Anabolic Agents in Bone Repair

Chapter

Abstract

Systemically administered bone anabolic agents that stimulate bone and cartilage formation in fracture healing have attracted much attention. These anabolic agents include parathyroid hormone (PTH), osteogenic growth peptide (OGP), statins, and vitamin D (Vit D).

Keywords

Cholesterol Osteoporosis Polypeptide Statin Simvastatin 

References

  1. 1.
    Andreassen TT, Ejersted C, Oxlund H (1999) Intermittent parathyroid hormone (1–34) treatment increases callus formation and mechanical strength of healing rat fractures. J Bone Miner Res 14:960–968CrossRefGoogle Scholar
  2. 2.
    Andreassen TT, Fledelius C, Ejersted C, Oxlund H (2001) Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone. Acta Orthop Scand 72:304–307CrossRefGoogle Scholar
  3. 3.
    Komatsubara S, Mashiba T, Mori S (2009) Bone fracture and the healing mechanisms. The effect of human parathyroid hormone on fracture healing. Clin Calcium 19:660–666Google Scholar
  4. 4.
    Alexander JM, Bab I, Fish S, Mueller R, Uchiyama T, Gronowicz G, Nahounou M, Zhao Q, White DW, Chorev M, Gazit D, Rosenblatt M (2001) Human parathyroid hormone 1-34 reverses bone loss in ovariectomized mice. J Bone Miner Res 16:1665–1673CrossRefGoogle Scholar
  5. 5.
    Barnes GL, Kakar S, Vora S, Morgan EF, Gerstenfeld LC, Einhorn TA (2008) Stimulation of fracture-healing with systemic intermittent parathyroid hormone treatment. J Bone Joint Surg Am 1:120–127CrossRefGoogle Scholar
  6. 6.
    Bab I, Gazit D, Chorev M, Muhlrad A, Shteyer A, Greenberg Z, Namdar M, Khan AJ (1992) Histone H4-related osteogenic growth peptide (OGP): a novel circulating stimulator of osteoblastic activity. EMBO J 11:1867–1873Google Scholar
  7. 7.
    Amsel S, Maniatis A, Tavassoli M, Crosby WH (1969) The significance of intramedullary cancellous bone formation in the repair of bone marrow tissue. Anat Rec 164:101–111CrossRefGoogle Scholar
  8. 8.
    Patt HM, Maloney MA (1975) Bone marrow regeneration after local injury: a review. Exp Hematol 3:135–148Google Scholar
  9. 9.
    Gerasimov YV, Chailakhyan RK (1978) Effect of marrow cavity curettage on bone marrow stromal cell precursors. Biull Eksp Biol Med 86:362–365CrossRefGoogle Scholar
  10. 10.
    Bab I (1995) Post ablation bone marrow regeneration: an in vivo model to study differential regulation of bone formation and resorption. Bone 17:437S–441SGoogle Scholar
  11. 11.
    Bab I, Gazit D, Massarawa A, Sela J (1985) Removal of tibial marrow induces increased formation of bone and cartilage in rat mandibular condyle. Calcif Tissue Int 37:551–555CrossRefGoogle Scholar
  12. 12.
    Einhorn TA, Simon G, Devlin VJ, Warman J, Sidhu SP, Vigorita VJ (1990) The osteogenic response to distant skeletal injury. J Bone Joint Surg Am 72:1374–1378Google Scholar
  13. 13.
    Mueller M, Schilling T, Minne HW, Ziegler R (1991) A systemic acceleratory phenomenon (SAP) accompanies the regional acceleratory phenomenon (RAP) during healing of a bone defect in the rat. J Bone Miner Res 6:401–410CrossRefGoogle Scholar
  14. 14.
    Gazit D, Karmish M, Holzman L, Bab I (1990) Regenerating marrow induces systemic increase in osteo- and chondrogenesis. Endocrinology 126:2607–2613CrossRefGoogle Scholar
  15. 15.
    Gazit D, Shteyer A, Bab I (1989) Further characterization of osteogenic-cell growth promoting activity derived from healing bone marrow. Connect Tissue Res 23:153–161CrossRefGoogle Scholar
  16. 16.
    Bab I, Gazit D, Muhlrad A, Shteyer A (1988) Regenerating bone marrow produces a potent growth factor activity to osteogenic cells. Endocrinology 123:345–352CrossRefGoogle Scholar
  17. 17.
    Sun YQ, Ashhurst DE (1998) Osteogenic growth peptide enhances the rate of fracture healing in rabbits. Cell Biol Int 22:313–319CrossRefGoogle Scholar
  18. 18.
    Wozney JM, Rosen V, Byrne M, Celeste AJ, Moutsatsos I, Wang EA (1990) Growth factors influencing bone development. J Cell Sci Suppl 13:149–156Google Scholar
  19. 19.
    Touriol C, Roussigne M, Gensac MC, Prats H, Prats AC (2000) Alternative translation initiation of human fibroblast growth factor 2 mRNA controlled by its 3’-untranslated region involves a Poly(A) switch and a translational enhancer. J Biol Chem 275:19361–19367CrossRefGoogle Scholar
  20. 20.
    Greenberg Z, Chorev M, Muhlrad A, Shteyer A, Namdar-Attar M, Casap N, Vidson M, Bab I (1995) Structural and functional characterization of osteogenic growth peptide from human serum: identity with rat and mouse horologes. J Clin Endocrinol Metab 80:2330–2335CrossRefGoogle Scholar
  21. 21.
    Bab I, Smith E, Gavish H, Namdar-Attar M, Chorev M, Chen Y, Muhlrad A, Birnbaum MJ, Stein G, Frenkel B (1999) Biosynthesis of osteogenic growth peptide via alternative translational initiation at AUG85 of histone H4 mRNA. J Biol Chem 274:14474–14481CrossRefGoogle Scholar
  22. 22.
    Bab I, Einhorn TA (1993) Regulatory role of osteogenic growth polypeptides in bone formation and hemopoiesis. Crit Rev Eukaryot Gene Expr 3:31–46Google Scholar
  23. 23.
    Bab I, Einhorn TA (1994) Polypeptide factors regulating osteogenesis and bone marrow repair. J Cell Biochem 55:358–365CrossRefGoogle Scholar
  24. 24.
    Suva LJ, Seedor JG, Endo N, Quartuccio HA, Thompson DD, Bab I, Rodan GA (1993) Pattern of gene expression following rat tibial marrow ablation. J Bone Miner Res 8:379–388CrossRefGoogle Scholar
  25. 25.
    Greenberg Z, Gavish H, Muhlrad A, Chorev M, Shteyer A, Attar-Namdar M, Tartakovsky A, Bab I (1997) Isolation of osteogenic growth peptide from osteoblastic MC3T3 E1 cell cultures and demonstration of osteogenic growth peptide binding proteins. J Cell Biochem 65:359–367CrossRefGoogle Scholar
  26. 26.
    Miguel SM, Namdar-Attar M, Noh T, Frenkel B, Bab I (2005) ERK1/2-activated de novo Mapkapk2 synthesis is essential for osteogenic growth peptide mitogenic signaling in osteoblastic cells. J Biol Chem 11:37495–37502CrossRefGoogle Scholar
  27. 27.
    Gavish H, Bab I, Tartakovsky A, Chorev M, Mansur N, Greenberg Z, Namdar-Attar M, Muhlrad A (1997) Human α2-macroglobulin is an osteogenic growth peptide binding protein. Biochemistry 36:14883–14888CrossRefGoogle Scholar
  28. 28.
    Doenecke D, Albig W, Bode C, Drabent B, Franke K, Gavenis K, Witt O (1997) Histones: genetic diversity and tissue-specific gene expression. Histochem Cell Biol 107:1–10CrossRefGoogle Scholar
  29. 29.
    Bab I, Muhlrad A, Chorev M, Shteyer A, Greenberg Z, Mansur N (1998) Osteogenic growth oligopeptides and pharmaceutical compositions containing them. US Patent 5, 814,610Google Scholar
  30. 30.
    Bab I, Gavish H, Namdar-Attar M, Muhlrad A, Greenberg Z, Chen Y, Mansur N, Shteyer A, Chorev M (1999) Isolation of mitogenically active c-terminal truncated pentapeptide of osteogenic growth peptide from human plasma and culture medium of murine osteoblastic cells. J Pept Res 54:408–414CrossRefGoogle Scholar
  31. 31.
    Gabarin N, Gavish H, Muhlrad A, Chen YC, Namdar-Attar M, Nissenson RA, Chorev M, Bab I (2001) Mitogenic Gi protein-MAP kinase signaling cascade in MC3T3 E1 osteogenic cells: activation by C-terminal pentapeptide of osteogenic growth peptide [OGP(10-14)] and attenuation of activation by cAMP. J Cell Biochem 81:594–603CrossRefGoogle Scholar
  32. 32.
    Greenberg Z, Chorev M, Muhlrad A, Shteyer A, Namdar M, Mansur N, Bab I (1993) Mitogenic action of osteogenic growth peptide (OGP): role of amino and carboxy terminal regions and charge. Biochim Biophys Acta 1178:273–280CrossRefGoogle Scholar
  33. 33.
    Chen YC, Bab I, Mansur N, Muhlrad A, Shteyer A, Namdar-Attar M, Gavish H, Vidson M, Chorev M (2000) Structure-bioactivity of C-terminal truncated pentapeptide of osteogenic growth peptide [OGP(10-14)]. J Pept Res 56:147–156CrossRefGoogle Scholar
  34. 34.
    Chen YC, Muhlrad A, Shteyer A, Vidson M, Bab I, Chorev M (2002) Bioactive pseudopeptidic analogues and cyclostereoisomers of osteogenic growth peptide C-terminal pentapeptide, OGP (10-14). J Med Chem 45:1624–1632CrossRefGoogle Scholar
  35. 35.
    Goodman M, Chorev M (1979) On the concept of linear modified retro-peptide structures. Acc Chem Res 12:1–7CrossRefGoogle Scholar
  36. 36.
    Chorev M, Goodman M (1993) A dozen years of retro-inverso peptidomimetics. Acc Chem Res 26:266–273CrossRefGoogle Scholar
  37. 37.
    Fazzi R, Testi R, Trasciatti S, Galimberti S, Rosini S, Piras F, L’Abbate G, Conte A, Petrini M (2002) Bone and bone-marrow interactions: hematological activity of osteoblastic growth peptide (OGP)-derived carboxy-terminal pentapeptide. Mobilizing properties on white blood cells and peripheral blood stem cells in mice. Leuk Res 26:19–27CrossRefGoogle Scholar
  38. 38.
    Fazzi R, Pacini S, Testi R, Azzarà A, Galimberti S, Testi C, Trombi L, Metelli MR, Petrini M (2003) Carboxy-terminal fragment of osteogenic growth peptide in vitro increases bone marrow cell density in idiopathic myelofibrosis. Br J Haematol 121:76–85CrossRefGoogle Scholar
  39. 39.
    Robinson D, Bab I, Nevo Z (1995) Osteogenic growth peptide (OGP) regulates proliferation and osteogenic maturation of human and rabbit bone marrow stromal cells. J Bone Miner Res 10:690–696CrossRefGoogle Scholar
  40. 40.
    Gabet Y, Muller R, Regev E, Sela J, Shteyer A, Salisbury K, Chorev M, Bab I (2004) Osteogenic growth peptide modulates fracture callus structural and mechanical properties. Bone 35:65–73CrossRefGoogle Scholar
  41. 41.
    Skoglund B, Aspenberg P (2007) Locally applied Simvastatin improves fracture healing in mice. BMC Musculoskelet Disord 27:98CrossRefGoogle Scholar
  42. 42.
    Gutierrez GE, Edwards JR, Garrett IR, Nyman JS, Mccluskey B, Rossini G, Flores A, Neidre DB, Mundy GR (2008) Transdermal lovastatin enhances fracture repair in rats. J Bone Miner Res 23:1722–1730CrossRefGoogle Scholar
  43. 43.
    Chissas D, Stamatopoulos G, Verettas D, Kazakos K, Papalois A, Agrogiannis G, Papaeliou A, Agapitos E, Balanika A, Papadopoulou E, Anastopoulos G, Ntagiopoulos PG, Asimakopoulos A (2010) Can low doses of simvastatin enhance fracture healing? An experimental study in rabbits. Injury 41:687–692CrossRefGoogle Scholar
  44. 44.
    Tang QO, Tran GT, Gamie Z, Graham S, Tsialogiannis E, Tsiridis E, Linder T, Tsiridis E (2008) Statins: under investigation for increasing bone mineral density and augmenting fracture healing. Expert Opin Investig Drugs 17:1435–1463CrossRefGoogle Scholar
  45. 45.
    Patil S, Holt G, Raby N, Mclellan AR, Smith K, O’Kane S, Beastall G, Crossan JF (2009) Prospective, double blind, randomized, controlled trial of simvastatin in human fracture healing. J Orthop Res 27:281–285CrossRefGoogle Scholar
  46. 46.
    Delgado-Martinez AD, Martinez ME, Carrascal MT, Rodriguez-Avial M, Munuera L (1998) Effect of 25-OH-vitamin D on fracture healing in elderly rats. J Orthop Res 16:650–653CrossRefGoogle Scholar
  47. 47.
    Cao Y, Mori S, Mashiba T, Kaji Y, Manabe T, Iwata K, Miyamoto K, Komatsubara S, Yamamoto T (2007) 1Alpha, 25-dihydroxy-2beta(3-hydroxypropoxy)vitamin D3 (ED-71) suppressed callus remodeling but did not interfere with fracture healing in rat femora. Bone 40:132–139CrossRefGoogle Scholar
  48. 48.
    Koester MC, Spindler KP (2006) Pharmacologic agents in fracture healing. Clin Sport Med 5:63–73CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Bone Laboratory, Institute of Dental SciencesThe Hebrew University of JerusalemJerusalemIsrael

Personalised recommendations