Advanced Search

Journal Navigation

Journal Home

Subscriptions

Archive

Contact Us

Table of Contents

CiteULike is a free service for managing and discovering scholarly references - click here to get started.

Sign In to gain access to subscriptions and/or personal tools.
Toxicologic Pathology
This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Hartke, J. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hartke, J. R.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Preclinical Development of Agents for the Treatment of Osteoporosis

James R. Hartke

Procter and Gamble Pharmaceuticals, Mason, Ohio 45040

Because of the high cost and long time frame of clinical testing, animal models play a crucial role in the identification and selection of agents for the treatment of osteoporosis. The use of animal models early in a program focuses on the establishment of efficacy, while animal models used later in a program to examine bone safety. More specifically, animal models are used to gain information on the skeletal mechanism of action, to examine multiple skeletal sites (axial and appendicular), and to examine the effects of higher doses than will be used in humans. Animal models also predict the usefulness of surrogate markers in clinical trials, such as formation and resorption markers, as well as bone density. The hazard of using surrogate markers for fracture prevention is highlighted by high dose fluoride administration, which can increase bone density (considered a strong predictor of fracture protection) while not protecting against fractures. Estrogen-deficient models are most commonly used to mimic the postmenopausal bone loss in women; these models are characterized by increased bone turnover and a negative bone balance. The timing of the administration of the new therapy in animal models can help determine whether the agent will be more effective in the prevention of osteoporosis or in the treatment of established osteoporosis. New methods for the measurement of bone mass or volume are less invasive, require shorter acquisition time, and have enhanced resolution, resulting in increased knowledge concerning architectural changes and specific sites of bone deposition. Finally, the measurement of biomechanical strength of bones from animal models can be used to predict protective effects on fracture rates in clinical trials. When used in combination with other methods, animal models can greatly increase our understanding of the pathophysiology of osteoporosis and can expedite the development of new therapies.

Key Words: Osteopenia • postmenopausal • bone • animal models • therapy • review

References

  • Bagi CM, Mecham M., Weiss J., and Miller SC (1993). Comparative morphometric changes in rat cortical bone following ovariectomy and/or immobilization. Bone 14: 877-883.[Medline] [Order article via Infotrieve]
  • Boyce RW, Franks AF, Jankowsky ML, Orcutt CM, Piacquadio AM, White JM, and Bevan JA (1990). Sequential histomorphometric changes in cancellous bone from ovariohysterectomized dogs. J. Bone Miner. Res. 5: 947-953.[Web of Science][Medline] [Order article via Infotrieve]
  • Calvo MS, Eyre DR, and Gundberg CM (1996). Molecular basis and clinical application of biological markers of bone turnover. Endocrinol. Rev. 17: 333-368.[Abstract/Free Full Text]
  • Cann CE (1988). Quantitative CT for determination of bone mineral density: A review. Radiology 166: 509-522.[Abstract/Free Full Text]
  • Consensus Development Conference ( 1991). Diagnosis, prophylaxis, and treatment of osteoporosis. Am. J. Med. 90: 170-210.
  • Dannucci GA, Martin RB, and Patterson BP (1987). Ovariectomy and trabecular bone remodeling in the dog. Calcif. Tissue Int. 40: 194-199.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Delmas PD (1993). Biochemical markers of bone turnover. J. Bone Miner. Res. 8(suppl. 2): S549-S555[Web of Science][Medline] [Order article via Infotrieve]
  • Delmas PD (1993). Biochemical markers of bone turnover for the clinical investigation of osteoporosis. Osteoporos. Int. 3(suppl. 1): 81-86.[CrossRef][Medline] [Order article via Infotrieve]
  • Eriksen EF (1986). Normal and pathological remodeling of human trabecular bone: Three dimensional reconstruction of the remodeling sequence in normals and in metabolic bone disease. Endocrinol. Rev. 7: 379-408.[Abstract/Free Full Text]
  • Food and Drug Administration ( 1994). Guidelines for the Preclinical and Clinical Evaluation of Agents Used in the Prevention and Treatment of Post Menopausal Osteoporosis. Division of Metabolism and Endocrine Drug Products, Food and Drug Administration, Washington, D.C.
  • Frost HM and Jee WS (1992). On the rat model of human osteopenias and osteoporoses. Bone Miner. 18: 227-236.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Garnero P. and Delmas PD (1996). New developments in biochemical markers for osteoporosis. Calcif. Tissue Int. 59(suppl. 1): S2-S9[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Garnero P., Gineyts E., Riou JP, and Delmas PD (1994). Assessment of bone resorption with a new marker of collagen degradation in patients with metabolic bone disease. J. Clin. Endocrinol. Metab. 79: 780-785.[Abstract]
  • Garnero P., Sornay RE, Chapuy MC, and Delmas PD (1996). Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. J. Bone Miner. Res. 11: 337-349.[Web of Science][Medline] [Order article via Infotrieve]
  • Geddes AD (1996). Animal models of bone disease. In Principles of Bone Biology, JP Bilezikian, LG Raisz. and GA Rodan (eds). Academic Press, New York, pp. 1343-1354.
  • Globus RK, Bikle DD, Halloran B., and Morey HE (1986). Skeletal response to dietary calcium in a rat model simulating weightlessness. J. Bone Miner. Res. 1: 191-197.[Web of Science][Medline] [Order article via Infotrieve]
  • Grampp S., Jergas M., Gluer CC, Lang P., Brastow P., and Genant HK (1993). Radiologic diagnosis of osteoporosis. Current methods and perspectives. Radiol. Clin. North Am. 31: 1133-1145.[Web of Science][Medline] [Order article via Infotrieve]
  • Hornby SB, Ford SL, Mase CA, and Evans GP (1995). Skeletal changes in the ovariectomised ewe and subsequent response to treatment with 17 beta oestradiol. Bone 17: 389S-394S.[Medline] [Order article via Infotrieve]
  • Jayo MJ, Jerome CP, Lees CJ, Rankin SE, and Weaver DS (1994). Bone mass in female cynomolgus macaques: A cross-sectional and longitudinal study by age. Calcif. Tissue Int. 54: 231-236.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Jensen KS and Mosekilde L. (1990). A model of vertebral trabecular bone architecture and its mechanical properties. Bone 11: 417-423.[Medline] [Order article via Infotrieve]
  • Jerome CP, Carlson CS, Register TC, Bain FT, Jayo MJ, Weaver DS, and Adams MR (1994). Bone functional changes in intact, ovariectomized, and ovariectomized, hormone-supplemented adult cynomolgus monkeys (Macaca fascicularis) evaluated by serum markers and dynamic histomorphometry. J. Bone Miner. Res. 9: 527-540.[Web of Science][Medline] [Order article via Infotrieve]
  • Jerome CP, Lees CJ, and Weaver DS (1995). Development of osteopenia in ovariectomized cynomolgus monkeys (Macaca fascicularis). Bone 17: 403S-408S.[Medline] [Order article via Infotrieve]
  • Jerome CP, Turner CH, and Lees CJ (1997). Decreased bone mass and strength in ovariectomized cynomolgus monkeys (Macaca fascicularis). Calcif. Tissue Int. 60: 265-270.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Kalu DN (1991). The ovariectomized rat model of postmenopausal bone loss. Bone Miner. 15: 175-191.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Malluche HH, Faugere MC, Rush M., and Friedler R. (1986). Osteoblastic insufficiency is responsible for maintenance of osteopenia after loss of ovarian function in experimental beagle dogs. Endocrinology 119: 2649-2654.[Abstract/Free Full Text]
  • Mann DR, Gould KG, and Collins DC (1990). A potential primate model for bone loss resulting from medical oophorectomy or menopause. J. Clin. Endocrinol. Metab. 71: 105-110.[Abstract/Free Full Text]
  • Marcus R., Greendale G., Blunt BA, Bush TL, Sherman S., Sherwin R., Wahner H., and Wells B. (1994). Correlates of bone mineral density in the postmenopausal estrogen/progestin interventions trial. J. Bone Miner. Res. 9: 1467-1476.[Web of Science][Medline] [Order article via Infotrieve]
  • Melton LJ (1993). Hip fractures: A worldwide problem today and tomorrow. Bone 14(suppl. 1): S1-S8
  • Melton LJ (1995). How many women have osteoporosis now? J. Bone Miner. Res. 10: 175-177.[Web of Science][Medline] [Order article via Infotrieve]
  • Melton LJ, Atkinson EJ, O'Fallon WM, Wahner HW, and Riggs BL (1993). Long-term fracture prediction by bone mineral assessed at different skeletal sites. J. Bone Miner. Res. 8: 1227-1233.[Web of Science][Medline] [Order article via Infotrieve]
  • Miller LC, Weaver DS, McAlister JA, and Koritnik DR (1986). Effects of ovariectomy on vertebral trabecular bone in the cynomolgus monkey (Macaca fascicularis). Calcif. Tissue Int. 38: 62-65.[Web of Science][Medline] [Order article via Infotrieve]
  • Miller SC, Bowman BM, and Jee WS (1995). Available animal models of osteopenia—Small and large. Bone 17: 117S-123S.[Medline] [Order article via Infotrieve]
  • Miller SC and Wronski TJ (1993). Long-term osteopenic changes in cancellous bone structure in ovariectomized rats. Anat. Rec. 236: 433-441.[CrossRef][Medline] [Order article via Infotrieve]
  • Mosekilde L. (1990). Consequences of the remodelling process for vertebral trabecular bone structure: A scanning electron microscopy study (uncoupling of unloaded structures). Bone Miner. 10: 13-35.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Mosekilde L. (1995). Assessing bone quality—Animal models in preclinical osteoporosis research. Bone 17: 343S-352S.[Medline] [Order article via Infotrieve]
  • Mosekilde L., Weisbrode SE, Safron JA, Stills HF, Jankowsky ML, Ebert DC, Danielsen CC, Sogaard CH, Franks AF, Stevens ML, Paddock CL, and Boyce RW (1993). Calcium-restricted ovariectomized Sinclair S-1 minipigs: an animal model of osteopenia and trabecular plate perforation. Bone 14: 379-382.[Medline] [Order article via Infotrieve]
  • Mosekilde L., Weisbrode SE, Safron JA, Stills HF, Jankowsky ML, Ebert DC, Danielsen CC, Sogaard CH, Franks AF, Stevens ML, Paddock CL, and Boyce RW (1993). Evaluation of the skeletal effects of combined mild dietary calcium restriction and ovariectomy in Sinclair S-1 minipigs: A pilot study. J. Bone Miner. Res. 8: 1311-1321.[Web of Science][Medline] [Order article via Infotrieve]
  • Newman E., Turner AS, and Wark JD (1995). The potential of sheep for the study of osteopenia: Current status and comparison with other animal models. Bone 16: 277S-284S.[Medline] [Order article via Infotrieve]
  • Pope NS, Gould KG, Anderson DC, and Mann DR (1989). Effects of age and sex on bone density in the rhesus monkey. Bone 10: 109-112.[Medline] [Order article via Infotrieve]
  • Riggs BL, Hodgson SF, O'Fallon WM, Chao EY, Wahner HW, Muhs JM, Cedel SL, and Melton LJ (1990). Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis [see comments]. N. Engl. J. Med. 322: 802-809.[Abstract]
  • Riggs BL and Melton LJ (1995). The worldwide problem of osteoporosis: Insights afforded by epidemiology. Bone 17: 505S-511S.[Medline] [Order article via Infotrieve]
  • Sietsema WK (1995). Animal models of cortical porosity. Bone 17: 297S-305S.[Medline] [Order article via Infotrieve]
  • Sogaard CH, Mosekilde L., Schwartz W., Leidig G., Minne HW, and Ziegler R. (1995). Effects of fluoride on rat vertebral body biomechanical competence and bone mass. Bone 16: 163-169.[Medline] [Order article via Infotrieve]
  • Spencer GR (1979). Pregnancy and lactational osteoporosis. Animal model: Porcine lactational osteoporosis. Am. J. Pathol. 95: 277-280.[Web of Science][Medline] [Order article via Infotrieve]
  • Thomas T., Skerry TM, Vico L., Caulin F., Lanyon LE, and Alexandre C. (1995). Ineffectiveness of calcitonin on a local-disuse osteoporosis in the sheep: A histomorphometric study. Calcif. Tissue Int. 57: 224-228.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
  • Turner AS, Mallinckrodt CH, Alvis MR, and Bryant HU (1995). Dose-response effects of estradiol implants on bone mineral density in ovariectomized ewes. Bone 17: 4215-427S.
  • Westerlind KC, Wronski TJ, Ritman EL, Luo ZP, An KN, Bell NH, and Turner RT (1997). Estrogen regulates the rate of bone turnover but bone balance in ovariectomized rats is modulated by prevailing mechanical strain. Proc. Natl. Acad. Sci. USA 94: 4199-4204.[Abstract/Free Full Text]
  • Wronski TJ, Cintron M., and Dann LM (1988). Temporal relationship between bone loss and increased bone turnover in ovariectomized rats. Calcif. Tissue Int. 43: 179-183.[Web of Science][Medline] [Order article via Infotrieve]
  • Wronski TJ, Cintron M., Doherty AL, and Dann LM (1988). Estrogen treatment prevents osteopenia and depresses bone turnover in ovariectomized rats. Endocrinology 123: 681-686.[Abstract/Free Full Text]
  • Wronski TJ, Dann LM, and Horner SL (1989). Time course of vertebral osteopenia in ovariectomized rats. Bone 10: 295-301.[Medline] [Order article via Infotrieve]
  • Wronski TJ, Dann LM, Scott KS, and Cintron M. (1989). Long-term effects of ovariectomy and aging on the rat skeleton. Calcif. Tissue Int. 45: 360-366.[Web of Science][Medline] [Order article via Infotrieve]
  • Wronski TJ and Morey HE (1987). Skeletal response to simulated weightlessness: A comparison of suspension techniques. Aviat. Space. Environ. Med. 58: 63-68.
  • Wronski TJ, Walsh CC, and Ignaszewski LA (1986). Histologic evidence for osteopenia and increased bone turnover in ovariectomized rats. Bone 7: 119-123.[Medline] [Order article via Infotrieve]

Toxicologic Pathology, Vol. 27, No. 1, 143-147 (1999)
DOI: 10.1177/019262339902700126
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 Lab AnimHome page
Y.-X. J Wang, H. Zhou, J. F Griffith, Y.-F. Zhang, D. K W Yeung, and A. T Ahuja
An in vivo magnetic resonance imaging technique for measurement of rat lumbar vertebral body blood perfusion
Lab Anim, July 1, 2009; 43(3): 261 - 265.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Free Full Text (Free PDF) Free
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Saved Citations
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Request Reprints
Right arrow Add to My Marked Citations
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Right arrow Citing Articles via Scopus
Google Scholar
Right arrow Articles by Hartke, J. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hartke, J. R.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?