Animal models for the investigation of the action of factors on bone metabolism

  • Colin R. Dunstan
  • Brendan F. Boyce


There is increasing interest from the world’s pharmaceutical industry in the problems of bone pathology, and many of the large companies and many smaller biotechnology companies have active bone research programmes. This chapter has been structured to encompass the requirements for both investigational (i.e. research) and preclinical assessment of factors with putative action (therapeutic or otherwise) on bone resorption or formation associated with bone modelling and remodelling. Models of fracture and repair of segmental defects are beyond the scope of this chapter. Investigational requirements centre around identification of an activity or validation of an activity identified in in vitro systems. Preclinical assessment centres around application of an activity to human disease. Under normal circumstances there is a progression from the investigational studies into preclinical assessment.


Bone Loss Bone Resorption Cancellous Bone Growth Plate Cynomolgus Monkey 


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  1. 1.
    Boyce, B.F., Aufdemorte, T.B., Garrett, I.R. et al. (1989) Effects of interleukin-1 on bone turnover in normal mice. Endocrinology 125), 1142–1150.PubMedGoogle Scholar
  2. 2.
    Yates, A.J., Gutierrez, G.E., Smolens, P. et al. (1988) Effects of a synthetic peptide of a parathyroid hormone-related protein on calcium homeostasis, renal tubular calcium reabsorption, and bone metabolism in vivo and in vitro in rodents. Journal of Clinical Investigation 81), 932–938.PubMedGoogle Scholar
  3. 3.
    Noda, M. and Camilliere, J.J. (1989) In vivo stimulation of bone formation by transforming growth factor-beta. Endocrinology 124), 2991–2994.PubMedCrossRefGoogle Scholar
  4. 4.
    Marcelli, C., Yates, A.J. and Mundy, G.R. (1990) In vivo effects of human recombinant transforming growth factor beta on bone turnover in normal mice. Journal of Bone and Mineral Research 10), 1087–1096.Google Scholar
  5. 5.
    Dunstan, C.R., Garrett, I.R., Adams, R. et al. (1995) Systemic fibroblast growth factor (FGF-1) prevents bone loss, increases new bone formation, and restores trabecular architecture in ovariectomized rats. Journal of Bone and Mineral Research 10(Suppl. 1), s198.Google Scholar
  6. 6.
    Schlechter, N.L., Russell, S.M., Greenberg, S. et al. (1986) A direct growth effect of growth hormone in rat hindlimb shown by arterial infusion. American Journal of Physiology 250), E231–235.PubMedGoogle Scholar
  7. 7.
    Takano-Yamamoto, T. and Rodan, G.A. (1990) Direct effects of 17 beta-estradiol on trabecular bone in ovariectomized rats. Proceedings of the National Academy of Sciences USA 87), 2172–2176.CrossRefGoogle Scholar
  8. 8.
    Russell, S.M. and Spencer, E.M. (1985) Local injections of human or rat growth hormone or on human somatomedin-C stimulate unilateral tibial epiphyseal growth in hypophysectomized rats. Endocrinology 116), 2563–2567.PubMedGoogle Scholar
  9. 9.
    Wang, J.S. and Aspenberg, P. (1994) Basic fibroblast growth factor increases allograft incorporation. Bone chamber study in rats. Acta Orthopaedica Scandinavica 65), 27–31.PubMedGoogle Scholar
  10. 10.
    Guise, T.A., Chirgwin, J.M., Favarato, G. et al. (1992) Chinese hamster ovarian cells transfected with human parathyroid hormone-related protein cDNA cause hypercal-cemia in mice. Laboratory Investigation 67), 477–485.PubMedGoogle Scholar
  11. 11.
    De la Mata, J., Uy, H.L., Guise, T.A. et al. (1995) Interleukin-6 enhances hypercalcemia and bone resorption mediated by parathyroid-hormone related protein in vivo. Journal of Clinical Investigation 95), 2846–2852.PubMedGoogle Scholar
  12. 12.
    Yates, A.J., Boyce, B.F., Favaroto, G. et al. (1992) Expression of human transforming growth factor alpha by Chinese hamster ovarian tumors in nude mice causes hyper-calcemia and increased osteoclastic bone resorption. Journal of Bone and Mineral Research 7), 847–853.PubMedGoogle Scholar
  13. 13.
    Wang, Z.Q., Ovitt, C., Grigoriadis, A.E. et al. (1992) Bone and haematopoietic defects in mice lacking c-fos. Nature 360), 741–745.PubMedCrossRefGoogle Scholar
  14. 14.
    Soriano, P., Montgomery, C, Geske, R. and Bradley, A. (1991) Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 64), 693–702.PubMedCrossRefGoogle Scholar
  15. 15.
    Lewis, D.B., Liggitt, H.D., Effman, E.L. et al. (1993) Osteoporosis induced in mice by overproduction of interleukin 4. Proceedings of the National Academy of Sciences USA 90), 11618–11612.CrossRefGoogle Scholar
  16. 16.
    Beamer, W.G., Donahue, L.R., Rosen, C.J. and Bay link, D.J. (1996) Genetic variability in adult bone density among inbred strains of mice. Bone 18), 397–403.PubMedCrossRefGoogle Scholar
  17. 17.
    Liu, C.C. and Howard, G.A. (1991) Bone-cell changes in estrogen-induced bone-mass increase in mice: dissociation of osteoclasts from bone surfaces. Anatomical Record 229), 240–250.PubMedCrossRefGoogle Scholar
  18. 18.
    Wronski, T.J., Lowry, P.L., Walsh, C.C. and Ignaszewski, L.A. (1985) Skeletal alterations in ovariectomized rats. Calcified Tissue International 37), 324–328.PubMedCrossRefGoogle Scholar
  19. 19.
    Kalu, D.N. (1991) The ovariectomized rat model of postmenopausal bone loss. Bone and Mineral 15), 175–191.PubMedCrossRefGoogle Scholar
  20. 20.
    Food and Drug Administration (1994) Guidelines for preclinical and clinical evaluation of agents used in the prevention of post menopausal osteoporosis. Division of Metabolism and Endocrine Drug Products. Draft, April.Google Scholar
  21. 21.
    Jerome, C.P., Lees, C.J. and Weaver, D.S. (1995) Development of osteopenia in ovariectomized cynomolgus monkeys (Macaca fascicularis). Bone 17 (Suppl.), 402S–408S.Google Scholar
  22. 22.
    Balena, R., Toolan, B.C., Shea, M. 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. Journal of Clinical Investigation 92), 2577–2586.PubMedCrossRefGoogle Scholar
  23. 23.
    Jerome, C.P., Carlson, C.S., Register, T.C. et al. (1994) Bone functional changes in intact, ovariectomized, and ovariectomized, hormone-supplemented adult cynomolgus monkeys (Macaca fascicularis) evaluated by serum markers and dynamic histomorphometry. Journal of Bone and Mineral Research 9), 527–540.PubMedGoogle Scholar
  24. 24.
    Longcope, C, Hoberg, L., Steuterman, S. and Baran, D. (1989) The effect of ovariectomy on spine bone mineral density in rhesus monkeys. Bone 10), 341–344.PubMedCrossRefGoogle Scholar
  25. 25.
    Malluche, H.H., Faugere, M.C., Friedler, R.M. and Fanti, P. (1988) 1,25-dihydroxyvitamin D3 corrects bone loss but suppresses bone remodeling in ovariohysterectomized beagle dogs. Endocrinology 122), 1998–2006.PubMedGoogle Scholar
  26. 26.
    Boyce, R.W., Franks, A.F., Jankowsky, M.L. et al. (1990) Sequential histomorphometric changes in cancellous bone from ovariohysterectomized dogs. Journal of Bone and Mineral Research 5), 947–953.PubMedGoogle Scholar
  27. 27.
    Shen, V., Dempster, D.W., Birchman, R. et al. (1992) Lack of changes in histomorphometric, bone mass, and biochemical parameters in ovariectomized dogs. Bone 13), 311–316.PubMedCrossRefGoogle Scholar
  28. 28.
    Mosekilde, L., Weisbrode, S.E., Safron, J.A. et al. (1993) Evaluation of the skeletal effects of combined mild dietary calcium restriction and ovariectomy in Sinclair S-1 minipigs: a pilot study. Journal of Bone and Mineral Research 8), 1311–1321.PubMedCrossRefGoogle Scholar
  29. 29.
    Hornby, S.B., Ford, S.L., Mase, C.A. and Evans, G.P. (1995) Skeletal changes in the ovariectomized ewe and subsequent response to treatment with 17 estradiol. Bone 17 (Suppl.), 389s–394s.PubMedGoogle Scholar
  30. 30.
    Turner, A.S., Mallinckrodt, C.H., Alvis, M.R. and Bryant, H.U. (1995) Dose response effects of estradiol implants on bone mineral density in ovariectomized ewes. Bone 17 (Suppl.), 421S–427S.PubMedCrossRefGoogle Scholar
  31. 31.
    Mackey, M.S., Stevens, M.L., Ebert, D.C. et al. (1995) The ferret as a small animal model with BMU-based remodeling for skeletal research. Bone 17 (Suppl.), 191S–196S.PubMedGoogle Scholar
  32. 32.
    Kalu, D.N., Liu, C.C., Hardin, R.R. and Hollis, B.W. (1989) The aged rat model of ovarian deficiency bone loss. Endocrinology 124), 7–16.PubMedGoogle Scholar
  33. 33.
    Mayahara, H., Ito, T., Nagai, H. et al. (1993) In vivo stimulation of endosteal bone formation by basic fibroblast growth factor in rats. Growth Factors 9), 73–80.PubMedGoogle Scholar
  34. 34.
    Weinreb, M., Rodan, G.A. and Thompson, D.D. (1989) Osteopenia in the immobilized rat limb is associated with increased bone resorption and decreased bone formation. Bone 10), 187–194.PubMedCrossRefGoogle Scholar
  35. 35.
    LeBlanc, A., Marsh, C, Evans, H. et al. (1985) Bone and muscle atrophy with suspension in the rat. Journal of Applied Physiology 58), 1669–1675.PubMedGoogle Scholar
  36. 36.
    Young, D.R., Niklowitz, W.J., Brown, R.J. and Jee, W.S.S. (1986) Immobilisation-associated osteoporosis in primates. Bone 7), 109–117.PubMedCrossRefGoogle Scholar
  37. 37.
    Waters, D.J., Caywood, D.D. and Turner, R.T. (1991) Effect of tamoxifen citrate on canine immobilization (disuse) osteoporosis. Veterinary Surg 20), 392–396.Google Scholar
  38. 38.
    Morey-Holton, E.R. and Arnaud, S.B. (1991) Skeletal responses to spaceflight. Adv Space Biol Med 1), 37–69.PubMedGoogle Scholar
  39. 39.
    Sietsema, W.K. (1995) Animal models of cortical porosity. Bone 17 (Suppl.), 297S–305S.PubMedGoogle Scholar
  40. 40.
    Insogna, K.L., Stewart, A.F., Vignery, A.M. et al. (1984) Biochemical and histomorphometric characterization of a rat model for humoral hypercalcemia of malignancy. Endocrinology 114), 888–896.PubMedCrossRefGoogle Scholar
  41. 41.
    Hilgard, P. Schmitt, W., Minne, H. and Ziegler, R. (1970) Acute hypercalcemia due to Walker carcinosarcoma 256 in the rat. Horm Metab Res 2), 255–256.PubMedCrossRefGoogle Scholar
  42. 42.
    Strassman, G., Jacob, C.O., Fong, M. and Bertolini, D.R. (1993) Mechanism of paraneoplastic syndromes of colon-26: involvement of interleukin 6 in hypercalcemia. Cytokine 5), 463–468.CrossRefGoogle Scholar
  43. 43.
    Sasaki, A., Boyce, B.F., Story, B. et al. (1995) Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice. Cancer Research 55), 3551–3557.PubMedGoogle Scholar

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© Chapman and Hall Ltd 1998

Authors and Affiliations

  • Colin R. Dunstan
  • Brendan F. Boyce

There are no affiliations available

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