Importance of preclinical studies in the development of drugs for treatment of osteoporosis: A review related to the 1998 WHO guidelines

Osteoporosis International

Volumn 9, Issue 5, 1999, Pages 379-393

  Bonjour, Jean Philippe ^a,b   Ammann, P ^a   Rizzoli, R ^a  

^a WORLD HEALTH ORGANIZATION   (Switzerland)

^b Faculty of Medicine   (Switzerland)

Author keywords

Animal models; Clinical trials; Drug registration; Guidelines; Osteoporosis; Preclinical program

Indexed keywords

ALENDRONIC ACID; BISPHOSPHONIC ACID DERIVATIVE; CALCITONIN; DROLOXIFENE; ESTROGEN; FLUORIDE; PARATHYROID HORMONE; RALOXIFENE; TAMOXIFEN;

ANIMAL MODEL; BONE MASS; BONE REMODELING; BONE STRENGTH; DRUG RESEARCH; HUMAN; MEDICAL RESEARCH; NONHUMAN; OSTEOLYSIS; OSTEOPOROSIS; PRACTICE GUIDELINE; PRIORITY JOURNAL; REVIEW; WORLD HEALTH ORGANIZATION;

ANIMALS; CLINICAL TRIALS; DISEASE MODELS, ANIMAL; HUMANS; OSTEOPOROSIS; PRACTICE GUIDELINES; RESEARCH; WORLD HEALTH ORGANIZATION;

EID: 0032945401     PISSN: 0937941X     EISSN: None     Source Type: Journal    
DOI: 10.1007/s001980050161     Document Type: Review

References (194)

1. Guidelines for preclinical and clinical evaluation of agents used in the prevention or treatment of postmenopausal osteoporosis. Division of Metabolism and Endocrine Drug Products, Food and Drug Administration (FDA) Draft, April, 1994.
2. Reginster JY, on behalf of the Group for the Respect of Ethics and Excellence in Science (GREES). Recommendations for the registration of new chemical entities used in the prevention of osteoporosis. Calcif Tissue Int 1995;57:247-50.
3. Ishii J. Summary of the draft Japanese guidelines for the evaluation of agents for treatment osteoporosis. In: Proceedings of the 11th Education Seminar of tha Japan Osteoporosis Foundation. Tokyo, Lifescience Publishing, 1995:14-18.
4. Kanis JA, Delmas P, Meunier PJ, Johnston CC, Bonjour JP, Christiansen C, et al. The GREES recommendations for the registration of new drugs in the prevention and treatment of osteoporosis [letter to the editor]. Calcif Tissue Int 1996;59:410-1.
5. Note for guidance on involutional osteoporosis in women. The European Agency for the Evaluation of Medicinal Products. London: EMEA, 1996.
6. Guidelines for preclinical evaluation and clinical trials in osteoporosis. Geneva: World Health Organization, 1998.
7. Peck WA, Burckhardt P, Christiansen C, Fleisch HA, Genant HK, Gennari C, et al. Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 1993;94:646-50.
8. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. WHO technical report series 843. Geneva: World Health Organization, 1994.
9. Seedor JG, Quartuccio HA, Thompson DD. The bisphosphonate alendronate (ALM) inhibits bone loss due to ovariectomy in rats. J Bone Miner Res 1991;6:339-46.
10. Balena R, Toolan BC, Shea M, Markatos A, Myers ER, Lee SC, et al. The effects of 2-year treatment with the aminobisphosphonate alendronate on bone metabolism, bone histomorphometry, and bone strength in ovariectomized nonhuman primate. J Clin Invest 1993;92:2577-86.
11. Guy JA, Shea M, Peter CP, Morrissey R, Hayes WC. Continuous alendronate treatment throughout growth, maturation, and aging in the rat results in increases in bone mass and mechanical properties. Calcif Tissue Int 1993;53:283-8.
12. Harris ST, Gertz BJ, Genant HK, Eyre DR, Survill TT, Ventura JN, et al. The effect of short term treatment with alendronate on vertebral density and biochemical markers of bone remodeling in early postmenopausal women. J Clin Endocrinol Metab 1993;76:1399-406.
13. Liberman UA, Weiss SR, Bröll J, Minne HW, Quan H, Bell NH, et al., for the Alendronate Phase III Osteoporosis Treatment Study Group. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437-43.
14. Chesnut III CH, McClung MR, Ensrud KE, Bell NH, Genant HK, Harris ST, et al. Alendronate treatment of the postmenopausal osteoporotic woman: effect of multiple dosages on bone mass and bone remodeling. Am J Med 1995;99:144-52.
15. Devogelaer JP, Broll H, Correa-Rotter R, Cumming DC, Nagant de Deuxchaisnes C, Geusens P, et al. Oral alendronate induces progressive increases in bone mass of the spine, hip, and total body over 3 years in postmenopausal women with osteoporosis. Bone 1996;18:141-50.
16. Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, et al., for the Fracture Intervention Trial Research Group. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348:1535-41.
17. Bone HG, Downs Jr RW, Tucci JR, Harris ST, Weinstein RS, Licata AA, et al., for the Alendronate Elderly Osteoporosis Study Centers. Dose-response relationships for alendronate treatment in osteoporotic elderly women. J Clin Endocrinol Metab 1997;82:265-74.
18. Bonjour JP, Rizzoli R, Ammann P, Chevalley T. Bisphosphonates in clinical medicine. Bone Miner Res 1994;8:205-64.
19. Fleisch H. Bisphosphonates in bone disease: from the laboratory to the patient. 3rd ed. New York: Parthenon Publishing, 1997.
20. Turner RT, Vandersteenhoven JJ, Bell NH. The effect of ovariectomy and 17β-estradiol on cortical bone histomorphometry in growing rats. J Bone Miner Res 1987;2:115-22.
21. Danielsen CC, Mosekilde L, Svenstrup B. Cortical bone mass, composition, and mechanical properties in female rats in relation to age, long-term ovariectomy, and estrogen substitution. Calcif Tissue Int 1992;52:26-33.
22. Wronski TJ, Yen CF, Dann LM. Parathyroid hormone is more effective than estrogen or bisphosphonates for restoration of lost bone in ovariectomized rats. Endocrinology 1993;132:823-31.
23. Mosekilde L, Danielsen C, Gasser J. The effect on vertebral bone mass and strength of long term treatment with antiresorptive agents (estrogen and calcitonin), human parathyroid hormone-(1-38), and combination therapy, assessed in aged ovariectomized rats. Endocrinology 1994;134:2126-34.
24. Vanin CM, MacLusky NJ, Chachra D, Kasra M, Grynpas MD, Casper RF. Lumbar vertebral density and mechanical properties in aged ovariectomized rats treated with estrogen and norethindrone or norgestimate. Am J Obstet Gynecol 1995;173:1491-8.
25. Azria M, Copp DH, Zanelli JM. Twenty-five years of salmon calcitonin: from synthesis to therapeutic use [editorial] Calcif Tissue Int 1995;57:405-8.
26. Christiansen C, Lindsay R. Estrogens, bone loss and preservation. Osteoporos Int 1991;1:7-13.
27. Stevenson JC, Cust MP, Gangar KF, Hillard TC, Lees B, Whitehead MI. Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women. Lancet 1990;336:265-9.
28. Harris ST, Genant HK, Baylink DJ, Gallagher JC, Karp SK, McConnell MA, et al. The effects of estrogen on spinal bone density of postmenopausal women. Arch Intern Med 1991;151:1980-4.
29. Ribot C, Tremollières F, Pouilles JM, Louvet JP, Peyron R. Preventive effects of transdermal administration of 17-beta-estradiol on postmenopausal bone loss: a 2-year prospective study. Gynecol Endocrinol 1989;3:259-67.
30. Thamsborg G, Storm TL, Sykluski R, Nielsen HK, Sorensen OH. Effect of different doses of nasal salmon calcitonin on bone mass. Calcif Tissue Int 1991;48:302-7.
31. Overgaard K, Hansen MA, Jensen SB, Christiansen C. Effect of salcatonin given intranasally on bone mass and fracture rates in established osteoporosis: a dose-response study. BMJ 1992;503:556-61.
32. Reginster JY. Management of high turnover osteoporosis with calcitonin. Bone 1992;13:S37-40.
33. Mosekilde L, Sogaard CH, McOsker JE, Wronski TJ. PTH has a more pronounced effect on vertebral bone mass and biomechanical competence than antiresorptive agents (estrogen and bisphosphonate): assessed in sexually mature, ovariectomized rats. Bone 1994;15:401-8.
34. Black LJ, Sato M, Rowley ER, Magee DE, Bekele A, Williams DC, et al. Raloxifene (LY 139481 HC1) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats. J Clin Invest 1994;93:63-9.
35. Turner CH, Sato M, Bryant HU. Raloxifene preserves bone strength and bone mass in ovariectomized rats. Endocrinology 1994;135:2001-5.
36. Sato M, McClintock C, Kim J, Turner CH, Bryant HU, Magee D, Slemenda CW. Dual-energy X-ray absorptiometry of raloxifene effects on the lumbar vertebrae and femora of ovariectomized rats. J Bone Miner Res 1994;9:715-24.
37. Ke HZ, Simmons HA, Pirie CM, Crawford DT, Thompson DD. Droloxifene, a new estrogen antagonist/agonist, prevents bone loss in ovariectomized rats. Endocrinology 1995;136:2435-41.
38. Ke HZ, Chen HK, Qi H, Pirie CM, Simmons HA, Ma YF, et al. Effects of droloxifene on prevention of cancellous bone loss and bone turnover in the axial skeleton of aged, ovariectomized rats. Bone 1995;17:491-6.
39. Chen HK, Ke HZ, Jee WSS, Ma YF, Pirie CM, Simmons HA, Thompson DD. Droloxifene prevents ovariectomy-induced bone loss in tibiae and femora of aged female rats: a dual-energy X-ray absorptiometric and histomorphometric study. J Bone Miner Res 1995;10:1256-62.
40. Frolik CA, Bryant HU, Black EC, Magee DE, Chandrasekhar S. Time-dependent changes in biochemical bone markers and serum cholesterol in ovariectomized rats: effects of raloxifene HC1, tamoxifen, estrogen, and alendronate. Bone 1996;18:621-7.
41. Sato M, Rippy MK, Bryant HU. Raloxifene, tamoxifen, nafoxidine, or estrogen effects on reproductive and nonreproductive tissues in ovariectomized rats. FASEB J 1996;10:905-12.
42. Kristensen B, Ejlertsen B, Dalgaard P, Larsen L, Holmegaard SN, Transbol I, Mouridsen HT. Tamoxifen and bone metabolism in postmenopausal low-risk breast cancer patients: a randomized study. J Clin Oncol 1994;12:992-7.
43. Kenny AM, Prestwood KM, Pilbeam CC, Raisz LG. The short term effects of tamoxifen on bone turnover in older women. J Clin Endocrinol Metab 1995;80:3287-91.
44. Powles TJ, Hickish T, Kanis JA, Tidy A, Ashley S. Effect of tamoxifen on bone mineral density measured by dual-energy X-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 1996;14:78-84.
45. Draper MW, Flowers DE, Huster WJ, Neild JA, Harper KD, Arnaud C. A controlled trial of raloxifene (LY139481) HC1: impact on bone turnover and serum lipid profile in healthy postmenopausal women. J Bone Miner Res 1996;11:835-42.
46. Delmas PD, Bjarnason NH, Mitlak BH, Ravoux AC, Shah AS, Huster WJ, et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women. N Engl J Med 1997;337:1641-7.
47. Briancon D, Meunier PJ. Treatment of osteoporosis with fluoride, calcium, and vitamin D. Orthop Clin North Am 1981;12:629-48.
48. Hansson T, Roos B. The effect of fluoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study. Calcif Tissue Int 1987;40:315-7.
49. Farley SM, Libanati CR, Odvina CV, Smith L, Eliel L, Wakley GK, et al. Efficacy of long-term fluoride and calcium therapy in correcting the deficit of spinal bone density in osteoporosis. J Clin Epidemiol 1989;42:1067-74.
50. Heaney RP, Baylink DJ, Johnston CC, Melton III LJ, Meunier PJ, Murray TM, Nagant de Deuxchaisnes C. Fluoride therapy for the vertebral crush fracture syndrome. Ann Intern Med 1989;111:678-80.
51. Pak CYC, Sakhaee K, Zerwekh JE, Parcel C, Peterson R, Johnson K. Safe and effective treatment of osteoporosis with intermittent slow release sodium fluoride: augmentation of vertebral bone mass and inhibition of fractures. J Clin Endocrinol Metab 1989;68:150-9.
52. Riggs BL, Hodgson SF, O'Fallon WM, Chao EYS, Wahner HW, Muhs JM, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990;322:802-9.
53. Pouilles JM, Tremollières F, Causse E, Louvet JP, Ribot C. Fluoride therapy in postmenopausal osteopenic women: effect on vertebral and femoral bone density and prediction of bone response. Osteoporos Int 1991;1:103-9.
54. Rizzoli R, Chevalley T, Slosman DO, Bonjour JP. Sodium monofluorophosphate increases vertebral bone mineral density in patients with corticosteroid-induced osteoporosis. Osteoporos Int 1995;5:39-46.
55. Riggs BL, Seeman E, Hodgson SF, Taves DR, O'Fallon WM. Effect of the fluoride/calcium regimen on vertebral fracture occurrence in postmenopausal osteoporosis: comparison with conventional therapy. N Engl J Med 1982;306:446-50.
56. Mamelle N, Dusan R, Martin JL, Prost A, Meunier PJ, Guillaume M, et al. Risk-benefit ratio of sodium fluoride treatment in primary vertebral osteoporosis. Lancet 1988;II:361-5.
57. Heldund LR, Gallagher JC. Increased incidence of hip fracture in osteoporotic women treated with sodium fluoride. J Bone Miner Res 1989;4:223-5.
58. Melton III LJ. Fluoride in the prevention of osteoporosis and fractures. J Bone Miner Res 1990;5(Suppl 1):163-7.
59. Schnitzler CM, Wing JR, Gear KA, Robson HJ. Bone fragility of the peripheral skeleton during fluoride therapy for osteoporosis. Clin Orthop 1990;261:268-75.
60. Farley SM, Wergedal JE, Farley JR, Javier GN, Schulz EE, Talbot JR, et al. Spinal fractures during fluoride therapy for osteoporosis: relationship to spinal bone density. Osteoporos Int 1992;2:213-8.
61. Kleerekoper M, Mendlovic DB. Sodium fluoride therapy of postmenopausal osteoporosis. Endocr Rev 1993;14:312-23.
62. Kleerekoper M. Fluoride: the verdict is in, but the controversy lingers. J Bone Miner Res 1996;11:565-7.
63. Sogaard CH, Mosekilde L, Schwartz W, Leidig G, Minne HW, Ziegler R. Effects of fluoride on rat vertebral body biomechanical competence and bone mass. Bone 1995;16:163-9.
64. Lafage MH, Balena R, Battle MA, Shea M, Seedor JG, Klein H, et al. Comparison of alendronate and sodium fluoride effects on cancellous and cortical bone in minipigs. J Clin Invest 1995;95:2127-33.
65. Turner CH, Garetto LP, Dunipace AJ, Zhang W, Wilson ME, Grynpas MD, et al. Fluoride treatment increased serum IGF-1 and bone mass, but not bone strength, in rabbits. J Bone Miner Res 1996;11(Suppl 1):S349.
66. Grynpas MD, Hamilton E, Cheung R, Tsouderos Y, Deloffre P, Hott M, Marie PJ. Strontium increases vertebral bone volume in rats at a low dose that does not induce detectable mineralization defect. Bone 1996;18:253-9.
67. Gerster JC, Charhon SA, Jaeger P, Boivin G, Briancon D, Rostan A, et al. Bilateral fractures of femoral neck in patients with moderate renal failure receiving fluoride for spinal osteoporosis. BMJ 1983;287:723-5.
68. Turner CH, Owan I, Brizendine EJ, Zhang W, Wilson ME, Dunipace AJ. High fluoride intakes cause osteomalacia and diminished bone strength in rats with renal deficiency. Bone 1996;19:595-601.
69. Hefti E, Trechsel U, Bonjour JP, Fleisch H, Schenk R. Increase of whole-body calcium and skeletal mass in normal and osteoporotic adult rats treated with parathyroid hormone. Clin Sci 1982;62:389-96.
70. Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R. Anabolic actions of parathyroid hormone on bone. Endocr Rev 1993;14:690-709.
71. Li M, Wronski TJ. Response of femoral neck to estrogen depletion and parathyroid hormone in aged rats. Bone 1995;16:551-7.
72. Mitlak BH, Burdette-Miller P, Schoenfeld D, Neer RM. Sequential effects of chronic human PTH (1-84) treatment of estrogen-deficiency osteopenia in the rat. J Bone Miner Res 1996;11:430-9.
73. Podbesek R, Edouard C, Meunier PJ, Parsons JA, Reeve J, Stevenson RW, Zanelli JM. Effects of two treatment regimes with synthetic human parathyroid hormone fragment on bone formation and the tissue balance of trabecular bone in greyhounds. Endocrinology 1983;112:1000-6.
74. Delmas PD, Vergnaud P, Arlot ME, Pastoureau P, Meunier PJ. The in vivo anabolic effect of hPTH(1-34) is blunted when bone resorption is blocked by a bisphosphonate. J Bone Miner Res 1991;6:S136.
75. Reeve J, Meunier PJ, Parsons JA, Bernat M, Bijvoet OL, Courpron P, et al. Anabolic effect of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: a multicentre trial. BMJ 1980;280:1340-4.
76. Slovik DM, Rosenthal DI, Doppelt SH, Potts JT, Daly MA, Campbell JA, Neer RM. Restoration of spinal bone in osteoporotic men by treatment with human parathyroid hormone (1-34) and 1,25-dihydroxyvitamin D. J Bone Miner Res 1986;1:377-81.
77. Neer RM, Slovik DM, Daly M, Potts JT, Nussbaum SR. Treatment of postmenopausal osteoporosis with daily parathyroid hormone plus calcitriol. Osteoporos Int 1993;3:204-5.
78. Lindsay R, Nieves J, Formica C, Henneman E, Woelfert L, Shen V, Dempster D, Cosman F. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet 1997;350:550-5.
79. Oxlund H, Ejersted C, Andreassen TT, Torring O, Nilsson MH. Parathyroid hormone (1-34) and (1-84) stimulate cortical bone formation both from periosteum and endosteum. Calcif Tissue Int 1993;53:394-9.
80. Ejersted C, Andreassen TT, Oxlund H, Jorgensen PH, Bak B, Haggblad J, et al. Human parathyroid hormone (1-34) and (1-84) increase the mechanical strength and thickness of cortical bone in rats. J Bone Miner Res 1993;8:1097-101.
81. Meunier PJ, Slosman D, Delmas PD, Sebert JL, Albanese C, Brandi ML, et al. Strontium ranelate as a treatment of vertebral osteoporosis. J Bone Miner Res 1997:11:(Suppl 1):S129.
82. 81a. Kimmel DB. Animal models for in vivo experimentation in osteoporosis research. In: Marcus R, Feldman D, Kelsey J, editors. Osteoporosis. San Diego: Academic Press, 1996:671-90.
83. 81b. Geddes AD. Animal models of bone disease. In: Bilezkian JP, Raisz LG, Rodan GA, editors. Principles of bone biology. San Diego: Academic Press, 1996:1343-59.
84. Kalu DN, Liu CC, Hardin RR, Hollis BW. The aged rat model of ovarian hormone deficiency bone loss. Endocrinology 1989;124:7-16.
85. Kalu DN. The ovariectomized rat as a model of postmenopausal osteopenia. Bone Miner 1991;15:175-91.
86. Wronski TJ, Yen CF. The ovariectomized rat as an animal model for postmenopausal bone loss. Cells Mater 1991;Suppl 1:69-74.
87. Frost HM, Jee WSS. On the rat model of human osteopenias and osteoporoses. Bone Miner 1992;18:227-36.
88. Schnitzler CM, Ripamonti U, Mesquita JM. Bone histomorphometry in baboons in captivity. Bone 1993;14:383-7.
89. 86a. Erben RG. Trabecular and endocortical bone surfaces in the rat: modeling or remodeling? Anat Rec 1996;246:39-46.
90. Ammann P, Rizzoli R, Slosman D, Bonjour JP. Sequential and precise in vivo measurement of bone mineral density in rats using dual energy X-ray absorptiometry. J Bone Miner Res 1992;7:311-6.
91. Ammann P, Rizzoli R, Bonjour JP. Preclinical evaluation of new therapeutic agents for osteoporosis. In: Meunier PJ, editor. Osteoporosis: diagnosis and management. London: Marktin Dunitz, 1998:257-73.
92. Wronski TJ, Dann LM, Scott KS, Cintron M. Long-term effects of ovariectomy and aging on the rat skeleton. Calcif Tissue Int 1989;45:360:6.
93. Wronski TJ, Dann LM, Scott KS, Croobe LR. Endocrine and pharmacological suppressors of hone turnover protect against osteopenia in ovariectomized rats. Endocrinology 1989;125:810-6.
94. Wronski TJ, Dann LM, Horner SL. Time course of vertebral osteopenia in ovariectomized rats. Calcif Tissue Int 1990;46:101-10.
95. Jee WSS. The aged rat model for bone biology studies. Cells Mater 1991;Suppl 1:131-42.
96. Li XJ, Jee WSS, Ke HZ, Mori S, Akamine T. Age-related changes of cancellous and cortical bone histomorphometry in female Sprague-Dawley rats. Cells Mater 1991;Suppl 1:25-35.
97. Dempster DW, Li XF, Birchman R, Xu R, Shen V, Lindsay R. On the mechanism of cancellous bone loss in the ovariectomized rat. In: Cohn DV, Gennari C, Tashjian Jr AJ, editors. Calcium regulating hormones and bone metabolism. Amsterdam: Elsevier, 1992:460-4.
98. Shen V, Dempster DW, Birchman R, Xu R, Lindsay R. Loss of cancellous bone mass and connectivity in ovariectomized rats can be restored by combined treatment with parathyroid hormone and estradiol. J Clin Invest 1993;91:2479-87.
99. Jorgensen PH, Bak B, Andreassen TT. Mechanical properties and biochemical composition of rat cortical femur and tibia after long-term treatment with biosynthetic human growth hormone. Bone 1991;12:353-9.
100. Toolan BC, Shea M, Myers ER, Borchers RE, Seedor JG, Quartuccio H, Rodan G, Hayes WC. Effects of 4-amino-1-hydroxybutylidene bisphosphonate on bone biomechanics in rats. J Bone Miner Res 1992;7:1399-406.
101. Ammann P, Rizzoli R, Caverzasio J, Müller K, Slosman D, Bonjour JP. IGF-1 and pamidronate increase bone mineral density in ovariectomized adult rats. Am J Physiol 1993;265:770-6.
102. Ammann P, Rizzoli R, Caverzasio J, Shigematsu T, Slosman D, Bonjour JP. Effects of bisphosphonate tiludronate on bone resorption, calcium balance, and bone mineral density. J Bone Miner Res 1993;8:1491-8.
103. 99a. Dawson AB. The age order of epiphyseal union in the long bones of the albino rat. Anat Rec 1925;31:1-17.
104. Kimmel DB. Quantitative histological changes in the proximal tibia growth cartilage of aged female rats. Cells Mater 1991;Suppl 1:19-24.
105. Ringe JD. Hip fractures in men. Osteoporos Int 1986;6(Suppl 3):S48-51.
106. Beck TJ, Ruff CB, Scott WW, Plato CC, Tobin JD, Quan CA. Sex differences in geometry of the femoral neck with aging: a structural analysis of bone mineral data. Calcif Tissue Int 1992;50:24-9.
107. Garn SM, Rohmann CG, Wagner B, Ascoli W. Continuing bone growth throughout life: a general phenomenon. Am J Phys Anthrop 1967;26:313-8.
108. Saville PD. Changes in skeletal mass and fragility with castration in the rat: a model of osteoporosis. Am Geriatr Soc 1969;17:155-66.
109. Verhas M, Schoutens A, L'Hermite-Baleriaux M, Dounov N, Verschaeren A, Mone M, et al. The effect of orchidectomy on bone metabolism in aging rats. Calcif Tissue Int 1986;39:74-7.
110. Hock JM, Gera I, Fonseca J, Raisz LG. Human parathyroid hormone (1-34) increases bone mass in ovariectomized and orchidectomized rats. Endocrinology 1988;122:2899-904.
111. Danielsen CC, Mosekilde L, Andreassen TT. Long-term effect of orchidectomy on cortical bone from rat femur: bone mass and mechanical properties. Calcif Tissue Int 1992;50:169-74.
112. Vanderschueren D, Van Herck E, Suiker AMH, Visser WJ, Schot LPC, Bouillon R. Bone and mineral metabolism in aged male rats: short and long term effects of androgen deficiency. Endocrinology 1992;130:2906-16.
113. Vanderschueren D, Van Herck E, Schot P, Rush E, Einhorn T, Geusens P, et al. The aged male rat as a model for human osteoporosis: evaluation by nondestructive measurements and biomechanical testing. Calcif Tissue Int 1993;53:342-7.
114. Vanderschueren D, Jans I, Van Herck E, Moermans K, Verhaeghe J, Bouillon R. Time-related increase of biochemical markers of bone turnover in androgen-deficient male rats. Bone Miner 1994;26:123-31.
115. Kalu DN, Hardin RR, Cockerham R, Yu BP. Aging and dietary modulation of the rat skeleton and parathyroid hormone. Endocrinology 1988;115:1239-47.
116. Kalu DN, Masoro EJ, Yu BP, Hardin RR, Hollis BW. Modulation of age-related hyperparathyroidism and senile bone loss in Fisher rats by soy protein and food restriction. Endocrinology 1988;122:1847-54.
117. 112a. Ammann P, Rizzoli R, Bonjour JP. Protein malnutrition-induced bone loss is associated with alteration of the growth hormone-IGF-I axis and with estrogen deficiency in adult rats. Osteoporos Int 1998;8(Suppl 3):10.
118. Fleisch H, Russell RGG, Simpson B, Mühlbauer RC. Prevention by a diphosphonate of immobilization 'osteoporosis' in rats. Nature 1969;223:211-2.
119. Jee WSS, Wronski TJ, Morey ER, Kimmel DB. Effects of spaceflight on trabecular bone in rats. Am J Physiol 1983;244:R310-4.
120. Wronski TJ, Morey ER. Effects of spaceflight on periosteal bone formation in rats. Am J Physiol 1983;244:R305-9.
121. Globus RK, Bikle DD, Morey-Holton E. The temporal response of bone to unloading. Endocrinology 1986;118:733-42.
122. Zhang RW, Supowit SC, Klein GL, Lu ZF, Christensen MD, Lozano R, et al. Rat tail suspension reduces messenger RNA level for growth factors and osteopontin and decreases the osteoblastic differentiation of bone marrow stromal cells. J Bone Miner Res 1995;10:415-23.
123. Trechsel U, Fleisch H. effect of a retinoid on Ca and vitamin D metabolism in thyroparathyroidectomized (TPTX) rats. In: Vitamin D: a chemical, biochemical and clinical update. Berlin: Walter de Gruyter, 1985:51-2.
124. Stutzer A, Fleisch H, Trechsel U. Short- and long-term effects of a single dose of bisphosphonates on retinoid-induced bone resorption in thyroparathyroidectomized rats. Calcif Tissue Int 1988;43:294-9.
125. Ammann P, Rizzoli R, Fleisch H. Influence of the disaccharide lactitol on intestinal absorption and body retention of calcium in rats. J Nutr 1988;118:793-5.
126. Bourrin S, Palle S, Rupier R, Vico L, Alexandre C. Effects of physical training on bone adaptation in three zones of the rat tibia. J Bone Miner Res 1995;10:1745-52.
127. Weiss A, Arbell I, Steinhagen-Thiessen E, Silbermann M. Structural changes in aging bone: osteopenia in the proximal femurs of female mice. Bone 1991;12:165-72.
128. Ammann P, Rizzoli R, Bonjour JP, Bourrin S, Meyer JM, Vassalli P, et al. Transgenic mice expressing high levels of soluble tumor necrosis factor receptor-1 are protected against bone loss caused by estrogen deficiency. J Clin Invest 1997;99:1699-703.
129. Matsushita M, Tsuboyama T, Kasai R, Okumura H, Yamamuro T, Higuchi K, et al. Age-related changes in bone mass in the senescence-accelerated mouse (SAM). Am J Pathol 1986;125:276-83.
130. Kawase M, Tsuda M, Matsuo T. Accelerated bone resorption in senescence-accelerated mouse (SAM-P/6). J Bone Miner Res 1989;4:359-64.
131. Tsuboyama T, Takahashi K, Yamamuro T, Hosokawa M, Takeda T. Cross-mating study on bone mass in the spontaneously osteoporotic mouse (SAM-P/6). Bone Miner 1993;23:57-64.
132. Poli V, Balena E, Fattori E, Marakatos A, Yamamoto M, Tanaka H, et al. Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J 1994;13:1189-96.
133. Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, et al. Increased bone formation in osteocalcin-deficient mice. Nature 1996;382:448-52.
134. Vargas SJ, Naprta A, Glaccum M, Lee SK, Kalinowski J, Lorenzo JA. Interleukin-6 expression and histomorphometry of bones from mice deficient in receptors for interleukin-1 or tumor necrosis factor. J Bone Miner Res 1996;11:1736-44.
135. Erlebacher A, Derynck R. Increased expression of TGF-beta 2 in osteoblasts results in an osteoporosis-like phenotype. J Cell Biol 1996;132:195-210.
136. Amizuka N, Karaplis AC, Henderson JE, Washawsky H, Lipman ML, Matsuki Y, et al. Haploinsufficiency of parathyroid hormone-related peptide (PTHrP) results in abnormal postnatal bone development. Dev Biol 1996;175:166-76.
137. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (IGF-1) and type 1 IGF receptor (IGF1r). Cell 1993;75:59-72.
138. Bonad J, Jepsen KJ, Mansoura MK, Jaenisch R, Kuhn JL, Goldstein SA. A murine skeletal adaptation that significantly increases cortical bone mechanical properties. J Clin Invest 1993;92:1691-705.
139. Beamer WG, Donahue LR, Rosen CJ, Baylink DJ. Genetic variability in adult bone density among inbred strains of mice. Bone 1996;18:397-403.
140. Li XJ, Stevens ML, Mackey MS, Combs KS, Tressler DL, McOsker JE. The ferret: skeletal responses to treatment with PTH [abstract]. J Bone Miner Res 1994;9(Suppl 1):S258.
141. Mackey MS, Stevens ML, Ebert DC, Tressler DL, Combs KS, Lowry CK, et al. The ferret as a small animal model with BMU-based remodeling for skeletal research. Bone 1995;17:S191-6.
142. Karambolova KK, Snow GR, Anderson C. Differences in periosteal and corticoendosteal bone envelope activities in spayed and intact beagles: a histomorphometric study. Calcif Tissue Int 1985;41:665-8.
143. Malluche HH, Faugere MC, Rush M, Friedler R. Osteoblastic insufficiency is responsible for maintenance of osteopenia after loss of ovarian function in experimental beagle dogs. Endocrinology 1986;119:2649-54.
144. Snow GR, Anderson C. The effects of 17β-estradiol and progestagen on trabecular bone remodeling in oophorectomized dogs. Calcif Tissue Int 1986;39:198-205.
145. Dannucci GA, Martin RB, Patterson-Buckendahl P. Ovariectomy and trabecular bone remodeling in the dog. Calcif Tissue Int 1987;40:194-9.
146. Faugere MC, Fanti P, Friedler RM, Malluche HH. Bone changes occurring early after cessation of ovarian function in beagle dogs: a histomorphometric study employing sequential biopsies. J Bone Miner Res 1990;5:263-72.
147. Kimmel DB. The oophorectomized beagle as an experimental model for estrogen-depletion bone loss in the adult human. Cells Mater 1991; Suppl 1:75-84.
148. Shen V, Dempster DW, Birchman R, Mellish RWE, Church E, Kohn D, et al. Lack of changes in histomorphometric, bone mass, and biochemical parameters in ovariohysterectomized dogs. Bone 1992;13:311-6.
149. Motoie H, Nakamura T, O'uchi N, Nishikawa H, Kanoh H, Abe T, et al. Effects of the bisphosphonate YM175 on bone mineral density, strength, structure, and turnover in ovariectomized beagles on concomitant dietary calcium restriction. J Bone Miner Res 1995;10:910-20.
150. Mosekilde L, Kragstrup J, Richards A. Compressive strength, ash weight, and volume of vertebral trabecular bone in experimental fluorosis in pigs. Calcif Tissue Int 1987;40:318-22.
151. Mosekilde L, Weisbrode SE, Safron JA, Stills HF, Jankowsky ML, Ebert DC, et al. Calcium-restricted ovariectomized Sinclair S-1 minipigs: an animal model of osteopenia and trabecular plate perforation. Bone 1993;14:379-82.
152. Stevens ML, Sacco-Gibson N, Coombs KS, Lowry C, Li XJ. Evaluation of skeletal parameters in the Sinclair S-1 minipig: histomorphometric assessment of skeletal changes at 3 months post-ovariectomy [abstract]. J Bone Miner Res 1994;9:S258.
153. Fratzl P, Schreiber S, Roschger P, Lafage MH, Rodan G, Klaushofer K. Effects of sodium fluoride and alendronate on the bone mineral in minipigs: a small-angle x-ray scattering and back scattered electron imaging study. J Bone Miner Res 1996;11:248-53.
154. Chavassieux P, Pastoureau P, Boivin G, Chapuy MC, Delmas PD, Meunier PJ. Dose effects on ewe bone remodeling of short-term sodium fluoride administration: a histomorphometric and biochemical study. Bone 1991;12:421-7.
155. Chavassieux P, Pastoureau P, Boivin G, Chapuy MC, Delmas PD, Milhaud G, et al. Fluoride-induced bone changes in lambs during and after exposure to sodium fluoride. Osteoporos Int 1991;2:26-33.
156. Hornby SB, Ford SL, Mase CA, Evans GP. Skeletal changes in the ovariectomized ewe and subsequent response to treatment with 17β oestradiol. Bone 1995;17:S389-94.
157. Newman E, Turner AS, Wark JD. The potential of sheep for the study of osteopenia: current status and comparison with other animal models. Bone 1995;16:S277-84.
158. Turner AS, Mallinckrodt CH, Alvis MR, Bryant HU. Dual-energy X-ray absorptiometry in sheep: experiences with in vivo and ex vivo studies. Bone 1995;17:S381-8.
159. Turner AS, Alvis M, Myers W, Stevens ML, Lundy MW. Changes in bone mineral density and bone-specific alkaline phosphatase in ovariectomized ewes. Bone 1995;17:S395-402.
160. Hodgen GD, Goodman AL, O'Connor A, Johnson DK. Menopause in rhesus monkeys: model for study of disorders in the human climacteric. Am J Obstet Gynecol 1977;127:581-4.
161. Miller C, Weaver DS, McAlister JA, Koritnik DR. Effects of ovariectomy on vertebral trabecular bone in the cynomolgus monkey. Calcif Tissue Int 1986;38:62-5.
162. Pope NS, Gould KG, Anderson DC, Mann DR. Effects of age and sex on bone density in the rhesus monkey. Bone 1989;10:109-12.
163. Mann DR, Gould KG, Collins DC. A potential primate model for bone loss resulting from medical oophorectomy or menopause. J Lab Clin Med 1990;71:105-10.
164. Lundon KL, Grynpas M. The longterm effect of ovariectomy on the quality and quantity of cortical bone in the young cynomolgus monkey: comparison of density fractionation and histomorphometric techniques. Bone 1993;14:389-95.
165. Quarles LD. Prednisone-induced osteopenia in beagles: variable effects mediated by differential suppression of bone formation. Endocrinol Metab 1992;26:E136-41.
166. Deloffre P, Hans D, Rumelhart C, Mitton D, Tsouderos Y, Meunier PJ. Comparison between bone density and bone strength in glucocorticoid-treated aged ewes. Bone 1995;17:S409-14.
167. Hipp JA, Jansujwicz A, Simmons CA, Snyder BD. Trabecular bone morphology from micro-magnetic resonance imaging. J Bone Miner Res 1996;11:286-92.
168. Safadi M, Shapira D, Leichter I, Reznick A, Silbermann M. Ability of different techniques of measuring bone mass to determine vertebral bone loss in aging female rats. Calcif Tissue Int 1988;42:375-82.
169. Jayo MJ, Rankin SE, Weaver DS, Carlson CS, Clarkson TB. Accuracy and precision of lumbar bone mineral content by DPA in live female monkeys. Calcif Tissue Int 1991;49:438-40.
170. Ferretti JL. Perspectives of pQCT technology associated to biomechanical studies in skeletal research employing rat models. Bone 1995;17:S353-64.
171. Gasser JA. Assessing bone quantity by pQCT. Bone 1995;17:S145-54.
172. Ammann P, Rizzoli R, Meyer JM, Bonjour JP. Bone density and shape as determinants of bone strength in IGF-I and/or pamidronate-treated ovariectomized rats. Osteoporos Int 1996;6:219-27.
173. Schenk R, Merz WA, Mühlbauer R, Russell RG, Fleisch H. Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (C1 2 MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats. Calcif Tissue Res 1973;11:196-214.
174. Rüegsegger P, Koller B, Müller R. A microtomographic system for the nondestructive evaluation of bone architecture. Calcif Tissue Int 1996;58:24-9.
175. Amo C, Revilla M, Hernandez ER, Gonzalezriola J, Villa LF, Seco C, et al.
176. Parfitt AM. Stereologic basis of bone histomorphometry: theory of quantitative microscopy and reconstruction of the third dimension. In: Recker RR, editors. Bone histomorphometry: techniques and interpretation. Boca Raton: CRC Press, 1983:53-89.
177. Parfitt AM. Bone histomorphometry: standardization of nomenclature, symbols and units. J Bone Miner Res 1987;2:595-610.
178. Meunier PJ, Boivin G. Bone mineral density reflects bone mass but also degree of mineralization of bone: therapeutical implications. Bone 1997;21:373-7.
179. Grynpas M. Age and disease-related changes in the mineral of bone. Calcif Tissue Int 1993;53(Suppl 1):S57-64.
180. Einhorn TA. Bone strength: the bottom line. Calcif Tissue Int 1992;51:333-9.
181. Turner CH, Burr DB. Basic biomechanical measurements of bone: a tutorial. Bone 1993;14:595-608.
182. Granhed H, Johnson R, Hansson T. Mineral content and strength of lumbar vertebrae: a cadaver study. Acta Orthop Scand 1989;60:105-9.
183. Hayes WC, Gerhart TN. Biomechanics of bone: applications for assessment of bone strength. Bone Miner Res 1995;3:259-94.
184. Mosekilde L, Danielsen CC. Biomechanical competence of vertebral trabecular bone in relation to ash density and age in normal individuals. Bone 1987;8:79-85.
185. Lang SM, Moyle DD, Berg CEW, Detorie N, Gilpin AT, Pappas NJ, et al. Correlation of mechanical properties of vertebral trabecular bone with equivalent mineral density as measured by computed tomography. J Bone Joint Surg [Am] 1988;70:1531-8.
186. Kenedi RM. Textbook of biochemical engineering. Glasgow: Blackie, 1980:39-73.
187. Egger CD, Muhlbauer RC, Felix R, Delmas PD, Marks SC, Fleisch H. Evaluation of urinary pyridinium crosslink excretion as a marker of bone resorption in the rat. J Bone Miner Res 1994;9:1211-9.
188. Torjman C, Lhumeau A, Pastoureau P, Meunier F, Serkiz B, Volland JP, et al. Evaluation and comparison of urinary pyridinium crosslinks in two rat models of bone loss - ovariectomy and adjuvant polyarthritis - using a new automated HPLC method. Bone Miner 1994;26:155-67.
189. Pecile A, Netti C, Sibilia V, Villa I, Calori G, Tenni R, et al. Comparison between urinary pyridinium cross-links and hydroxylysine glycosides in monitoring the effects of ovariectomy and 17 beta-estrdiol replacement in aged rats. J Endocrinol 1996;150:383-90.
190. Claassen N, Potgieter HC, Seppa M, Vermaack WJH, Coetzer H, Vanpapendorp DH, et al. Supplemented gamma-linolenic acid and eicosapentaenoic acid influence bone status in young male rats: effects on free urinary collagen crosslinks, total urinary hydroxyproline, and bone calcium content. Bone 1995;16:S385-92.
191. Carter DR, Hayes WC. Bone compressive strength: The influence of density and strain rate. Science 1976;194:1174-6.
192. Bonnarens F, Einhorn TA. Production of a standard closed fracture in laboratory animal bone. J Orthop Res 1984;2:97-101.
193. Einhorn TA, Bonnarens F, Burstein AH. The contributions of dietary protein and mineral to the healing of experimental fractures: a biomechanical study. J Bone Joint Surg Am 1986;68:1389-95.
194. Friedman RJ, Parent T, Draughn RA. Production of a standard closed fracture in the rat tibia. J Orthop Trauma 1994;8:111-5.