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Drug Development for Pediatric Diseases with Bone Loss

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Bone Drugs in Pediatrics

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Abstract

Osteoporosis is the most common metabolic bone disease. It is characterized by a marked decrease in bone mineral density and strength, resulting in fragility fractures associated with high morbidity and mortality. Osteoporosis is becoming a global public health concern and represents a considerable medical and socioeconomic burden for modern societies. It is generally known as a health problem affecting adults; however, pediatric osteoporosis is a new and evolving area, with unique diagnostic and clinical challenges. Although prevention and treatment of pediatric osteoporosis are less well established than in adults, awareness and recognition of osteoporosis in children are increasing. Some genetic mutations and enzyme deficiencies have been associated with primary pediatric osteoporosis. In this chapter, we will discuss current treatment of orthopedic diseases with bone loss in children. We will provide the rationale for developing new anabolic drugs for treatment of bone loss in children. Three different approaches for drug discovery will be described, and new development of bone biology related to drug discovery target will be discussed in detail. Finally, we will talk about drug development approval process in the USA.

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References

  1. Zhang C, Liu Z, Klein GL. Overview of pediatric bone problems and related osteoporosis. J Musculoskelet Neuronal Interact. 2012;12:174–82.

    CAS  PubMed  Google Scholar 

  2. Branski LK, Herndon DN, Barrow RE, et al. Randomized controlled trial to determine the efficacy of long-term growth hormone treatment in severely burned children. Ann Surg. 2009;250:514–23.

    PubMed Central  PubMed  Google Scholar 

  3. Porro LJ, Herndon DN, Rodriguez NA, et al. Five-year outcomes after oxandrolone administration in severely burned children: a randomized clinical trial of safety and efficacy. J Am Coll Surg. 2012;214:489–502; discussion 504.

    Google Scholar 

  4. Glorieux FH. Treatment of osteogenesis imperfecta: who, why, what? Horm Res. 2007;68 Suppl 5:8–11.

    Article  PubMed  Google Scholar 

  5. Carpenter TO. The expanding family of hypophosphatemic syndromes. J Bone Miner Metab. 2012;30:1–9.

    Article  CAS  PubMed  Google Scholar 

  6. Klein GL, Wimalawansa SJ, Kulkarni G, Sherrard DJ, Sanford AP, Herndon DN. The efficacy of acute administration of pamidronate on the conservation of bone mass following severe burn injury in children: a double-blind, randomized, controlled study. Osteoporos Int. 2005;16:631–5.

    Article  CAS  PubMed  Google Scholar 

  7. Przkora R, Herndon DN, Sherrard DJ, Chinkes DL, Klein GL. Pamidronate preserves bone mass for at least 2 years following acute administration for pediatric burn injury. Bone. 2007;41:297–302.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Subbiah V, Madsen VS, Raymond AK, Benjamin RS, Ludwig JA. Of mice and men: divergent risks of teriparatide-induced osteosarcoma. Osteoporos Int. 2010;21:1041–5.

    Article  CAS  PubMed  Google Scholar 

  9. Linglart A, Rothenbuhler A, Gueorgieva I, Lucchini P, Silve C, Bougneres P. Long-term results of continuous subcutaneous recombinant PTH (1–34) infusion in children with refractory hypoparathyroidism. J Clin Endocrinol Metab. 2011;96:3308–12.

    Article  CAS  PubMed  Google Scholar 

  10. Liu H, Li Y, Song M, et al. Structure-based discovery of potassium channel blockers from natural products: virtual screening and electrophysiological assay testing. Chem Biol. 2003;10:1103–13.

    Article  CAS  PubMed  Google Scholar 

  11. Fischer HP, Heyse S. From targets to leads: the importance of advanced data analysis for decision support in drug discovery. Curr Opin Drug Discov Devel. 2005;8:334–46.

    CAS  PubMed  Google Scholar 

  12. Chen S, Do JT, Zhang Q, et al. Self-renewal of embryonic stem cells by a small molecule. Proc Natl Acad Sci U S A. 2006;103:17266–71.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Desbordes SC, Placantonakis DG, Ciro A, et al. High-throughput screening assay for the identification of compounds regulating self-renewal and differentiation in human embryonic stem cells. Cell Stem Cell. 2008;2:602–12.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Wu X, Ding S, Ding Q, Gray NS, Schultz PG. Small molecules that induce cardiomyogenesis in embryonic stem cells. J Am Chem Soc. 2004;126:1590–1.

    Article  CAS  PubMed  Google Scholar 

  15. Diamandis P, Wildenhain J, Clarke ID, et al. Chemical genetics reveals a complex functional ground state of neural stem cells. Nat Chem Biol. 2007;3:268–73.

    Article  CAS  PubMed  Google Scholar 

  16. St-Jacques B, Hammerschmidt M, McMahon AP. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. 1999;13:2072–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Komori T, Yagi H, Nomura S, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997;89:755–64.

    Article  CAS  PubMed  Google Scholar 

  18. Nakashima K, Zhou X, Kunkel G, et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 2002;108:17–29.

    Article  CAS  PubMed  Google Scholar 

  19. Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107:513–23.

    Article  CAS  PubMed  Google Scholar 

  20. 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. 2002;70:11–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Babij P, Zhao W, Small C, et al. High bone mass in mice expressing a mutant LRP5 gene. J Bone Miner Res. 2003;18:960–74.

    Article  CAS  PubMed  Google Scholar 

  22. Zhang C, Cho K, Huang Y, et al. Inhibition of Wnt signaling by the osteoblast-specific transcription factor Osterix. Proc Natl Acad Sci U S A. 2008;105:6936–41.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Vladimirova V, Waha A, Luckerath K, Pesheva P, Probstmeier R. Runx2 is expressed in human glioma cells and mediates the expression of galectin-3. J Neurosci Res. 2008;86:2450–61.

    Article  CAS  PubMed  Google Scholar 

  24. Zhou X, Zhang Z, Feng JQ, et al. Multiple functions of Osterix are required for bone growth and homeostasis in postnatal mice. Proc Natl Acad Sci U S A. 2010;107:12919–24.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Tang W, Li Y, Osimiri L, Zhang C. Osteoblast-specific transcription factor Osterix (Osx) is an upstream regulator of Satb2 during bone formation. J Biol Chem. 2011;286:32995–3002.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Zhang C, Tang W, Li Y, Yang F, Dowd DR, MacDonald PN. Osteoblast-specific transcription factor Osterix increases vitamin D receptor gene expression in osteoblasts. PLoS One. 2011;6:e26504.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Tang W, Yang F, Li Y, et al. Transcriptional regulation of vascular endothelial growth factor (VEGF) by osteoblast-specific transcription factor Osterix (Osx) in osteoblasts. J Biol Chem. 2012;287:1671–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Yang F, Tang W, So S, de Crombrugghe B, Zhang C. Sclerostin is a direct target of osteoblast-specific transcription factor osterix. Biochem Biophys Res Commun. 2010;400:684–8.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang C, Dai H, de Crombrugghe B. Characterization of Dkk1 gene regulation by the osteoblast-specific transcription factor Osx. Biochem Biophys Res Commun. 2012;420:782–6.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang C, Tang W, Li Y. Matrix metalloproteinase 13 (MMP13) Is a direct target of osteoblast-specific transcription factor Osterix (Osx) in osteoblasts. PLoS One. 2012;7:e50525.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Timpson NJ, Tobias JH, Richards JB, et al. Common variants in the region around Osterix are associated with bone mineral density and growth in childhood. Hum Mol Genet. 2009;18:1510–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, et al. New sequence variants associated with bone mineral density. Nat Genet. 2009;41:15–7.

    Article  CAS  PubMed  Google Scholar 

  33. Zhang JH, Chung TD, Oldenburg KR. A simple statistical parameter for use in evaluation and validation of high throughput screening assays. J Biomol Screen. 1999;4:67–73.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Orthopaedic Surgery and Rehabilitation, University of Texas Medical Branch and Shriners Burns Hospital, 4429 Belvedere Dr, Plano, TX, 75093, USA

    Chi Zhang M.D., Ph.D.

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  1. Chi Zhang M.D., Ph.D.
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Correspondence to Chi Zhang M.D., Ph.D. .

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Editors and Affiliations

  1. Department of Orthopaedic Surgery, University of Texas Medical Branch, Galveston, Texas, USA

    Gordon L. Klein

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Zhang, C. (2014). Drug Development for Pediatric Diseases with Bone Loss. In: Klein, G. (eds) Bone Drugs in Pediatrics. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-7436-5_3

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  • DOI: https://doi.org/10.1007/978-1-4899-7436-5_3

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  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4899-7435-8

  • Online ISBN: 978-1-4899-7436-5

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