA. (1994). Integrins. Kidney Int. Suppl. 44, S17–S22.
Giancotti, FG, & Mainiero, F. (1994). Integrin-mediated adhesion and signaling in tumorigenesis. Biochem. Biophys. 1198, 47–64.Google ScholarPubMed
Cox, D, Aoki, T, Seki, J, Motoyama, Y, & Yoshida, K. (1994). The pharmacology of the integrins. Med. Res. Rev. 14, 195–228.CrossRefGoogle ScholarPubMed
Sato, M, Sardana, MK, Grasser, WA, Garsky, VM, Murray, JM, & Gould, RJ. (1990). Echistatin is a potent inhibitor of bone resorption in culture. J. Cell Biol. 111, 1713–1723.CrossRefGoogle ScholarPubMed
Horton, MA, Dorey, EL, Nesbitt, SA, Samamen, J, Ali, FE, Stadel, JM et al. (1993). Modulation of vitronectin-receptor mediated osteoclast adhesion by the Arg-Gly-Asp peptide analogs: A structure-function analysis. J. Bone Miner. Res. 8, 239–247.CrossRefGoogle ScholarPubMed
Sato, M, Garsky, V, Majeska, RJ, Einhorn, TA, Murray, J, Tashjian, AH, et al. (1994). Structure-activity studies of the s-echistatin inhibition of bone resorption. J. Bone Miner. Res. 9, 1441–1449.CrossRefGoogle ScholarPubMed
Yamamoto, M, Fisher, JE, Gentile, M, Seedor, JG, Len, CT, Rodan, SB, et al. (1998). The integrin ligand echistatin prevents bone loss in ovariectomized mice and rats. Endocrinol. 139, 1411–1419.CrossRefGoogle ScholarPubMed
Masarachia, P, Yamomoto, M, Lee, C-T, Rodan, G, & Duong, L. (1998). Histomorphometric evidence for echistatin inhibition of bone resorption in mice with secondary hyperparathyroidism. Endocrinology. 139, 1401–1410.CrossRefGoogle ScholarPubMed
Scarborough, RM, Rose, JW, Naughton, MA, Phillips, DR, Nannizzi, L, Arfsten, A, et al. (1993). Characterization of the integrin specificities of disintegrins isolated from American pit viper venoms. J. Biol. Chem. 268, 1058–1063.Google ScholarPubMed
McHugh, KP, Hodivala-Dilke, K, Zheng, M-H, Namba, N, Lam, J, Novack, D, et al. (2000). Mice lacking β3 integrins are osteosclerotic because of dysfunctional osteoclasts. J. Clin. Invest. 105, 433–440.CrossRefGoogle ScholarPubMed
Teitelbaum, SL. (2006). Osteoclasts and integrins. Ann. N. Y. Acad. Sci. 1068, 95–99.CrossRefGoogle ScholarPubMed
McHugh, KP, Kitazawa, S, Teitelbaum, SL, & Ross, FP. (2001). Cloning and characterization of the murine β3 integrin gene promoter: Identification of an interleukin-4 responsive element and regulation by Stat-6. J. Cell. Biochem. 81, 320–325.3.0.CO;2-M>CrossRefGoogle ScholarPubMed
Teitelbaum, SL. (2005). Editorial: Osteoporosis and integrins. J. Clin. Endocrinol. Metab. 90, 2466–2468.CrossRefGoogle ScholarPubMed
Hutchinson, JH, Halczenko, W, Brashear, KM, Breslin, MJ, Coleman, PJ, Duong, LT, et al. (2003). Nonpeptide αvβ3 antagonists. 8. In vitro and in vivo evaluation of a potent αvβ3 antagonist for the prevention and treatment of osteoporosis. J. Med. Chem. 46, 4790–4798.CrossRefGoogle ScholarPubMed
Hoffman, SJ, Vasko-Moser, J, Miller, WH, Lark, MW, Gown, M, & Stroup, S. (2002). Rapid inhibition of thyroxine-induced bone resorption in the rat by an orally active vitronectin receptor antagonist. J. Pharmacol. Exp. Ther. 302, 201–211.CrossRefGoogle ScholarPubMed
Murphy, GM, Cerchio, K, Stoch, SA, Gottesdiener, K, Wu, M, & Recker, R, for the L-000845704 Study Group. (2005). 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, 2022–2028.CrossRefGoogle ScholarPubMed
Yamani, MH, Tuzcu, RC, Starling, NB, Ratliff, Y, Yu, D, Vince, G, et al. (2002). Myocardial ischemic injury after heart transplantation is associated with upregulation of vitronectin receptor (αvβ3), activation of the matrix metalloproteinase induction system, and subsequent development of coronary vasculopathy. Circulation. 105b, 1955–1961.CrossRefGoogle Scholar
Gao, W, Kim, J, & Dalton, JT. (2006). Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor ligands. Pharm. Res. 23, 1641–1658.CrossRefGoogle ScholarPubMed
Kawano, H, Sato, T, Takashi, Y, Matsumoto, T, Sekine, K, Watanabe, T, et al. (2003). Suppressive function of androgen receptor in bone resorption. Proc. Natl. Acad. Sci. U. S. A. 100, 9416–9421.CrossRefGoogle ScholarPubMed
Sato, T, Matsumoto, T, Yamada, T, Watanabe, T, Kawano, H, & Kato, S. (2003). Late onset of obesity in male androgen receptor-deficient (ARKO) mice. Biochem. Biophys. Res. Commun. 300, 161–171.CrossRefGoogle Scholar
Montero, M, Quiroga, I, Rubert, M, Diaz-Curiel, M, Bauss, F, & Piedra, C. (2008). PINP, a new available rat bone formation marker. Usefulness in osteopenia studies due to androgen lack and ibandronate treatment. J. Bone Miner. Res. 23(Suppl), S190.Google Scholar
Morko, J, Peng, Z, Rissanen, J, Suominen, M, Fagerlund, K, Ravanti, L, et al. (2009). A novel selective androgen receptor modulator (SARM) as monotherapy and combination therapy with alendronate in the treatment of established osteopenia in orchidectomized rats. J. Bone Miner. Res. 24(Suppl), S226.Google Scholar
Rissanen, J, Peng, Z, Morko, J, Suominen, M, Ravanti, L, Kallio, P, & Halleen, J. (2009). The effects of a novel selective androgen receptor modulator (SARM) ORM-11984 on prevention of osteopenia in ovariectomized rats. J. Bone Miner. Res. 24(Suppl), S354.Google Scholar
Peng, Z, Morko, J, Rissanen, J, Suominen, M, Ravanti, L, Kallio & Halleen, J. (2009). The effects of a selective androgen receptor modulator (SARM) ORM-11984 on prevention of osteoporosis in rat immobilization model. J. Bone Miner. Res. 24(Suppl), S483.Google Scholar
Stoch, SA, Tanaka, WK, Hilliard, DA, Chappell, DL, Modur, VR, Phillips, RL, et al. (2006). Identification of skin biomarkers following testosterone administration in postmenopausal women. Clin. Pharmacol. Ther. 79, P84.CrossRefGoogle Scholar
Colvard, DS, Eriksen, EF, Keeting, PE, Wilson, EM, Lubahn, DB, French, FS, et al. (1989). Identification of androgen receptors in normal human osteoblast-like cells. Proc. Natl. Acad. Sci. U. S. A. 86, 854–857.CrossRefGoogle ScholarPubMed
Orwoll, ES, Stibrska, I, Ramsey, EE, & Keenan, EJ. (1991). Androgen receptors in osteoblast-like cell lines. Calcif. Tiss. Int. 49, 183–187.CrossRefGoogle ScholarPubMed
Raisz, LG, Wiita, B, Artis, A, Bowen, A, Schwartz, S, Trahiotis, M, et al. (1996). Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption in postmenopausal women. J. Clin. Endocrinol. Metab. 81, 37–43.Google ScholarPubMed
Awdishu, S, West, SL, Scheid, JL, & De Souza, MJ. (2008). Elevated androgens associated with increased bone formation in premenopausal exercising oligomenorrheic women. J. Bone Miner. Res. 23(Suppl), S287.Google Scholar
Hassager, C, Jensen, LT, Podenphant, J, Riis, BJ, & Christiansen, C. (1990). Collagen synthesis in postmenopausal women during therapy with anabolic steroid or female sex hormones. Metabolism. 39, 1167–1169.CrossRefGoogle ScholarPubMed
Stoch, SA, Friedman, EJ, Zhu, H, Xu, Y, Wong, P, Chappell, DL, et al. (2008). A 12-week pharmacokinetic and pharmacodynamic (PD) study of MK-0773 in healthy postmenopausal (PMP) subjects. The Endocrine Society 90th Annual Meeting, June 12–15, San Francisco, CA.Google Scholar
Brown, EM, Gamba, G, Riccardi, D, Lombardi, M, Butters, R, Kifor, O, et al.(1993). Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid. Nature. 366, 575–580.CrossRefGoogle ScholarPubMed
Wuthrich, RP, Martin, D, & Bilezikian, JP. (2008). The role of calcimimetics in the treatment of hyperparathyroidism. Eur. J. Clin. Invest. 37, 915–922.CrossRefGoogle Scholar
Silverberg, SJ, Rubin, MR, Faiman, C, Peacock, M, Shoback, DM, Smallridge, RC, et al. (2007). Cinacalcet HCl reduces the serum calcium concentration in inoperable parathyroid carcinoma. J. Clin. Endocrinol. Metab. 92, 3803–3808.CrossRefGoogle ScholarPubMed
Peacock, M, Bilezikian, JP, Klassen, PS, Guo, MD, Turner, SA, & Shoback, D. (2005). Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 90, 135–141.CrossRefGoogle ScholarPubMed
Bilezikian, JP, Matsumoto, T, Bellido, T, Khosla, S, Martin, J, Recker, RR, et al. (2009). Targeting bone remodeling for the treatment of osteoporosis: Summary of the proceedings of an ASBMR workshop. J. Bone Miner. Res. 24, 373–385.CrossRefGoogle ScholarPubMed
Nemeth, EF. (2002). Receptor antagonists. The search for calcium receptor antagonists (calcilytics). J. Mol. Endocrinol. 29, 15–21.CrossRefGoogle ScholarPubMed
Brown, EM. (2007). The calcium-sensing receptor: Physiology, pathophysiology and CarR-based therapeutics. Subcell. Biochem. 45, 139–167.CrossRefGoogle ScholarPubMed
Brown, EM, & Macleod, RJ. (2001). Extracellular calcium sensing and extracellular calcium signaling. Physiol. Rev. 81, 239–297.CrossRefGoogle ScholarPubMed
Bai, M, Trivedi, S, Lane, CR, Yang, Y, Quinn, SJ, & Brown, EM. (1998). Protein kinase C phosphorylation of threonine position 888 in Ca2+ sensing receptor (CaR) inhibits coupling to Ca2+ store release. J. Biol. Chem. 273, 21267–21275.CrossRefGoogle ScholarPubMed
Nemeth, EF, & Scarpa, A. (1986). Cytosolic Ca2+ and the regulation of secretion of parathyroid cells. FEBS. Lett. 203, 15–19.CrossRefGoogle ScholarPubMed
Nemeth, EF, Steffey, ME, Hammerland, L, Hung, BCP, Wagenen, BC, DelMar, EG, et al. (1998). Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc. Natl. Acad. Sci. U. S. A. 95, 4040–4045.CrossRefGoogle ScholarPubMed
Nemeth, EF, DelMar, EG, Heaton, WL, Miller, MA, Lambert, LD, Conklin, RL, et al. (2001). Calcilytic compounds: Potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone. J. Pharmacol. Exp. Ther. 299, 323–331.Google ScholarPubMed
Gowen, M, Stroup, GB, Dodds, RA, James, IE, Votta, BJ, Smith, BR, et al. (2000). Antagonizing the parathyroid calcium receptor stimulates parathyroid hormone secretion and bone formation in osteopenic rats. J. Clin. Invest. 105, 1595–1604.CrossRefGoogle ScholarPubMed
Kessler, A, Faure, H, Petrel, C, Rognan, D, Césario, M, Ruat, M, et al. (2006). N1-benzoyl-N2-[1-(1-naphthyl)ethyl]-trans-1,2-diaminocyclohexanes: Development of 4-chlorophenylcarboxamide (Calhex 231) as a new calcium sensing receptor ligand demonstrating potent calcilytic activity. J. Med. Chem. 46, 5119–5128.CrossRefGoogle Scholar
Arey, BJ, Seethala, R, Ma, Z, Fura, A, Morin, J, Swartz, J, et al. (2005). A novel calcium receptor antagonist transiently stimulates parathyroid hormone secretion in vivo. Endocrinology. 146, 2015–2022.CrossRefGoogle ScholarPubMed
Yang, W, Wang, Y, Roberge, JY, Ma, Z, Liu, Y, Lawrence, RM, et al. (2005). Discovery and structure-activity relationships of 2-benzylpyrrolidine-situated aryloxypropanols as calcium-sensing receptor antagonists. Bioorg. Med. Chem. Lett. 15, 1225–1228.CrossRefGoogle ScholarPubMed
Shcherbakova, I, Balandrin, MF, Fox, J, Ghatak, A, Heaton, WL, & Conklin, RL (2005). 3H-Quinazolin-4-ones as a new calcilytic template for the potential treatment of osteoporosis. Bioorg. Med. Chem. Lett. 15, 1557–1560.CrossRefGoogle ScholarPubMed
Petrel, C, Kessler, A, Maslah, F, Dauban, P, Dodd, RH, Rognan, D, et al. (2003). Modeling and mutagenesis of the binding site of Calhex 231, a novel negative allosteric modulator of the extracellular Ca2+-sensing receptor. J. Biol. Chem. 278, 49487–49494.CrossRefGoogle Scholar
Petrel, C, Kessler, A, Dauban, P, Dodd, RH, Rognan, D, & Ruat, M. (2004). Positive and negative allosteric modulators of the Ca2+-sensing receptor interact within the overlapping but not identical binding sites in the transmembrane domain. J. Biol. Chem. 279, 18990–18997.CrossRefGoogle Scholar
Silverberg, SJ, Gartenberg, F, Jacobs, TP, Shane, E, Siris, E, Staron, RB, et al. (1995). Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 80, 729–734.Google ScholarPubMed
Dobnig, H, & Turner, RT. (1997). The effects of programmed administration of human parathyroid hormone fragment (1–34) on bone histomorphometry and serum chemistry in rats. Endocrinology. 138, 4607–4612.CrossRefGoogle Scholar
Fox, J, Miller, MA, Stroup, GB, Nemeth, EF, & Miller, SC. (1997). Plasma levels of parathyroid hormone that induce anabolic effects in bone of ovariectomized rats can be achieved by stimulation of endogenous hormone secretion. Bone. 21, 163–169.CrossRefGoogle ScholarPubMed
Ham, AW, Littner, BA, Drake, TGH, Robertson, EC, & Tisdall, FF. (1940). Physiological hypertrophy of the parathyroids, its cause and its relation to rickets. Am. J. Pathol. 16, 277–286.Google ScholarPubMed
Wernerson, A, Widholm, SM, Svensson, O, Reinholt, FP. (1991). Parathyroid cell number and size in hypocalcemic young rats. APMIS. 99, 1096–1102.CrossRefGoogle ScholarPubMed
Naveh-Many, T, Rahamimov, R, Livni, N, & Silver, J. (1995). Parathyroid cell proliferation in normal and chronic renal failure rats. The effects of calcium, phosphate, and vitamin D. J. Clin. Invest. 96, 1786–1793.CrossRefGoogle ScholarPubMed
Gasser, JA, Ingold, P, Venturiere, A, & Markus, J. (2009). Splitting the daily dose of parathyroid hormone PTH (1–34) results in a faster bone anabolic response in rats. J. Bone Miner. Res. 24, S144.Google Scholar
Fukumoto, S, Nakamura, T, Nishizawa, Y, Hayashi, M, & Matsumoto, T. (2009). Randomized, single-blinded placebo-controlled study of a novel calcilytic, JTT-305, in patients with postmenopausal osteoporosis. J. Bone Miner. Res. 24(Suppl), S40.Google Scholar
Fitzpatrick, L, Dabrowski, C, Cicconetti, G, Papapoulos, S, Bone, H, & Bilezikian, J. (2009). Roncaleret, a calcium-sensing receptor antagonist: Results of a 1 year double-blind, placebo-controlled, dose-ranging phase II study. J. Bone Miner. Res. 24(Suppl), S40.Google Scholar
Fitzpatrick, L, Dabrowski, C, Cicconetti, G, Fuerst, T, Engelke, K, & Genant, H. (2009). The calcium-sensing receptor antagonist, ronacaleret (SB-751689), causes modest increases in trabecular but not cortical BMD by QCT in postmenopausal women. J. Bone Miner. Res. 24(Suppl), S39.Google Scholar
Caltabiano, S, Desjardins, J, Hossain, M, Kurtineez, M, & Fitzpatrick, L. (2009). Characterization of the effect of ronacaleret, a calcium-sensing receptor antagonist on renal calcium excretion. J. Bone Miner. Res. 24(Suppl), S16.Google Scholar
Fitzpatrick, L, Smith, PL, McBride, TA, Fries, MA, Hossain, M, & Dabrowski, C. (2009). Ronacaleret (SB-751689), a calcium-sensing receptor antagonist, has no significant effect on radial fracture healing time: Results from a randomized, double-blinded, placebo-controlled phase II clinical trial. J. Bone Miner. Res. 24(Suppl), S214.Google Scholar
Cosman, F, Lane, NE, Bolognese, MA, Zanchetta, JR, Garcia-Hernandez, PA, Sees, K, et al. (2010). Effect of transdermal teriparatide administration on bone mineral density in postmenopausal women. J. Clin. Endocrinol. Metab. 95, 151–158.CrossRefGoogle Scholar
Gong, Y, Slee, RB, Fukai, N, Rawadi, G, Roman-Roman, S, Reginator, AM, et al. (2001). LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 107, 513–523.CrossRefGoogle ScholarPubMed
Gong, Y, Vikkula, M, Boon, L, Liu, J, Beighton, P, Ramesar, R, et al. (1996). Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12–13. Am. J. Hum. Genet. 59, 146–151.Google ScholarPubMed
Little, RD, Carulli, JP, Del Mastro, RG, Dupuis, J, Osborne, M, Folz, C, et al. (2002). 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.CrossRefGoogle ScholarPubMed
Boyden, LM, Mao, J, Belsky, J, Mitzner, L, Farhi, A, Mitnick, MA, et al. (2002). High bone density due to a mutation in LDL-receptor-related protein 5. N. Engl. J. Med. 346, 1513–1521.CrossRefGoogle ScholarPubMed
Van Wesenbeeck, L, Cleiren, E, Gram, J, Beals, RK, Bénichou, O, Scopelliti, D, et al. (2003). Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am. J. Hum. Genet. 72, 763–771.CrossRefGoogle ScholarPubMed
Raisz, LG. (2005). Pathogenesis of osteoporosis: Concepts, conflicts, and prospects. J. Clin. Invest. 115, 3318–3325.CrossRefGoogle ScholarPubMed
Cadigan, KM, & Nusse, R. (1997). Wnt signaling: A common theme in animal development. Genes Dev. 11, 3286–3305.CrossRefGoogle ScholarPubMed
Krishnan, A, Bryant, HU, & MacDonald, OA. (2006). Regulation of bone mass by Wnt signaling. J. Clin. Invest. 116, 1202–1209.CrossRefGoogle ScholarPubMed
Westendorf, JJ, Kahler, RA, & Schroeder, TM. (2004). Wnt signaling in osteoblasts and bone diseases. Gene. 341, 19–39.CrossRefGoogle ScholarPubMed
Rawadi, G, & Roman-Roman, S. (2005). Wnt signalling pathway: A new target for the treatment of osteoporosis. Expert Opin. Ther. Targets. 9, 1063–1077.CrossRefGoogle ScholarPubMed
Glinka, A, Wu, W, Delius, H, Monaghan, AP, Blumenstock, C, & Niehrs, C. (1998). Dickkopf-1 is a member of a new family of secreted proteins and functions in head induction. Nature. 391, 357–362.CrossRefGoogle ScholarPubMed
Terpos, E. (2006). Antibodies to dickkopf-1 protein. Expert Opin. Ther. Patents. 16, 1453–1458.CrossRefGoogle Scholar
Bodine, PVN, Stauffer, B, Ponce-de-Leon, H, Bhat, RA, Mangine, A, Seestaller-Wehr, LM, et al. (2009). A small molecule inhibitor of the Wnt antagonist secreted fizzled-related potein-1 stimulates bone formation. Bone. 44, 1063–1068.CrossRefGoogle Scholar
Moore, WJ, Kern, JC, Bhat, R, Bodine, PV, Fukyama, S, Krishnamurthy, G, et al. (2010). Modulation of Wnt signaling through inhibition of secreted frizzled-related protein (sFRP-1) with N-substituted piperidinyl diphenylsulfonyl sulfonamides. Bioorg. Med. Chem. 18, 190–201.CrossRefGoogle ScholarPubMed
Babij, P, Zhao, W, Small, C, Kharode, Y, Yaworsky, PJ, Bouxsein, ML, et al. (2003). High bone mass in mice expressing a mutant LRP5 gene. J. Bone Miner. Res. 18, 960–974.CrossRefGoogle ScholarPubMed
Koay, MA, & Brown, MA. (2005). Genetic disorders of the LRP5-Wnt signalling pathway affecting the skeleton. Trends. Molec. Med. 11, 129–137.CrossRefGoogle ScholarPubMed
Kato, M, Patel, MS, Levasseur, R, Lobov, I, Chang, BH-J, Glass, DA 2nd, et al. (2002). Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice-deficient in Lrp5 a Wnt coreceptor. J. Cell Biol. 157, 303–314.CrossRefGoogle ScholarPubMed
Fujino, T, Asaba, H, Kang, MJ, Ikeda, Y, Sone, H, Takada, S, et al. (2003). Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Proc. Natl. Acad. Sci. U. S. A. 100, 229–234.CrossRefGoogle ScholarPubMed
Albers, J, Gebauer, M, Friedrich, F, Schulze, J, Priemel, M, Francke, U, et al. (2008). Mice lacking the Wnt receptor frizzled-9 display osteopenia caused by decreased bone formation. J. Bone Miner. Res. 23(Suppl), S3.Google Scholar
Li, X, Grisanti, M, Geng, Z, Niu, Q, Fan, W, Daris, M, et al. (2006). Dickkopf-1 delivery by adeno-associated virus caused bone loss in adult mice. J. Bone Miner. Res. 21(Suppl), S8.Google Scholar
Grisanti, M, Niu, QT, Fan, W, Asuncion, F, Lee, J, Steavenson, S, et al. (2006). Dkk-1 inhibition increases bone mineral density in rodents. J. Bone Miner. Res. 21(Suppl), S25.Google Scholar
Pelletier, JC, Lundquist, JT 4th, Gilbert, AM, Alon, N, Bex, FJ, Bhat, BM, et al. (2009). (1-(4-(Naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine: A Aingless β-catenin agonist that increases bone formation rate. J. Med. Chem. 52, 6962–6965.CrossRefGoogle ScholarPubMed
Balemans, W, Ebeling, M, Patel, N, Hul, E, Olson, P, Dioszegi, M, et al. (2001). Increased bone density in sclerostosis is due to deficiency of a novel secreted protein (SOST). Hum. Mol. Genet. 10, 537–543.CrossRefGoogle Scholar
Martin, TJ, Sims, NA, & Ng, KW. (2008). Regulatory pathways revealing new approaches to the development of anabolic drugs for osteoporosis. Osteoporos. Int. 19, 1125–1138.CrossRefGoogle ScholarPubMed
Brunkow, ME, Gardner, JC, Ness, J, Paeper, BW, Kovacevich, BR, Proll, S, et al. (2001). Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine-knot containing protein. Am. J. Hum. Genet. 68, 577–589.CrossRefGoogle ScholarPubMed
Balemans, W, Patel, N, Eberling, M, Hul, E, Wuyts, W, Lacza, C, et al. (2002). Identification of a 52 kb deletion downstream of the SOST gene in patients with Van Buchem disease. J. Med. Genet. 39, 91–97.CrossRefGoogle ScholarPubMed
Staehling-Hampton, K, Proll, S, Paeper, BW, Zhao, L, Charmley, P, Brown, A, et al. (2002). A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with Van Buchem disease in the Dutch population. Am. J. Med. Genet. 110, 144–152.CrossRefGoogle ScholarPubMed
Gardner, JC, Bezooijen, RL, Mervis, B, Hamdy, NA, Löwik, CW, Hamersma, H, et al. (2005). Bone mineral density in sclerosteosis; affected individuals and gene carriers. J. Clin. Endocrinol. Metab. 90, 6392–6395.CrossRefGoogle ScholarPubMed
ten Dijke, P, Krause, C, Gorter, DJ, Löwik, CW, & Bezooijen, RL. (2008). Osteocyte-derived sclerostin inhibits bone formation: Its role in bone morphogenetic protein and Wnt signaling. J. Bone Joint Surg. Am. 90(Suppl 1), 31–35.CrossRefGoogle ScholarPubMed
Wergedal, JE, Veskovic, K, Hellan, M, Nyght, C, Balemans, W, Libanati, C, et al. (2003). Patients with Van Buchem disease, an osteosclerotic genetic disease, have elevated bone formation markers, higher bone density, and greater derived polar moment of inertia than normal. J. Clin. Endocrinol. Metab. 88, 5778–5783.CrossRefGoogle Scholar
Noble, BS. (2008). The osteocyte lineage. Arch. Biochem. Biophys. 473, 106–111.CrossRefGoogle ScholarPubMed
Suva, LJ. (2009). Sclerostin and the unloading of bone. J. Bone Miner. Res. 24, 1649–1650.CrossRefGoogle Scholar
Robling, AG, Bellido, T, & Turner, CH. (2006). Mechanical stimulation in vivo reduces osteocyte expression of sclerostin. J. Musculoskelet. Neuronal Interact. 6, 354.Google Scholar
Li, X, Zhang, Y, Kang, H, Liu, W, Liu, P, Zhang, J, et al. (2005). Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 280, 19883–19887.CrossRefGoogle ScholarPubMed
Bezooijen, RL, Svensson, JP, Eefting, D, Visser, A, Horst, G, Karperien, M, et al. (2007). Wnt but not BMP signaling is involved in the inhibitory action of sclerostin on BMP-stimulated bone formation. J. Bone Miner. Res. 21, 19–28.Google Scholar
Li, X, Ominsky, MS, Niu, QT, Sun, N, Daugherty, B, D'Agostin, D, et al. (2008). Targeted disruption of the sclerostin gene in mice results in increased bone formation and bone strength. J. Bone Miner. Res. 23, 860–869.CrossRefGoogle Scholar
Winkler, DG, Sutherland, MK, Geoghegan, JC, Yu, C, Hayes, T, Skonier, JE, et al. (2003). Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J. 22, 6267–6276.CrossRefGoogle ScholarPubMed
Desbois, C, Hogue, DA, & Karsenty, G. (1994). The mouse osteocalcin gene cluster contains three genes with two separate spatial and temporal patterns of expression. J. Biol. Chem. 269, 1183–1190.Google Scholar
Moustafa, A, Sugiyama, T, Zaman, G, Lanvon, L, & Price, J. (2009). Sclerostin expression in trabecular and cortical bone osteocytes is increased by disuse and reversed by loading with a distribution related to new bone formation. J. Bone Miner. Res. 24(Suppl), S310.Google Scholar
Robing, AG, Niziolek, PJ, Baldridge, , Condon, KW, Allen, MR, Alam, I, et al. (2008). Mechanical stimulation of bone in vivo reduces osteocyte expression of SOST/sclerostin. J. Biol. Chem. 283, 5866–5875.CrossRefGoogle Scholar
Moustafa, A, Sugiyama, T, Saxon, LK, Zaman, G, Sunters, A, Armstrong, VJ, et al. (2009). The mouse fibula as a suitable bone for the study of functional adaptation to mechanical loading. Bone. 44, 930–935.CrossRefGoogle Scholar
Li, X, Ominsky, MS, Warmington, KS, Morony, S, Gong, J, Cao, J, et al. (2009). Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner. Res. 24, 578–588.CrossRef
Li, X, Warmington, K, Niu, QT, Asuncion, F, Grisanti, M, Dwyer, D, et al. (2008). Effects of co-treatment with an anti-sclerostin monoclonal antibody and alendronate in ovariectomized rats. J. Bone Miner. Res. 23, S60.Google Scholar
Ominsky, MS, Vlasseros, F, Jolette, J, Smith, SY, Stouch, B, Doellgast, G, et al. (2010). Two doses of sclerostin antibody to cynomolgus monkeys increases bone formation, bone mineral density, and bone strength. J. Bone Miner. Res. 25, 948–959.CrossRefGoogle ScholarPubMed
Padhi, D, Stouch, B, Jang, G, Fang, L, Darling, M, Glise, H, et al. (2007). Anti-sclerostin antibody increases markers of bone formation in healthy postmenopausal women. J. Bone Miner. Res. 22(Suppl), S37.Google Scholar
Gaudio, A, Pennisi, P, Bratengeier, C, Torrisi, V, Lindner, B, Mangiafico, RA, et al. (2010). Increased sclerostin serum levels associated with bone formation and resorption markers in patients with immobilization-induced bone loss. J. Clin. Endocrinol. Metab. 95, 2248–2253.CrossRefGoogle ScholarPubMed
Mirza, FS, Padhi, IS, Raisz, LG, & Lorenzo, JA. (2010). Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women. J. Clin. Endocrinol. Metab. 95, 1991–1997.CrossRefGoogle ScholarPubMed

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