Advertisement

Osteoporosis International

, Volume 16, Supplement 2, pp S129–S138 | Cite as

Animal models for fracture treatment in osteoporosis

  • Marcus EgermannEmail author
  • J. Goldhahn
  • E. Schneider
Review

Abstract

Demographic changes in the age structure of occidental populations are giving rise to osteoporosis and associated fractures, which are becoming a major public health burden. Various animal models have been established and used to investigate the pathogenesis of osteoporosis and to facilitate the preclinical testing of new treatment options such as antiresorptive drugs. Although osteoporosis can be induced in animals, spontaneous fractures without adequate trauma were only found in nonhuman primates. An animal model designed to investigate new ways to treat fractures of osteoporotic bone has to fulfill requirements that are very different from those of pharmacological testing. The aspects of major interest in orthopedic applications are bone fragility, efficacy of implant fixation and bone healing. Existing animal models for osteoporosis were critically reviewed focusing on these aspects. The advantages and disadvantages of the models with regard to their application in the testing of new fracture-fixation devices or biological approaches to stimulate bone healing are discussed. Ovariectomy alone does not cause the bone loss seen in osteoporotic human patients. New models to simulate fracture of osteoporotic bone need to be explored and used to address the specific aims of an experiment.

Keywords

Animal models Bone fragility Bone healing Fracture Implant fixation Osteoporosis  

References

  1. 1.
    Boyle P, Leon ME, Autier P (2001) Epidemiology of osteoporosis. J Epidemiol Biostat 6:185–192CrossRefGoogle Scholar
  2. 2.
    Cummings SR, Black DM, Rubin SM (1989) Lifetime risks of hip, Colles’, or vertebral fracture and coronary heart disease among white postmenopausal women. Arch Intern Med 149:2445–2448CrossRefPubMedGoogle Scholar
  3. 3.
    Barrios C, Brostrom LA, Stark A, Walheim G (1993) Healing complications after internal fixation of trochanteric hip fractures: the prognostic value of osteoporosis. J Orthop Trauma 7:438–442PubMedGoogle Scholar
  4. 4.
    Cornell CN (2003) Internal fracture fixation in patients with osteoporosis. J Am Acad Orthop Surg 11:109–119Google Scholar
  5. 5.
    Sterck JG, Klein-Nulend J, Lips P, Burger EH (1998) Response of normal and osteoporotic human bone cells to mechanical stress in vitro. Am J Physiol 274:E1113–E1120PubMedGoogle Scholar
  6. 6.
    Haberland M, Schilling AF, Rueger JM, Amling M (2001) Brain and bone: central regulation of bone mass. A new paradigm in skeletal biology. J Bone Joint Surg Am 83:1871–1876Google Scholar
  7. 7.
    Lill CA, Hesseln J, Schlegel U, Eckhardt C, Goldhahn J, Schneider E (2003) Biomechanical evaluation of healing in a non-critical defect in a large animal model of osteoporosis. J Orthop Res 21:836–842CrossRefPubMedGoogle Scholar
  8. 8.
    Namkung-Matthai H, Appleyard R, Jansen J, Hao LJ, Maastricht S, Swain M, Mason RS, Murrell GA, Diwan AD, Diamond T (2001) Osteoporosis influences the early period of fracture healing in a rat osteoporotic model. Bone 28:80–86CrossRefPubMedGoogle Scholar
  9. 9.
    Walsh WR, Sherman P, Howlett CR, Sonnabend DH, Ehrlich MG (1997) Fracture healing in a rat osteopenia model. Clin Orthop 218–227Google Scholar
  10. 10.
    Food and Drug Administration (1994) Guidelines for preclinical and clinical evaluation of agents used in the prevention or treatment of postmenopausal osteoporosis. FDA Division of Metabolism and Endocrine Drug Products, Washington, DCGoogle Scholar
  11. 11.
    US National Institutes of Health (2000) Osteoporosis prevention, diagnosis, and therapy. NIH Consensus Statement 17:1–45Google Scholar
  12. 12.
    Martin RB, Butcher RL, Sherwood LL, Buckendahl P, Boyd RD, Farris D, Sharkey N, Dannucci G (1987) Effects of ovariectomy in beagle dogs. Bone 8:23–31Google Scholar
  13. 13.
    Shen V, Dempster DW, Birchman R, Mellish RW, Church E, Kohn D, Lindsay R (1992) Lack of changes in histomorphometric, bone mass, and biochemical parameters in ovariohysterectomized dogs. Bone 13:311–316Google Scholar
  14. 14.
    Kasra M, Grynpas MD (1994) Effect of long-term ovariectomy on bone mechanical properties in young female cynomolgus monkeys. Bone 15:557–561Google Scholar
  15. 15.
    Wronski TJ, Dann LM, Scott KS, Cintron M (1989) Long-term effects of ovariectomy and aging on the rat skeleton. Calcif Tissue Int 45:360–366PubMedGoogle Scholar
  16. 16.
    Thompson DD, Simmons HA, Pirie CM, Ke HZ (1995) FDA guidelines and animal models for osteoporosis. Bone 17:125S–133SCrossRefPubMedGoogle Scholar
  17. 17.
    Miller SC, Wronski TJ (1993) Long-term osteopenic changes in cancellous bone structure in ovariectomized rats. Anat Rec 236:433–441PubMedGoogle Scholar
  18. 18.
    Aerssens J, Boonen S, Lowet G, Dequeker J (1998) Interspecies differences in bone composition, density, and quality: potential implications for in vivo bone research. Endocrinology 139:663–670CrossRefPubMedGoogle Scholar
  19. 19.
    Greenspan SL, Maitl-Ramsey L, Myers E (1996) Classification of osteoporosis in the elderly is dependent on site-specific analysis. Calcif Tissue Int 58:409–414CrossRefPubMedGoogle Scholar
  20. 20.
    Li B, Aspden RM (1997) Composition and mechanical properties of cancellous bone from the femoral head of patients with osteoporosis or osteoarthritis. J Bone Miner Res 12:641–651Google Scholar
  21. 21.
    Niedhart C, Braun K, Graf Stenbock-Fermor N, Bours F, Schneider P, Zilkens KW, Niethard FU (2003) [The value of peripheral quantitative computed tomography (pQCT) in the diagnosis of osteoporosis] Z Orthop Ihre Grenzgeb 141:135–142Google Scholar
  22. 22.
    Simmons A, Simpson DE, O’Doherty MJ, Barrington S, Coakley AJ (1997) The effects of standardization and reference values on patient classification for spine and femur dual-energy X-ray absorptiometry. Osteoporos Int 7:200–206Google Scholar
  23. 23.
    Jerome CP, Turner CH, Lees CJ (1997) Decreased bone mass and strength in ovariectomized cynomolgus monkeys ( Macaca fascicularis). Calcif Tissue Int 60:265–270Google Scholar
  24. 24.
    Balena R, Toolan BC, Shea M, Markatos A, Myers ER, Lee SC, Opas EE, Seedor JG, Klein H, Frankenfield D et al (1993) The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primates. J Clin Invest 92:2577–2586Google Scholar
  25. 25.
    Lill CA, Gerlach UV, Eckhardt C, Goldhahn J, Schneider E (2002) Bone changes due to glucocorticoid application in an ovariectomized animal model for fracture treatment in osteoporosis. Osteoporos Int 13:407–414Google Scholar
  26. 26.
    Vanderschueren D, Van Herck E, Schot P, Rush E, Einhorn T, Geusens P, Bouillon R (1993) The aged male rat as a model for human osteoporosis: evaluation by nondestructive measurements and biomechanical testing. Calcif Tissue Int 53:342–347Google Scholar
  27. 27.
    Bagi CM, Ammann P, Rizzoli R, Miller SC (1997) Effect of estrogen deficiency on cancellous and cortical bone structure and strength of the femoral neck in rats. Calcif Tissue Int 61:336–344Google Scholar
  28. 28.
    Chen H, Shoumura S, Emura S (2004) Ultrastructural changes in bones of the senescence-accelerated mouse (SAMP6): a murine model for senile osteoporosis. Histol Histopathol 19:677–685Google Scholar
  29. 29.
    Dickenson RP, Hutton WC, Stott JR (1981) The mechanical properties of bone in osteoporosis. J Bone Joint Surg Br 63:233–238Google Scholar
  30. 30.
    Mosekilde L, Danielsen CC, Knudsen UB (1993) The effect of aging and ovariectomy on the vertebral bone mass and biomechanical properties of mature rats. Bone 14:1–6Google Scholar
  31. 31.
    Peng Z, Tuukkanen J, Zhang H, Jamsa T, Vaananen HK (1994) The mechanical strength of bone in different rat models of experimental osteoporosis. Bone 15:523–532Google Scholar
  32. 32.
    Silva MJ, Brodt MD, Uthgenannt BA (2004) Morphological and mechanical properties of caudal vertebrae in the SAMP6 mouse model of senile osteoporosis. Bone 35:425–431Google Scholar
  33. 33.
    Silva MJ, Brodt MD, Ettner SL (2002) Long bones from the senescence accelerated mouse SAMP6 have increased size but reduced whole-bone strength and resistance to fracture. J Bone Miner Res 17:1597–1603PubMedGoogle Scholar
  34. 34.
    Keaveny TM, Morgan EF, Niebur GL, Yeh OC (2001) Biomechanics of trabecular bone. Annu Rev Biomed Eng 3:307–333Google Scholar
  35. 35.
    Kimmel DB, Recker RR, Gallagher JC, Vaswani AS, Aloia JF (1990) A comparison of iliac bone histomorphometric data in post-menopausal osteoporotic and normal subjects. Bone Miner 11:217–235Google Scholar
  36. 36.
    Dalle CL, Arlot ME, Chavassieux PM, Roux JP, Portero NR, Meunier PJ (2001) Comparison of trabecular bone microarchitecture and remodeling in glucocorticoid-induced and postmenopausal osteoporosis. J Bone Miner Res 16:97–103PubMedGoogle Scholar
  37. 37.
    Ito M, Nishida A, Nakamura T, Uetani M, Hayashi K (2002) Differences of three-dimensional trabecular microstructure in osteopenic rat models caused by ovariectomy and neurectomy. Bone 30:594–598CrossRefPubMedGoogle Scholar
  38. 38.
    Laib A, Kumer JL, Majumdar S, Lane NE (2001) The temporal changes of trabecular architecture in ovariectomized rats assessed by MicroCT. Osteoporos Int 12:936–941Google Scholar
  39. 39.
    Lane NE, Haupt D, Kimmel DB, Modin G, Kinney JH (1999) Early estrogen replacement therapy reverses the rapid loss of trabecular bone volume and prevents further deterioration of connectivity in the rat. J Bone Miner Res 14:206–214Google Scholar
  40. 40.
    Newman E, Turner AS, Wark JD (1995) The potential of sheep for the study of osteopenia: current status and comparison with other animal models. Bone 16:277S–284SGoogle Scholar
  41. 41.
    Chavassieux P, Garnero P, Duboeuf F, Vergnaud P, Brunner-Ferber F, Delmas PD, Meunier PJ (2001) Effects of a new selective estrogen receptor modulator (MDL 103,323) on cancellous and cortical bone in ovariectomized ewes: a biochemical, histomorphometric, and densitometric study. J Bone Miner Res 16:89–96Google Scholar
  42. 42.
    Stromsoe K (2004) Fracture fixation problems in osteoporosis. Injury 35:107–113Google Scholar
  43. 43.
    Seebeck J, Goldhahn J, Stadele H, Messmer P, Morlock MM, Schneider E (2004) Effect of cortical thickness and cancellous bone density on the holding strength of internal fixator screws. J Orthop Res 22:1237–1242Google Scholar
  44. 44.
    Brockstedt H, Kassem M, Eriksen EF, Mosekilde L, Melsen F (1993) Age- and sex-related changes in iliac cortical bone mass and remodeling. Bone 14:681–691PubMedGoogle Scholar
  45. 45.
    Feik SA, Thomas CD, Clement JG (1997) Age-related changes in cortical porosity of the midshaft of the human femur. J Anat 191 (Part 3):407–416Google Scholar
  46. 46.
    Roschger P, Rinnerthaler S, Yates J, Rodan GA, Fratzl P, Klaushofer K (2001) Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women. Bone 29:185–191CrossRefGoogle Scholar
  47. 47.
    Ritzel H, Amling M, Posl M, Hahn M, Delling G (1997) The thickness of human vertebral cortical bone and its changes in aging and osteoporosis: a histomorphometric analysis of the complete spinal column from thirty-seven autopsy specimens. J Bone Miner Res 12:89–95Google Scholar
  48. 48.
    Lauritzen DB, Balena R, Shea M, Seedor JG, Markatos A, Le HM, Toolan BC, Myers ER, Rodan GA, Hayes WC (1993) Effects of combined prostaglandin and alendronate treatment on the histomorphometry and biomechanical properties of bone in ovariectomized rats. J Bone Miner Res 8:871–879Google Scholar
  49. 49.
    Ibbotson KJ, Orcutt CM, D’Souza SM, Paddock CL, Arthur JA, Jankowsky ML, Boyce RW (1992) Contrasting effects of parathyroid hormone and insulin-like growth factor I in an aged ovariectomized rat model of postmenopausal osteoporosis. J Bone Miner Res 7:425–432Google Scholar
  50. 50.
    Sietsema WK (1995) Animal models of cortical porosity. Bone 17:297S–305SGoogle Scholar
  51. 51.
    Wilson AK, Bhattacharyya MH, Miller S, Mani A, Sacco-Gibson N (1998) Ovariectomy-induced changes in aged beagles: histomorphometry of rib cortical bone. Calcif Tissue Int 62:237–243Google Scholar
  52. 52.
    Burr DB, Hirano T, Turner CH, Hotchkiss C, Brommage R, Hock JM (2001) Intermittently administered human parathyroid hormone(1–34) treatment increases intracortical bone turnover and porosity without reducing bone strength in the humerus of ovariectomized cynomolgus monkeys. J Bone Miner Res 16:157–165Google Scholar
  53. 53.
    Kubo T, Shiga T, Hashimoto J, Yoshioka M, Honjo H, Urabe M, Kitajima I, Semba I, Hirasawa Y (1999) Osteoporosis influences the late period of fracture healing in a rat model prepared by ovariectomy and low calcium diet. J Steroid Biochem Mol Biol 68:197–202CrossRefPubMedGoogle Scholar
  54. 54.
    Meyer RA Jr, Tsahakis PJ, Martin DF, Banks DM, Harrow ME, Kiebzak GM (2001) Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats. J Orthop Res 19:428–435Google Scholar
  55. 55.
    Xu SW, Yu R, Zhao GF, Wang JW (2003) Early period of fracture healing in ovariectomized rats. Chin J Traumatol 6:160–166Google Scholar
  56. 56.
    Kim WY, Han CH, Park JI, Kim JY (2001) Failure of intertrochanteric fracture fixation with a dynamic hip screw in relation to pre-operative fracture stability and osteoporosis. Int Orthop 25:360–362CrossRefPubMedGoogle Scholar
  57. 57.
    Rodriguez JP, Garat S, Gajardo H, Pino AM, Seitz G (1999) Abnormal osteogenesis in osteoporotic patients is reflected by altered mesenchymal stem cells dynamics. J Cell Biochem 75:414–423Google Scholar
  58. 58.
    Rodriguez JP, Montecinos L, Rios S, Reyes P, Martinez J (2000) Mesenchymal stem cells from osteoporotic patients produce a type I collagen-deficient extracellular matrix favoring adipogenic differentiation. J Cell Biochem 79:557–565Google Scholar
  59. 59.
    Sterck JG, Klein-Nulend J, Lips P, Burger EH (1998) Response of normal and osteoporotic human bone cells to mechanical stress in vitro. Am J Physiol 274:E1113–E1120PubMedGoogle Scholar
  60. 60.
    Torricelli P, Fini M, Giavaresi G, Rocca M, Pierini G, Giardino R (2000) Isolation and characterization of osteoblast cultures from normal and osteopenic sheep for biomaterials evaluation. J Biomed Mater Res 52:177–182Google Scholar
  61. 61.
    Torricelli P, Fini M, Giavaresi G, Giardino R (2003) Osteoblasts cultured from osteoporotic bone: a comparative investigation on human and animal-derived cells. Artif Cells Blood Substit Immobil Biotechnol 31:263–277Google Scholar
  62. 62.
    Cerroni AM, Tomlinson GA, Turnquist JE, Grynpas MD (2000) Bone mineral density, osteopenia, and osteoporosis in the rhesus macaques of Cayo Santiago. Am J Phys Anthropol 113:389–410Google Scholar
  63. 63.
    Jerome CP, Peterson PE (2001) Nonhuman primate models in skeletal research. Bone 29:1–6Google Scholar
  64. 64.
    Faugere MC, Friedler RM, Fanti P, Malluche HH (1990) Bone changes occurring early after cessation of ovarian function in beagle dogs: a histomorphometric study employing sequential biopsies. J Bone Miner Res 5:263–272Google Scholar
  65. 65.
    Boyce RW, Franks AF, Jankowsky ML, Orcutt CM, Piacquadio AM, White JM, Bevan JA (1990) Sequential histomorphometric changes in cancellous bone from ovariohysterectomized dogs. J Bone Miner Res 5:947–953Google Scholar
  66. 66.
    Lill CA, Fluegel AK, Schneider E (2000) Sheep model for fracture treatment in osteoporotic bone: a pilot study about different induction regimens. J Orthop Trauma 14:559–565CrossRefPubMedGoogle Scholar
  67. 67.
    Lill CA, Fluegel AK, Schneider E (2002) Effect of ovariectomy, malnutrition and glucocorticoid application on bone properties in sheep: a pilot study. Osteoporos Int 13:480–486Google Scholar
  68. 68.
    Turner AS, Alvis M, Myers W, Stevens ML, Lundy MW (1995) Changes in bone mineral density and bone-specific alkaline phosphatase in ovariectomized ewes. Bone 17:395S–402SCrossRefPubMedGoogle Scholar
  69. 69.
    Spencer GR (1979) Pregnancy and lactational osteoporosis. Animal model: porcine lactational osteoporosis. Am J Pathol 95:277–280Google Scholar
  70. 70.
    Chavassieux P, Buffet A, Vergnaud P, Garnero P, Meunier PJ (1997) Short-term effects of corticosteroids on trabecular bone remodeling in old ewes. Bone 20:451–455Google Scholar
  71. 71.
    Palle S, Vico L, Bourrin S, Alexandre C (1992) Bone tissue response to four-month antiorthostatic bedrest: a bone histomorphometric study. Calcif Tissue Int 51:189–194Google Scholar
  72. 72.
    Damrongrungruang T, Kuroda S, Kondo H, Aoki K, Ohya K, Kasugai S (2004) A simple murine model for immobilization osteopenia. Clin Orthop 244–251Google Scholar
  73. 73.
    Jee WS, Ma Y (1999) Animal models of immobilization osteopenia. Morphologie 83:25–34Google Scholar
  74. 74.
    Uhthoff HK, Jaworski ZF (1978) Bone loss in response to long-term immobilisation. J Bone Joint Surg Br 60:420–429Google Scholar
  75. 75.
    Young DR, Niklowitz WJ, Brown RJ, Jee WS (1986) Immobilization-associated osteoporosis in primates. Bone 7:109–117Google Scholar
  76. 76.
    Takeda T (1999) Senescence-accelerated mouse (SAM): a biogerontological resource in aging research. Neurobiol Aging 20:105–110Google Scholar
  77. 77.
    Jilka RL, Weinstein RS, Takahashi K, Parfitt AM, Manolagas SC (1996) Linkage of decreased bone mass with impaired osteoblastogenesis in a murine model of accelerated senescence. J Clin Invest 97:1732–1740PubMedGoogle Scholar
  78. 78.
    Campbell AW, Bain WE, McRae AF, Broad TE, Johnstone PD, Dodds KG, Veenvliet BA, Greer GJ, Glass BC, Beattie AE et al (2003) Bone density in sheep: genetic variation and quantitative trait loci localization. Bone 33:540–548Google Scholar
  79. 79.
    Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G (2000) Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100:197–207CrossRefPubMedGoogle Scholar
  80. 80.
    Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G (2002) Leptin regulates bone formation via the sympathetic nervous system. Cell 111:305–317CrossRefPubMedGoogle Scholar
  81. 81.
    Haberland M, Schilling AF, Rueger JM, Amling M (2001) Brain and bone: central regulation of bone mass. A new paradigm in skeletal biology. J Bone Joint Surg Am 83:1871–1876Google Scholar
  82. 82.
    Macpherson P, Matheson MS (1979) Comparison of calcification of pineal, habenular commissure and choroid plexus on plain films and computed tomography. Neuroradiology 18:67–72Google Scholar
  83. 83.
    Sandyk R, Anastasiadis PG, Anninos PA, Tsagas N (1992) Is postmenopausal osteoporosis related to pineal gland functions? Int J Neurosci 62:215–225Google Scholar
  84. 84.
    Harms HM, Neubauer O, Kayser C, Wustermann PR, Horn R, Brosa U, Schlinke E, Kulpmann WR, von zur MA, Hesch RD (1994) Pulse amplitude and frequency modulation of parathyroid hormone in early postmenopausal women before and on hormone replacement therapy. J Clin Endocrinol Metab 78:48–52Google Scholar
  85. 85.
    Ostrowska Z, Kos-Kudla B, Swietochowska E, Marek B, Kajdaniuk D, Gorski J (2001) Assessment of the relationship between dynamic pattern of nighttime levels of melatonin and chosen biochemical markers of bone metabolism in a rat model of postmenopausal osteoporosis. Neuro Endocrinol Lett 22:129–136Google Scholar
  86. 86.
    Ostrowska Z, Kos-Kudla B, Marek B, Kajdaniuk D, Staszewicz P, Szapska B, Strzelczyk J (2002) The influence of pinealectomy and melatonin administration on the dynamic pattern of biochemical markers of bone metabolism in experimental osteoporosis in the rat. Neuro Endocrinol Lett 23 [Suppl 1]:104–109Google Scholar
  87. 87.
    Koyama H, Nakade O, Takada Y, Kaku T, Lau KH (2002) Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. J Bone Miner Res 17:1219–1229Google Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2005

Authors and Affiliations

  1. 1.AO Research InstituteDavos PlatzSwitzerland

Personalised recommendations