Bone physiology, disease and treatment: Towards disease system analysis in osteoporosis

Clinical Pharmacokinetics

Volumn 49, Issue 2, 2010, Pages 89-118

  Post, Teun M ^a   Cremers, Serge C L M ^b   Kerbusch, Thomas ^a   Danhof, Meindert ^c  

^a Pharmacokinetics Pharmacodynamics and Pharmacometrics   (Netherlands)

^b Columbia University ^*  (United States)

^c LEIDEN UNIVERSITY   (Netherlands)

Author keywords

[No Author keywords available]

Indexed keywords

ACID PHOSPHATASE TARTRATE RESISTANT ISOENZYME; ALENDRONIC ACID; ALKALINE PHOSPHATASE BONE ISOENZYME; AMINO TERMINAL TELOPEPTIDE; BISPHOSPHONIC ACID DERIVATIVE; CALCITONIN; CALCIUM; CARBOXY TERMINAL TELOPEPTIDE; CATHEPSIN K; CATHEPSIN K INHIBITOR; CLODRONIC ACID; COLLAGEN; COLONY STIMULATING FACTOR 1; DENOSUMAB; DEOXYPYRIDINOLINE; FLUORIDE SODIUM; IBANDRONIC ACID; OSTEOCALCIN; OSTEOCLAST DIFFERENTIATION FACTOR; OSTEOPROTEGERIN; PARATHYROID HORMONE[1-34]; PROCOLLAGEN N PROTEINASE; PYRIDINOLINE; RECEPTOR ACTIVATOR OF NUCLEAR FACTOR KAPPA B; RISEDRONIC ACID; SELECTIVE ESTROGEN RECEPTOR MODULATOR; STRONTIUM RANELATE; VITAMIN D; ZOLEDRONIC ACID;

BONE; BONE CELL; BONE DENSITY; BONE GROWTH; BONE MATRIX; BONE REMODELING; BONE STRENGTH; BONE STRUCTURE; BONE TURNOVER; CALCIUM DEFICIENCY; COMPUTER ASSISTED TOMOGRAPHY; CORTICAL BONE; DIET SUPPLEMENTATION; DISEASE COURSE; DRUG EFFECT; DRUG MECHANISM; DUAL ENERGY X RAY ABSORPTIOMETRY; DYNAMICS; ECHOGRAPHY; FRACTURE; FRAGILITY FRACTURE; HOMEOSTASIS; HORMONE SUBSTITUTION; HUMAN; IDIOPATHIC OSTEOPOROSIS; JUVENILE OSTEOPOROSIS; MATHEMATICAL MODEL; MICRO-COMPUTED TOMOGRAPHY; OSSIFICATION; OSTEOBLAST; OSTEOCLAST; OSTEOLYSIS; OSTEOPOROSIS; PATHOPHYSIOLOGY; PHYSIOLOGY; POPULATION MODEL; POSTMENOPAUSE OSTEOPOROSIS; PREDICTION; PRIORITY JOURNAL; QUANTITATIVE ANALYSIS; REVIEW; RISK FACTOR; SECONDARY OSTEOPOROSIS; SENILE OSTEOPOROSIS; SIGNAL TRANSDUCTION; STATISTICAL MODEL; SYSTEM ANALYSIS; THEORY; THREE DIMENSIONAL IMAGING; TRABECULAR BONE; TREATMENT OUTCOME; VITAMIN D DEFICIENCY;

BIOLOGICAL MARKERS; BONE AND BONES; BONE DENSITY; BONE DENSITY CONSERVATION AGENTS; FRACTURES, BONE; HUMANS; MODELS, BIOLOGICAL; OSTEOPOROSIS; RANK LIGAND; RECEPTOR ACTIVATOR OF NUCLEAR FACTOR-KAPPA B; SIGNAL TRANSDUCTION; SYSTEMS ANALYSIS;

EID: 74249085991     PISSN: 03125963     EISSN: 11791926     Source Type: Journal    
DOI: 10.2165/11318150-000000000-00000     Document Type: Review

References (409)

1. Sambrook P, Cooper C. Osteoporosis. Lancet 2006; 367: 2010-2018.
2. Cummings SR, Bates D, Black DM. Clinical use of bone densitometry: sci-entific review. JAMA 2002; 288: 1889-1897 (Pubitemid 35168145)
3. Melton III LJ. The prevalence of osteoporosis: gender and racial comparison. Calcif Tissue Int 2001; 69: 179-181
4. WHO. Prevention and management of osteoporosis [technical report series no. 921]. Geneva: WHO, 2003 [online]. Available from URL: http:// whqlibdoc.who.int/trs/WHO-TRS-921.pdf [Accessed 2009 Nov 13]
5. van Geel AC, Geusens PP, Nagtzaam IF, et al. Timing and risk factors for clinical fractures among postmenopausal women:a5-year prospective study. BMC Med 2006; 4: 24
6. van Geel TA, Geusens PP, Nagtzaam IF, et al. Risk factors for clinical fractures among postmenopausal women: a 10-year prospective study. Menopause Int 2007; 13: 110-115
7. Kanis JA, Burlet N, Cooper C, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2008; 19: 399-428
8. Seeman E. Unmet needs in fracture prevention: new European guidelines for the investigation and registrationoftherapeutic agents. Osteoporos Int 2007; 18: 569-573
9. Post TM, Freijer JI, DeJongh J, et al. Disease system analysis: basic disease progression models in degenerative disease. Pharm Res 2005; 22: 1038-1049
10. Hadjidakis DJ, Androulakis II. Bone remodeling. Ann N Y Acad Sci 2006; 1092: 385-396
11. Leeming DJ, Alexandersen P, Karsdal MA, et al. An update on biomarkers of bone turnover and their utility in biomedical research and clinical practice. Eur J Clin Pharmacol 2006; 62: 781-792
12. Dogan E, Posaci C. Monitoring hormone replacement therapy by biochem-ical markers of bone metabolism in menopausal women. Postgrad Med J 2002; 78: 727-31 Compston JE. Sex steroids and bone. Physiol Rev 2001; 81: 419-47
13. Seeman E, Delmas PD. Bone quality: the material and structural basis of bone strength and fragility. N Engl J Med 2006; 354: 2250-2261
14. Seibel MJ, Robins SP, Bilezikian JP. Dynamics of bone and cartilage meta-bolism: principles and clinical applications. 2nd ed. San Diego (CA): Academic Press, 2006
15. Frost HM. The mechanostat: a proposed pathogenic mechanism of osteo-poroses and the bone mass effects of mechanical and nonmechanical agents. Bone Miner 1987; 2: 73-85
16. Frost HM. Skeletal structural adaptations to mechanical usage (SATMU): 1. Redefining Wolff's law: the bone modeling problem. Anat Rec 1990; 226: 403-413
17. Frost HM. Skeletal structural adaptations to mechanical usage (SATMU): 2. Redefining Wolff's law: the remodeling problem. Anat Rec 1990; 226: 414-422
18. Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest 2005; 115: 3318-3325
19. Weitzmann MN, Pacifici R. Estrogen deficiency and bone loss: an in-flammatory tale. J Clin Invest 2006; 116: 1186-1194
20. Rosen CJ. Pathogenesis of osteoporosis. Baillieres Best Pract Res Clin Endocrinol Metab 2000; 14: 181-193
21. Robling AG, Castillo AB, Turner CH. Biomechanical and molecular reg-ulation of bone remodeling. Annu Rev Biomed Eng 2006; 8: 455-498
22. Parfitt AM. Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. J Cell Biochem 1994; 55: 273-286
23. Hazenberg JG, Taylor D, Lee TC. The role of osteocytes and bone micro-structure in preventing osteoporotic fractures. Osteoporos Int 2007; 18: 1-8
24. Hernandez CJ, Beaupre GS, Carter DR. A model of mechanobiologic and metabolic influences onbone adaptation. J Rehabil Res Dev 2000; 37: 235-244
25. Watts NB. Clinical utility of biochemical markers of bone remodeling. Clin Chem 1999; 45: 1359-1368
26. Compston J. Local biosynthesis of sex steroids in bone. J Clin Endocrinol Metab 2002; 87: 5398-5400
27. Compston JE. Bone marrow and bone: a functional unit. J Endocrinol 2002; 173: 387-394
28. Eriksen EF, Eghbali-Fatourechi GZ, Khosla S. Remodeling and vascular spaces in bone. J Bone Miner Res 2007; 22: 1-6
29. Hofbauer LC, Kuhne CA, Viereck V. The OPG/RANKL/RANK system in metabolic bone diseases. J Musculoskelet Neuronal Interact 2004; 4: 268-275
30. Lerner UH. Bone remodeling in post-menopausal osteoporosis. J Dent Res 2006; 85: 584-595
31. Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev 2008; 29: 155-192
32. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003; 423: 337-342
33. Colotta F, Re F, Muzio M, et al. Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science 1993; 261: 472-475
34. Vega D, Maalouf NM, Sakhaee K. The role of receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications. J Clin Endocrinol Metab 2007; 92: 4514-4521
35. Tanaka S. Signaling axis in osteoclast biology and therapeutic targeting in the RANKL/RANK/OPG system. Am J Nephrol 2007; 27: 466-478
36. Rogers A, Eastell R. Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment. J Clin Endocrinol Metab 2005; 90: 6323-6331
37. Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology 2001; 142: 5050-5055
38. Jilka RL. Biology of the basic multicellular unit and the pathophysiology of osteoporosis. Med Pediatr Oncol 2003; 41: 182-185
39. Raisz LG. Physiology and pathophysiology of bone remodeling. Clin Chem 1999; 45: 1353-1358
40. Canalis E, Giustina A, Bilezikian JP. Mechanisms of anabolic therapies for osteoporosis. N Engl J Med 2007; 357: 905-916
41. Rubin MR, Bilezikian JP. The anabolic effects of parathyroid hormone therapy. Clin Geriatr Med 2003; 19: 415-432
42. Rubin MR, Cremers S, Dempster DW, et al. PTH increases bone turnover in hypoparathyroidism [abstract no. F485]. 30th Annual Meeting, American Society for Bone and Mineral Research; 2008 Sep 12-16; Montreal (QC) [online]. Available from URL: http://www.abstractsonline.com/viewer/ ?mkey={DCB70C83-5B38-431A- B0E1-9221D66718D0} [Accessed 2009 Nov 13]
43. Teitelbaum SL. Bone resorption by osteoclasts. Science 2000; 289: 1504-8
44. Zaidi M, Blair HC, Moonga BS, et al. Osteoclastogenesis, bone resorption, and osteoclast-based therapeutics. J Bone Miner Res 2003; 18: 599-609
45. Schoppet M, Preissner KT, Hofbauer LC. RANK ligand and osteoprote-gerin: paracrine regulators of bone metabolism and vascular function. Arterioscler Thromb Vasc Biol 2002; 22: 549-553
46. Sattler AM, Schoppet M, Schaefer JR, et al. Novel aspects on RANK ligand and osteoprotegerin in osteoporosis and vascular disease. Calcif Tissue Int 2004; 74: 103-106
47. Tanaka S, Nakamura I, Inoue J, et al. Signal transduction pathways reg-ulating osteoclast differentiation and function. J Bone Miner Metab 2003; 21: 123-133
48. Eastell R. Role of oestrogen in the regulation of bone turnover at the menarche. J Endocrinol 2005; 185: 223-234 (Pubitemid 40691789)
49. Hofbauer LC, Heufelder AE. Role of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in bone cell biology. JMol Med 2001; 79: 243-253
50. Hofbauer LC, Khosla S, Dunstan CR, et al. The roles of osteoprotegerin and osteoprotegerin ligand inthe paracrine regulation of bone resorption. J Bone Miner Res 2000; 15: 2-12
51. Hofbauer LC, Schoppet M. Clinical implications of the osteoproteger-in/RANKL/RANK system for bone and vascular diseases. JAMA 2004; 292: 490-495
52. Lemaire V, Tobin FL, Greller LD, et al. Modeling the interactions between osteoblast and osteoclast activities in bone remodeling. J Theor Biol 2004; 229: 293-309 [online]. Available from URL: http://www.sciencedirect.com/ science/journal/00225193 [Accessed 2009 Nov 17]
53. Peterson MC, Riggs MM. Calcium homeostasis and bone remodeling: devel-opment of an integrated model for evaluation and simulation of therapeutic responses to bone-related therapies [abstract no. 1218]. 16th Meeting, Population Approach Group in Europe; 2007 Jun 13-15; Copenhagen [online]. Available from URL: http://www.page-meeting.org/default.asp?abstract=1218 [Accessed 2009 Nov 13]
54. Turner CH. Homeostatic control of bone structure: an application of feed-back theory. Bone 1991; 12: 203-217
55. Turner CH. Toward a mathematical descriptionof bone biology: the principle of cellular accommodation. Calcif Tissue Int 1999; 65: 466-471
56. WHO. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis [technical report series no. 843]. Geneva: WHO, 1994
57. Seibel MJ. Biochemical markers of bone turnover: part I. Biochemistry and variability. Clin Biochem Rev 2005; 26: 97-122
58. Cremers S, Garnero P. Biochemical markers of bone turnover in the clinical development of drugs for osteoporosis and metastatic bone disease: potential uses and pitfalls. Drugs 2006; 66: 2031-2058
59. Henriksen K, Tanko LB, Qvist P, et al. Assessment of osteoclast number and function: application in the development of new and improved treatment modalities for bone diseases. Osteoporos Int 2007; 18: 681-685
60. Arlot M, Meunier PJ, Boivin G, et al. Differential effects of teriparatide and alendronate on bone remodeling in postmenopausal women assessed by histomorphometric parameters. J Bone Miner Res 2005; 20: 1244-1253
61. Charles P, Eriksen EF, Mosekilde L, et al. Bone turnover and balance evaluated by a combined calcium balance and 47calcium kinetic study and dynamic histomorphometry. Metabolism 1987; 36: 1118-1124
62. Eastell R, Delmas PD, Hodgson SF, et al. Bone formation rate in older normal women: concurrent assessment with bone histomorphometry, calcium kinetics, and biochemical markers. J Clin Endocrinol Metab 1988; 67: 741-748
63. Raposo JF, Sobrinho LG, Ferreira HG. A minimal mathematical model of calcium homeostasis. J Clin Endocrinol Metab 2002; 87: 4330-4340
64. Division of Metabolism and Endocrine Drug Products, US FDA. Guidelines for preclinical and clinical evaluation of agents used in the prevention or treatment of postmenopausal osteoporosis. Rockville (MD): FDA, 1994
65. Truscott JG, Simpson DS, Fordham JN. A suggested methodology for the construction of national bone densitometry reference ranges: 1372 Caucasian women from four UK sites. Br J Radiol 1997; 70: 1245-1251
66. Truscott JG. Reference data for ultrasonic bone measurement: variation with age in 2087 Caucasian women aged 16-93 years. Br J Radiol 1997; 70: 1010-1016
67. El-Maghraoui A, Achemlal L, Bezza A. Monitoring of dual-energy X-ray absorptiometry measurement in clinical practice. J Clin Densitom 2006; 9: 281-286
68. El-Maghraoui A, Do Santos Zounon AA, Jroundi I, et al. Reproducibility of bone mineral density measurements using dual X-ray absorptiometry in daily clinical practice. Osteoporos Int 2005; 16: 1742-1748
69. Louis O, Verlinde S, Thomas M, et al. Between-centre variability versus variability over time in DXA whole body measurements evaluated using a whole body phantom. Eur J Radiol 2006; 58: 431-434
70. Blank RD, Malone DG, Christian RC, et al. Patient variables impact lumbar spine dual energy X-ray absorptiometry precision. Osteoporos Int 2006; 17: 768-774
71. Shepherd JA, Lu Y, Wilson K, et al. Cross-calibration and minimum preci-sion standardsfor dual-energy X-ray absorptiometry: the 2005 ISCD official positions. J Clin Densitom 2006; 9: 31-36
72. Lodder MC, Lems WF, Ader HJ, et al. Reproducibility of bone mineral density measurement in daily practice. Ann Rheum Dis 2004; 63: 285-289
73. Wong JC, Griffiths MR. Precision of bone densitometry measurements: when is change true change and does it vary across bone density values? Australas Radiol 2003; 47: 236-239
74. Ravaud P, Reny JL, Giraudeau B, et al. Individual smallest detectable difference in bone mineral density measurements. J Bone Miner Res 1999; 14: 1449-1456
75. Sadatsafavi M, Moayyeri A, Wang L, et al. Heteroscedastic regression analysis of factors affecting BMD monitoring. J Bone Miner Res 2008; 23: 1842-1849
76. Seibel MJ. Biochemical markers of bone turnover: part II. Clinical applica-tions in the management of osteoporosis. Clin Biochem Rev 2006; 27: 123-138
77. Delmas PD, Eastell R, Garnero P, et al. The use of biochemical markers of bone turnover in osteoporosis. Committee of Scientific Advisors of the International Osteoporosis Foundation. Osteoporos Int 2000; 11 Suppl. 6: S2-17
78. Miller PD, Baran DT, Bilezikian JP, et al. Practical clinical application of biochemical markers of bone turnover: consensus of an expert panel. J Clin Densitom 1999; 2: 323-342
79. Eastell R, Mallinak N, Weiss S, et al. Biological variability of serum and urinary N-telopeptides of type I collagen in postmenopausal women. J Bone Miner Res 2000; 15: 594-598
80. Szulc P, Delmas PD. Biochemical markers of bone turnover: potential use in the investigation and management of postmenopausal osteoporosis. Osteoporos Int 2008; 19: 1683-1704
81. Garnero P. New biochemical markers of bone turnover. IBMS BoneKEy 2008 Mar; 5 (3): 84-102
82. Hannon R, Eastell R. Preanalytical variability of biochemical markers of bone turnover. Osteoporos Int 2000; 11 Suppl. 6: S30-44
83. Ebeling PR, Atley LM, Guthrie JR, et al. Bone turnover markers and bone density across the menopausal transition. J Clin Endocrinol Metab 1996; 81: 3366-3371
84. Garnero P, Mulleman D, Munoz F, et al. Long-term variability of markers of bone turnover in postmenopausal women and implications for their clinical use: the OFELY study. J Bone Miner Res 2003; 18: 1789-1794
85. Yang L, Grey V. Pediatric reference intervals for bone markers. Clin Biochem 2006; 39: 561-568
86. Woitge HW, Knothe A, Witte K, et al. Circaannual rhythms and interactions of vitamin D metabolites, parathyroid hormone, and biochemical markers of skeletal homeostasis: a prospective study. J Bone Miner Res 2000; 15: 2443-2450
87. Rapuri PB, Kinyamu HK, Gallagher JC, et al. Seasonal changes in calciotro-pic hormones, bone markers, and bone mineral density in elderly women. J Clin Endocrinol Metab 2002; 87: 2024-2032
88. Hamano T, Fujii N, Nagasawa Y, et al. Serum NTX is a practical marker for assessing antiresorptive therapy for glucocorticoid treated patients with chronic kidney disease. Bone 2006; 39: 1067-1072
89. Hannon R, Blumsohn A, Naylor K, et al. Response ofbiochemical markers of bone turnover to hormone replacement therapy: impact of biological variability. J Bone Miner Res 1998; 13: 1124-1133
90. Looker AC, Bauer DC, Chesnut III CH, et al. Clinical use of biochemical markers of bone remodeling: current status and future directions. Osteo-poros Int 2000; 11: 467-480
91. Delmas PD. Markers of bone turnover for monitoring treatment of osteo-porosis with antiresorptive drugs. Osteoporos Int 2000; 11 Suppl. 6: S66-76
92. Delmas PD, Hardy P, Garnero P, et al. Monitoring individual response to hormone replacement therapy with bone markers. Bone 2000; 26: 553-560
93. Saag K, Lindsay R, Kriegman A, et al. A single zoledronic acid infusion reduces bone resorption markers more rapidly than weekly oral alendronate in postmenopausal women with low bone mineral density. Bone 2007; 40: 1238-1243
94. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in post-menopausal women with low bone mineral density. N Engl J Med 2006; 354: 821-831
95. Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. J Clin Endocrinol Metab 2008; 93: 2149-2157
96. Lewiecki EM, Miller PD, McClung MR, et al. Two-year treatment with de-nosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J Bone Miner Res 2007; 22: 1832-1841
97. Miller PD, Bolognese MA, Lewiecki EM, et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: a randomized blinded phase 2 clinical trial. Bone 2008; 43: 222-229
98. Dobnig H, Sipos A, Jiang Y, et al. Early changes in biochemical markers of bone formation correlate with improvements in bone structure during teriparatide therapy. J Clin Endocrinol Metab 2005; 90: 3970-3977 (Pubitemid 41058159)
99. Grados F, Brazier M, Kamel S, et al. Prediction of bone mass density varia-tion by bone remodeling markers in postmenopausal women with vitamin D insufficiency treated with calcium and vitamin D supplementation. J Clin Endocrinol Metab 2003; 88: 5175-5179
100. Greenspan SL, Resnick NM, Parker RA. Early changes in biochemical markers of bone turnover are associated with long-term changes in bone mineral density in elderly women on alendronate, hormone replacement therapy, or combination therapy: a three-year, double-blind, placebo-controlled, randomized clinical trial. J Clin Endocrinol Metab 2005; 90: 2762-2767
101. Greenspan SL, Rosen HN, Parker RA. Early changes in serum N-telopeptide and C-telopeptide cross-linked collagen type 1 predict long-term response to alendronate therapy in elderly women. J Clin Endocrinol Metab 2000; 85: 3537-3540
102. Greenspan SL, Parker RA, Ferguson L, et al. Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: a randomized clinical trial. J Bone Miner Res 1998; 13: 1431-1438
103. Shoback D. Update in osteoporosis and metabolic bone disorders. J Clin Endocrinol Metab 2007; 92: 747-753
104. Seeman E. Bone quality: the material and structural basis of bone strength. J Bone Miner Metab 2008; 26: 1-8 (Pubitemid 350308006)
105. Riggs BL, Melton III LJ. Involutional osteoporosis. N Engl J Med 1986; 314: 1676-86
106. Riggs BL. Overview of osteoporosis. West J Med 1991; 154: 63-77
107. Arlot ME, Sornay-Rendu E, Garnero P, et al. Apparent pre-and post-menopausal bone loss evaluatedby DXA at different skeletal sites inwomen: the OFELY cohort. J Bone Miner Res 1997; 12: 683-690
108. Riggs BL. Endocrine causes of age-related bone loss and osteoporosis. Novartis Found Symp 2002; 242: 247-59; discussion 260-264
109. Recker R, Lappe J, Davies K, et al. Characterization of perimenopausal bone loss: a prospective study. J Bone Miner Res 2000; 15: 1965-1973
110. Recker R, Lappe J, Davies KM,et al. Bone remodeling increasessubstantially in the years after menopause and remains increased in older osteoporosis patients. J Bone Miner Res 2004; 19: 1628-1633
111. Becker C. Pathophysiology and clinical manifestations of osteoporosis. Clin Cornerstone 2006; 8: 19-27
112. Balasch J. Sex steroids and bone: current perspectives. Hum Reprod Update 2003; 9: 207-222
113. Riggs BL. Role of the vitamin D-endocrine system in the pathophysiology of postmenopausal osteoporosis. J Cell Biochem 2003; 88: 209-215
114. Garnero P, Delmas PD. Contribution of bone mineral density and bone turnover markers to the estimation of risk of osteoporotic fracture in post-menopausal women. J Musculoskelet Neuronal Interact 2004; 4: 50-63
115. Garnero P, Delmas PD. Noninvasive techniques for assessing skeletal changes in inflammatory arthritis: bone biomarkers. Curr Opin Rheumatol 2004; 16: 428-434
116. Garnero P, Delmas PD. Biochemical markers of bone turnover: applications for osteoporosis. Endocrinol Metab Clin North Am 1998; 27: 303-323
117. Garnero P. Biomarkers for osteoporosis management: utility in diagnosis, fracture risk prediction and therapy monitoring. Mol Diagn Ther 2008; 12: 157-170
118. Garnero P, Dargent-Molina P, Hans D, et al. Do markers of bone resorption add to bone mineral density and ultrasonographic heel measurement for the prediction of hip fracture in elderly women? The EPIDOS prospective study. Osteoporos Int 1998; 8: 563-569
119. Lips P, Hosking D, Lippuner K, et al. The prevalence of vitamin D inade-quacy amongst women with osteoporosis: an international epidemiological investigation. J Intern Med 2006; 260: 245-254
120. Rogers A, Saleh G, Hannon RA, et al. Circulating estradiol and osteopro-tegerin as determinants of bone turnover and bone density in postmeno-pausal women. J Clin Endocrinol Metab 2002; 87: 4470-4475
121. Zallone A. Direct and indirect estrogen actions on osteoblasts and osteoclasts. Ann N Y Acad Sci 2006; 1068: 173-179
122. Fitzpatrick LA. Estrogen therapy for postmenopausal osteoporosis. Arq Bras Endocrinol Metabol 2006; 50: 705-719
123. Ross PD, Knowlton W. Rapid bone loss is associated with increased levels of biochemical markers. J Bone Miner Res 1998; 13: 297-302
124. Reeve J, Walton J, Russell LJ, et al. Determinants of the first decade of bone loss after menopause at spine, hip and radius. QJM 1999; 92: 261-273
125. Finkelstein JS, Brockwell SE, Mehta V, et al. Bone mineral density changes during the menopause transition in a multiethnic cohort of women. J Clin Endocrinol Metab 2008; 93: 861-868
126. Greer W, Smith R, Shipman AJ. A multi-exponential model of postmeno-pausal decline in vertebral bone mineral density: a new approach to the BMD reference range. J Clin Densitom 2003; 6: 113-124
127. Riggs BL, Khosla S, Atkinson EJ, et al. Evidence that type I osteoporosis results from enhanced responsiveness of bone to estrogen deficiency. Osteo-poros Int 2003; 14: 728-733
128. Riggs BL, Khosla S, Melton III LJ, et al. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal womenand contributes to bone loss in aging men. J Bone Miner Res 1998; 13: 763-773
129. Gallagher JC. Effect of early menopause on bone mineral density and frac-tures. Menopause 2007; 14: 567-571
130. Chapurlat RD, Garnero P, Sornay-Rendu E, et al. Longitudinal study of bone loss in pre-and perimenopausal women: evidence for bone loss in perimenopausal women. Osteoporos Int 2000; 11: 493-498 (Pubitemid 30681646)
131. Pi YZ, Wu XP, Liu SP, et al. Age-related changes in bone biochemical mar-kers and their relationship with bone mineral density in normal Chinese women. J Bone Miner Metab 2006; 24: 380-385
132. Picard D, Imbach A, Couturier M, et al. Longitudinal study of bone density and its determinants in women in peri-or early menopause. Calcif Tissue Int 2000; 67: 356-360
133. Kanis JA, Johnell O, Oden A, et al. Ten-year risk of osteoporotic fracture and the effect of risk factors on screening strategies. Bone 2002; 30: 251-258
134. Kanis JA. Assessing the risk of vertebral osteoporosis. Singapore Med J 2002; 43: 100-105
135. Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteoporos Int 2005; 16: 581-589
136. Kanis JA, Oden A, Johnell O, et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int 2007; 18: 1033-1046
137. Kanis JA. Diagnosis of osteoporosis and assessment of fracture risk. Lancet 2002; 359: 1929-1936
138. Hansen MA, Overgaard K, Riis BJ, et al. Role of peak bone mass and bone loss in postmenopausal osteoporosis: 12 year study. BMJ 1991; 303: 961-964
139. Riis BJ, Hansen MA, Jensen AM, et al. Low bone mass and fast rate of bone loss at menopause: equal risk factors for future fracture: a 15-year follow-up study. Bone 1996; 19: 9-12
140. Chen YT, Miller PD, Barrett-Connor E, et al. An approach for identifying postmenopausal women age 50-64 years at increased short-term risk for osteoporotic fracture. Osteoporos Int 2007; 18: 1287-1296
141. WHO. Guidelines for preclinical evaluation and clinical trials in osteoporosis. Geneva: WHO, 1998 [online]. Available from URL: http://whqlibdoc. who.int/publications/1998/9241545224-eng.pdf [Accessed 2009 Nov 13]
142. International Osteoporosis Foundation. Health economics [online]. Available from URL: http://www.iofbonehealth.org/health-professionals/health- econo mics.html [Accessed 2009 Nov 19]
143. Ammann P, Rizzoli R. Bone strength and its determinants. Osteoporos Int 2003; 14 Suppl. 3: S13-8
144. Schoenau E, Land C, Stabrey A, et al. The bone mass concept: problems in short stature. Eur J Endocrinol 2004; 151 Suppl. 1: S87-91
145. Schoenau E, Saggese G, Peter F, et al. From bone biology to bone analysis. Horm Res 2004; 61: 257-269
146. Lu Y, Genant HK, Shepherd J, et al. Classification of osteoporosis based on bone mineral densities. J Bone Miner Res 2001; 16: 901-910
147. Singer A. Osteoporosis diagnosis and screening. Clin Cornerstone 2006; 8: 9-18
148. Kanis JA, Delmas P, Burckhardt P, et al. Guidelines for diagnosis and management of osteoporosis. The European Foundation for Osteoporosis and Bone Disease. Osteoporos Int 1997; 7: 390-406
149. Kanis JA, Black D, Cooper C, et al. A new approach to the development of assessment guidelines for osteoporosis. Osteoporos Int 2002; 13: 527-536
150. Binkley N, Kiebzak GM, Lewiecki EM, et al. Recalculation of the NHANES database SD improves T-score agreement and reduces osteoporosis prevalence. J Bone Miner Res 2005; 20: 195-201
151. Binkley N, Bilezikian JP, Kendler DL, et al. Official positions of the Inter-national Society for Clinical Densitometry and executive summary of the 2005 Position Development Conference. J Clin Densitom 2006; 9: 4-14 (Pubitemid 43775507)
152. Binkley NC, Schmeer P, Wasnich RD, et al. What are the criteria by which a densitometric diagnosis of osteoporosis can be made in males and non-Caucasians? J Clin Densitom 2002; 5 Suppl.: S19-27
153. Havill LM, Mahaney MC, Binkley L, et al. Effects of genes, sex, age, and activity on BMC, bone size, and areal and volumetric BMD. J Bone Miner Res 2007; 22: 737-746
154. Kiebzak GM, Binkley N, Lewiecki EM, et al. Diagnostic agreement at the total hip using different DXA systems and the NHANESIII database. J Clin Densitom 2007; 10: 132-137
155. Leib ES, Lewiecki EM, Binkley N, et al. Official positionsof the International Society for Clinical Densitometry. South Med J 2004; 97: 107-110 (Pubitemid 38112489)
156. Lofman O, Larsson L, Toss G. Bone mineral density in diagnosis of osteo-porosis: reference population, definition of peak bone mass, and measured site determine prevalence. J Clin Densitom 2000; 3: 177-186
157. Leib ES, Lenchik L, Bilezikian JP, et al. Position statements of the Interna-tional Society for Clinical Densitometry: methodology. J Clin Densitom 2002; 5 Suppl.: S5-10
158. Stone KL, SeeleyDG, Lui LY,et al. BMD atmultiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures. J Bone Miner Res 2003; 18: 1947-1954
159. Sievanen H, Kannus P, Jarvinen TL. Bone quality: an empty term. PLoS Med 2007; 4: e27
160. Hernandez CJ. How can bone turnover modify bone strength independent of bone mass? Bone 2008; 42: 1014-1020
161. Bouxsein ML. Mechanisms of osteoporosis therapy: a bone strength per-spective. Clin Cornerstone 2003; Suppl. 2: S13-21
162. Bouxsein ML. Bone quality: where do we go from here? Osteoporos Int 2003; 14 Suppl. 5: S118-27
163. Boivin G, Meunier PJ. Changes in bone remodeling rate influence the degree of mineralization of bone. Connect Tissue Res 2002; 43: 535-537
164. Compston J. Bone quality: what is it and how is it measured? Arq Bras Endocrinol Metabol 2006; 50: 579-585
165. Jarvinen TL, Kannus P, Sievanen H. Bone quality: emperor's new clothes. J Musculoskelet Neuronal Interact 2008; 8: 2-9
166. Cohen A, Recker RR, Dempster D, et al. Marked abnormalities in cortical and trabecular microarchitecture and strength in premenopausal women with idiopathic osteoporosis: a bone biopsy study [abstract no. M310]. 30th Annual Meeting, American Society for Bone and Mineral Research; 2008 Sep 12-16; Montreal (QC) [online]. Available from URL: http://www.ab stractsonline.com/ viewer/?mkey={DCB70C83-5B38-431A-B0E1-9221D66718 D0} [Accessed 2009 Nov 13]
167. Boutroy S, Van RB, Sornay-Rendu E, et al. Finite element analysis based on in vivo HR-pQCT images of the distal radiusis associated with wrist fracture in postmenopausal women. J Bone Miner Res 2008; 23: 392-399
168. Muller R. Long-term prediction of three-dimensional bone architecture in simulations of pre-, peri-and post-menopausal microstructural bone remodeling. Osteoporos Int 2005; 16 Suppl. 2: S25-35
169. Hernandez CJ, Keaveny TM. A biomechanical perspective on bone quality. Bone 2006; 39: 1173-1181
170. Ross PD. Predicting bone loss and fracture risk with biochemical markers: a review. J Clin Densitom 1999; 2: 285-294
171. Delmas PD. Treatment of postmenopausal osteoporosis. Lancet 2002; 359: 2018-2026
172. Delmas PD, Licata AA, Reginster JY, et al. Fracture risk reduction during treatment with teriparatide is independent of pretreatment bone turnover. Bone 2006; 39: 237-243
173. Bjarnason NH, Christiansen C. Early response in biochemical markers pre-dicts long-term response in bone mass during hormone replacement therapy in early postmenopausal women. Bone 2000; 26: 561-569 (Pubitemid 30301647)
174. Bjarnason NH, Sarkar S, Duong T, et al. Six and twelve month changes in bone turnover are related to reduction in vertebral fracture risk during 3 years of raloxifene treatment in postmenopausal osteoporosis. Osteoporos Int 2001; 12: 922-930
175. Bauer DC, Garnero P, Bilezikian JP, et al. Short-term changes in bone turnover markers and bone mineral density response to parathyroid hormone in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2006; 91: 1370-1375
176. Bauer DC, Garnero P, Hochberg MC, et al. Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the Fracture Intervention Trial. J Bone Miner Res 2006; 21: 292-299
177. Bauer DC, Black DM, Garnero P, et al. Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the Fracture Intervention Trial. J Bone Miner Res 2004; 19: 1250-1258
178. Bauer DC, Sklarin PM, Stone KL, et al. Biochemical markers of bone turnover and prediction of hip bone loss in older women: the study of osteoporotic fractures. J Bone Miner Res 1999; 14: 1404-1410
179. Riggs BL, Melton III LJ. Bone turnover matters: the raloxifene treatment paradox of dramatic decreases in vertebral fractures without commensurate increases in bone density. J Bone Miner Res 2002; 17: 11-14
180. Eastell R, Barton I, Hannon RA, et al. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res 2003; 18: 1051-1056
181. EastellR,Hannon RA. Biomarkersofbone health and osteoporosis risk. Proc Nutr Soc 2008; 67: 157-162
182. Reginster JY, Collette J, Neuprez A, et al. Role of biochemical markers of bone turnover as prognostic indicator of successful osteoporosis therapy. Bone 2008; 42: 832-836
183. Delmas PD, Vrijens B, Eastell R, et al. Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab 2007; 92: 1296-1304
184. Sornay-Rendu E, Garnero P, Munoz F, et al. Effect of withdrawal of hor-mone replacement therapy on bone mass and bone turnover: the OFELY study. Bone 2003; 33: 159-166
185. Sornay-Rendu E, Munoz F, Garnero P, et al. Identification of osteopenic women at high risk of fracture: the OFELY study. J Bone Miner Res 2005; 20: 1813-1819 (Pubitemid 41361882)
186. Boivin G, Meunier PJ. The degree of mineralization of bone tissue measured by computerized quantitative contact microradiography. Calcif Tissue Int 2002; 70: 503-511
187. Chavassieux P, Seeman E, Delmas PD. Insights into material and structural basis of bone fragility from diseases associated with fractures: how determinants of the biomechanical properties of bone are compromised by disease. Endocr Rev 2007; 28: 151-164
188. Recker RR, Weinstein RS, Chesnut III CH, et al. Histomorphometric evaluation of daily and intermittent oral ibandronate in women with postmenopausal osteoporosis: results from the BONE study. Osteoporos Int 2004; 15: 231-237
189. Zoehrer R, Roschger P, Paschalis EP, et al. Effects of 3-and 5-year treat-ment with risedronate on bone mineralization density distribution in triple biopsies of the iliac crest in postmenopausal women. J Bone Miner Res 2006; 21: 1106-12
190. Seeman E. Bone quality. Osteoporos Int 2003; 14 Suppl. 5: S3-7
191. Delmas PD, Seeman E. Changes in bone mineral density explain little of the reduction in vertebral or nonvertebral fracture risk with anti-resorptive therapy. Bone 2004; 34: 599-604
192. Sarkar S, Reginster JY, Crans GG, et al. Relationship between changes in biochemical markers of bone turnover and BMD to predict vertebral fracture risk. J Bone Miner Res 2004; 19: 394-401
193. Sarkar S, Mitlak BH, Wong M, et al. Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res 2002; 17: 1-10
194. Melton III LJ, Khosla S, Atkinson EJ, et al. Relationship of bone turnover to bone density and fractures. J Bone Miner Res 1997; 12: 1083-1091
195. Garnero P, Sornay-Rendu E, Duboeuf F, et al. Markers of bone turnover predict postmenopausal forearm bone loss over 4 years: the OFELY study. J Bone Miner Res 1999; 14: 1614-1621
196. Greenspan SL, Bone HG, Ettinger MP, et al. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med 2007; 146: 326-339
197. Greenspan SL, Emkey RD, Bone HG, et al. Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 2002; 137: 875-883
198. Greenspan SL, Harris ST, Bone H, et al. Bisphosphonates: safety and efficacy in the treatment and prevention of osteoporosis. Am Fam Physician 2000; 61: 2731-2736
199. Hochberg MC, Greenspan S, Wasnich RD, et al. Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents. J Clin Endocrinol Metab 2002; 87: 1586-1592
200. Iki M, Morita A, Ikeda Y, et al. Biochemical markers of bone turnover may predict progression to osteoporosis in osteopenic women: the JPOS cohort study. J Bone Miner Metab 2007; 25: 122-129
201. Iki M,Morita A, Ikeda Y, et al. Biochemical markersof bone turnover predict bone loss in perimenopausal women but not in postmenopausal women: the Japanese Population-based Osteoporosis (JPOS) cohort study. Osteoporos Int 2006; 17: 1086-1095
202. Johnell O, Oden A, De LaetC, et al. Biochemical indices of bone turnover and the assessment of fracture probability. Osteoporos Int 2002; 13: 523-526
203. Lenora J, Ivaska KK, Obrant KJ, et al. Prediction of bone loss using bio-chemical markers of bone turnover. Osteoporos Int 2007; 18: 1297-1305
204. Lofman O, Magnusson P, Toss G, et al. Common biochemical markers of bone turnover predict future bone loss: a 5-year follow-up study. Clin Chim Acta 2005; 356: 67-75
205. Lukaszkiewicz J, Karczmarewics E, Marowska J, et al. Bone turnover rate in postmenopausal women: bimodal distribution? J Clin Densitom 2001; 4: 343-352
206. Marcus R, Holloway L, Wells B, et al. The relationship of biochemical markers of bone turnover to bone density changes in postmenopausal women: results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial. J Bone Miner Res 1999; 14: 1583-1595
207. McClung MR, San MJ, Miller PD, et al. Opposite bone remodeling effects of teriparatide and alendronateinincreasing bone mass. Arch Intern Med 2005; 165: 1762-1768
208. Rogers A, Hannon RA, Eastell R. Biochemical markers as predictors of rates of bone loss after menopause. J Bone Miner Res 2000; 15: 1398-1404
209. Watts NB, Cooper C, Lindsay R, et al. Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk. J Clin Densitom 2004; 7: 255-261
210. Rosenbrock H, Seifert-Klauss V, Kaspar S, et al. Changes of biochemical bone markers during the menopausal transition. Clin Chem Lab Med 2002; 40: 143-151
211. Garnero P, Hausherr E, Chapuy MC, et al. Markers of bone resorption predict hip fracture in elderly women: the EPIDOS prospective study. J Bone Miner Res 1996; 11: 1531-1538
212. Garnero P, Sornay-Rendu E, Claustrat B, et al. Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study. J Bone Miner Res 2000; 15: 1526-1536
213. Eastell R, Delmas PD. How to interpret surrogate markers of efficacy in osteoporosis. J Bone Miner Res 2005; 20: 1261-1262
214. Committee For Medicinal Products For Human Use, European Medicines Agency. Note for guidance on postmenopausal osteoporosis in women [doc. ref. CPMP/EWP/552/95 Rev. 1]. London: European Medicines Agency, 2001
215. Committee For Medicinal Products For Human Use, European Medicines Agency. Draft guideline on the evaluation of new medicinal products in the treatment of primary osteoporosis [doc. ref. CPMP/EWP/552/95 Rev. 2]. London: European Medicines Agency; 2005 Dec 14 [online]. Available from URL:http://www.emea.europa.eu/pdfs/human/ewp/055295en.pdf [Accessed 2009 Nov 13]
216. Kanis JA, Torgerson D, Cooper C. Comparison of the European and USA practice guidelines for osteoporosis. Trends Endocrinol Metab 2000; 11: 28-32
217. Miller PD, McClung MR, Macovei L, et al. Monthly oral ibandronate ther-apy in postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone Miner Res 2005; 20: 1315-1322
218. Miller PD, Epstein S, Sedarati F, et al. Once-monthly oral ibandronate compared with weekly oral alendronate in postmenopausal osteoporosis: results from the head-to-head MOTION study. Curr Med Res Opin 2008; 24: 207-213
219. Miller PD. Optimizing the management of postmenopausal osteoporosis with bisphosphonates: the emerging role of intermittent therapy. Clin Ther 2005; 27: 361-376
220. Pyon EY. Once-monthly ibandronate for postmenopausal osteoporosis: re-view of a new dosing regimen. Clin Ther 2006; 28: 475-490
221. Chesnut III CH, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004; 19: 1241-1249
222. Delmas PD, Recker RR, Chesnut III CH, et al. Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Osteoporos Int 2004; 15: 792-798
223. Reginster JY, Adami S, Lakatos P, et al. Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the MOBILE study. Ann Rheum Dis 2006; 65: 654-661
224. Reginster JY, Felsenberg D, Cooper C, et al. A new concept for bisphos-phonate therapy: a rationale for the development of monthly oral dosing of ibandronate. Osteoporos Int 2006; 17: 159-166
225. Reginster JY, Gieschke R. Clinical utility of a pharmacostatistical model for ibandronate in postmenopausal osteoporosis. Curr Drug Metab 2006; 7: 827-836
226. Reginster JY, Wilson KM, Dumont E, et al. Monthly oral ibandronate is well tolerated and efficacious in postmenopausal women: results from the Monthly Oral Pilot Study. J Clin Endocrinol Metab 2005; 90: 5018-5024
227. Recker RR, Delmas PD, Halse J, et al. Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure. J Bone Miner Res 2008; 23: 6-16
228. Reid IR, Brown JP, Burckhardt P, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 2002; 346: 653-661 (Pubitemid 34815869)
229. Cremers SC, Pillai G, Papapoulos SE. Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis. Clin Pharmacokinet 2005; 44: 551-570
230. Close P, Neuprez A, Reginster JY. Developments in the pharmacotherapeutic management of osteoporosis. Expert Opin Pharmacother 2006; 7: 1603-1615
231. Stoch SA, Wagner JA. Cathepsin K inhibitors: a novel target for osteoporosis therapy. Clin Pharmacol Ther 2008; 83: 172-176 [online]. Available from URL: http://www.nature.com/clpt [Accessed 2009 Nov 17]
232. Rosen CJ. Clinical practice: postmenopausal osteoporosis. N Engl J Med 2005; 353: 595-603
233. Riggs BL, Parfitt AM. Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling. J Bone Miner Res 2005; 20: 177-184
234. Parfitt AM. Morphologic basis of bone mineral measurements: transient and steady state effects of treatment in osteoporosis. Mineral Electrolyte Metab 1980; 4: 273-287
235. Eastell R. Treatment of postmenopausal osteoporosis. N Engl J Med 1998; 338: 736-746
236. Bilezikian JP. Combination anabolic and antiresorptive therapy for osteo-porosis: opening the anabolic window. Curr Osteoporos Rep 2008; 6: 24-30
237. Borges JL, Bilezikian JP. Update on osteoporosis therapy. Arq Bras Endocrinol Metabol 2006; 50: 755-763
238. Bone HG, Hosking D, Devogelaer JP, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 2004; 350: 1189-1199
239. Delmas PD. The use of bisphosphonates in the treatment of osteoporosis. Curr Opin Rheumatol 2005; 17: 462-466
240. Bauss F, Schimmer RC. Ibandronate: the first once-monthly oral bisphos-phonate for treatment of postmenopausal osteoporosis. Ther Clin Risk Manag 2006; 2: 3-18
241. Chapurlat RD, Delmas PD. Drug insight: bisphosphonates for post-menopausal osteoporosis. Nat Clin Pract Endocrinol Metab 2006; 2: 211-219
242. Chapurlat RD. Clinical pharmacology of potent new bisphosphonates for postmenopausal osteoporosis. Treat Endocrinol 2005; 4: 115-125
243. Colon-Emeric CS. Ten vs five years of bisphosphonate treatment for post-menopausal osteoporosis: enough of a good thing. JAMA 2006; 296: 2968-2969
244. Cramer JA, Gold DT, Silverman SL, et al. A systematic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos Int 2007; 18: 1023-1031
245. McClung M. Bisphosphonates. Arq Bras Endocrinol Metabol 2006; 50: 735-744
246. McClung M. Use of highly potent bisphosphonates in the treatment of os-teoporosis. Curr Osteoporos Rep 2003; 1: 116-122
247. Ravn P. Bisphosphonates for prevention of postmenopausal osteoporosis. Dan Med Bull 2002; 49: 1-18
248. Rodan GA, Reszka AA. Osteoporosis and bisphosphonates. J Bone Joint Surg Am 2003; 85-A Suppl. 3: 8-12
249. Russell RG, Watts NB, Ebetino FH, et al. Mechanisms of action of bisphos-phonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 2008; 19: 733-759
250. Delmas PD. HRT in the prevention and treatment of osteoporosis. J Epide-miol Biostat 1999; 4: 155-160
251. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004; 291: 1701-1712
252. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288: 321-333
253. Stepan JJ, Alenfeld F, Boivin G, et al. Mechanisms of action of antiresorptive therapies of postmenopausal osteoporosis. Endocr Regul 2003; 37: 225-238
254. Bjarnason NH, Byrjalsen I, Hassager C, et al. Low doses of estradiol in combination with gestodene to prevent early postmenopausal bone loss. Am J Obstet Gynecol 2000; 183: 550-560
255. Boivin G, Vedi S, Purdie DW, et al. Influence of estrogen therapy at con-ventional and high doses on the degree of mineralization of iliac bone tissue: a quantitative microradiographic analysis in postmenopausal women. Bone 2005; 36: 562-567
256. Bots ML, Evans GW, Riley W, et al. The effect of tibolone and continuous combined conjugated equine oestrogens plus medroxyprogesterone acetate on progression of carotid intima-media thickness: the Osteoporosis Prevention and Arterial effects oftiboLone (OPAL) study. Eur Heart J 2006; 27: 746-755
257. Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA 2003; 290: 1729-1738
258. Chen Z, Bassford T, Green SB, et al. Postmenopausal hormone therapy and body composition: a substudy of the estrogen plus progestin trial of the Women's Health Initiative. Am J Clin Nutr 2005; 82: 651-656
259. Chesnut III CH, Bell NH, Clark GS, et al. Hormone replacement therapy in postmenopausal women: urinary N-telopeptide of type I collagen monitors therapeutic effect and predicts response of bone mineral density. Am J Med 1997; 102: 29-37
260. de Valk-de Roo GW, Netelenbos JC, Peters-Muller IR, et al. Continuously combined hormone replacement therapy and bone turnover: the influence of dydrogesterone dose, smoking and initial degree ofbone turnover. Maturitas 1997; 28: 153-162
261. Ettinger B. Rationale for use of lower estrogen doses for postmenopausal hormone therapy. Maturitas 2007; 57: 81-84
262. Gambacciani M, Cappagli B, Ciaponi M, et al. Ultra low-dose hormone replacement therapy and bone protection in postmenopausal women. Maturitas 2008; 59: 2-6
263. Gambacciani M, Ciaponi M, Cappagli B, et al. Effects of low-dose, con-tinuous combined hormone replacement therapy on sleep in symptomatic postmenopausal women. Maturitas 2005; 50: 91-97
264. Hammar M, Christau S, Nathorst-Boos J, et al. A double-blind, randomised trial comparing the effects of tibolone and continuous combined hormone replacement therapy in postmenopausal women with menopausal symptoms. Br J Obstet Gynaecol 1998; 105: 904-911
265. Harris ST, Eriksen EF, Davidson M,et al. Effect of combined risedronate and hormone replacement therapies on bone mineral density in postmenopausal women. J Clin Endocrinol Metab 2001; 86: 1890-1897
266. Jackson RD, Shidham S. The role of hormone therapy and calcium plus vitamin D for reduction of bone loss and risk for fractures: lessons learned from the Women's Health Initiative. Curr Osteoporos Rep 2007; 5: 153-159
267. Jackson RD, Wactawski-Wende J, LaCroix AZ, et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the Women's Health Initiative randomized trial. J Bone Miner Res 2006; 21: 817-28
268. Jerome CP. Hormonal therapies and osteoporosis. ILAR J 2004; 45: 170-8
269. Nielsen TF, Ravn P, Bagger YZ, et al. Pulsed estrogen therapy in preven-tion of postmenopausal osteoporosis: a 2-year randomized, double blind, placebo-controlled study. Osteoporos Int 2004; 15: 168-174
270. Paschalis EP, Boskey AL, Kassem M, et al. Effect of hormone replacement therapy on bone quality in early postmenopausal women. J Bone Miner Res 2003; 18: 955-959
271. Prestwood KM, Kenny AM, UnsonC, et al. The effectof low dose micronized 17ss-estradiol on bone turnover, sex hormone levels, and side effects in older women: a randomized, double blind, placebo-controlled study. J Clin Endocrinol Metab 2000; 85: 4462-4469
272. Raisz LG, Wiita B, Artis A, et al. Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption in postmenopausal women. J Clin Endocrinol Metab 1996; 81: 37-43
273. Bagger YZ, Tanko LB, Alexandersen P, et al. Two to three years of hormone replacement treatment in healthy women have long-term preventive effects on bone mass and osteoporotic fractures: the PERF study. Bone 2004; 34: 728-735
274. Delmas PD, Ensrud KE, Adachi JD, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab 2002; 87: 3609-3617
275. Chapurlat RD, Blackwell T, Bauer DC, et al. Changes in biochemical markers of bone turnover in women treated with raloxifene: influence of regression to the mean. Osteoporos Int 2001; 12: 1006-1014
276. Delmas PD, Davis SR, Hensen J, et al. Effects of tibolone and raloxifene on bone mineral density in osteopenic postmenopausal women. Osteoporos Int 2008; 19: 1153-1160
277. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999; 282: 637-645
278. Hamdy RC, Chesnut III CH, Gass ML, et al. Review of treatment modalities for postmenopausal osteoporosis. South Med J 2005; 98: 1000-1014
279. Johnell O, Kanis JA, Black DM, et al. Associations between baseline risk factors and vertebral fracture risk in the Multiple Outcomes of Raloxifene Evaluation (MORE) study. J Bone Miner Res 2004; 19: 764-772
280. Morii H, Ohashi Y, Taketani Y, et al. Effect of raloxifene on bone mineral density and biochemical markers of bone turnover in Japanese postmeno-pausal women with osteoporosis: results from a randomized placebo-controlled trial. Osteoporos Int 2003; 14: 793-800
281. Neele SJ, Evertz R, De Valk-De Roo RG, et al. Effectof1year of discontinua-tionof raloxifeneor estrogen therapyonbone mineral density after 5 years of treatment in healthy postmenopausal women. Bone 2002; 30: 599-603
282. Prestwood KM, Gunness M, Muchmore DB, et al. A comparison of the effects of raloxifene and estrogen on bone in postmenopausal women. J Clin Endocrinol Metab 2000; 85: 2197-2202
283. Seeman E, Crans GG, Diez-Perez A, et al. Anti-vertebral fracture efficacy of raloxifene: a meta-analysis. Osteoporos Int 2006; 17: 313-316
284. Beardsworth SA, Kearney CE, Purdie DW. Prevention of postmenopausal bone loss at lumbar spine and upper femur with tibolone: a two-year randomised controlled trial. Br J Obstet Gynaecol 1999; 106: 678-683
285. BerningB,Bennink HJ, Fauser BC. Tibolone and its effects on bone: areview. Climacteric 2001; 4: 120-136
286. Berning B, van KC, Kuiper JW, et al. Increased loss of trabecular but not cortical bone density, 1 year after discontinuation of 2 years hormone replacement therapy with tibolone. Maturitas 1999; 31: 151-159
287. Berning B, Kuijk CV, Kuiper JW, et al. Effects of two doses of tibolone on trabecular and cortical bone loss in early postmenopausal women: a two-year randomized, placebo-controlled study. Bone 1996; 19: 395-399
288. Bjarnason NH, Bjarnason K, Haarbo J, et al. Tibolone: prevention of bone loss in late postmenopausal women. J Clin Endocrinol Metab 1996; 81: 2419-2422
289. Bots ML, Evans GW, Riley W, et al. The Osteoporosis Prevention and Arterial effects of tiboLone (OPAL) study: design and baseline characteristics. Control Clin Trials 2003; 24: 752-775
290. Gallagher JC, Baylink DJ, Freeman R, et al. Prevention of bone loss with tibolone in postmenopausal women: results of two randomized, double-blind, placebo-controlled, dose-finding studies. J Clin Endocrinol Metab 2001; 86: 4717-4726
291. Lippuner K, Haenggi W, Birkhaeuser MH, et al. Prevention of postmeno-pausal bone loss using tibolone or conventional peroral or transdermal hormone replacement therapy with 17beta-estradiol and dydrogesterone. J Bone Miner Res 1997; 12: 806-812
292. Modelska K, Cummings S. Tibolone for postmenopausal women: systematic review of randomized trials. J Clin Endocrinol Metab 2002; 87: 16-23
293. Prelevic GM, Markou A, Arnold A, et al. The effect of tibolone on bone mineral density in postmenopausal women with osteopenia or osteoporosis: 8 years follow-up. Maturitas 2004; 47: 229-234
294. Prelevic GM, Bartram C, Wood J, et al. Comparative effects on bone mineral density of tibolone, transdermal estrogen and oral estrogen/progestogen therapy in postmenopausal women. Gynecol Endocrinol 1996; 10: 413-420
295. Rymer J, Robinson J, Fogelman I. Ten years of treatment with tibolone 2.5mg daily: effects on bone loss in postmenopausal women. Climacteric 2002; 5: 390-398
296. Rymer J, Robinson J, Fogelman I. Effects of 8 years of treatment with tibolone 2.5mg daily on postmenopausal bone loss. Osteoporos Int 2001; 12: 478-483
297. Rymer J, Chapman MG, Fogelman I. Effect of tibolone on postmenopausal bone loss. Osteoporos Int 1994; 4: 314-319
298. Swegle JM, Kelly MW. Tibolone: a unique version of hormone replacement therapy. Ann Pharmacother 2004; 38: 874-881
299. Cummings SR, Ettinger B, Delmas PD, et al. The effects of tibolone in older postmenopausal women. N Engl J Med 2008; 359: 697-708
300. Adami S, Passeri M, Ortolani S, et al. Effects of oral alendronate and intranasal salmon calcitonin on bone mass and biochemical markers of bone turnover in postmenopausal women with osteoporosis. Bone 1995; 17: 383-390
301. Adami S, Baroni MC, Broggini M, et al. Treatment of postmenopausal osteoporosis with continuous daily oral alendronate in comparison with either placebo or intranasal salmon calcitonin. Osteoporos Int 1993;3 Suppl. 3: S21-7
302. Bagger YZ, Tanko LB, Alexandersen P, et al. Oral salmon calcitonin induced suppression of urinary collagen type II degradation in postmenopausal women: a new potential treatment of osteoarthritis. Bone 2005; 37: 425-430
303. Chesnut III CH, Majumdar S, Newitt DC, et al. Effects of salmon calcitonin on trabecular microarchitecture as determined by magnetic resonance imaging: results from the QUEST study. J Bone Miner Res 2005; 20: 1548-1561
304. Chesnut III CH, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group. Am J Med 2000; 109: 267-76
305. Silverman SL. Calcitonin. Endocrinol Metab Clin North Am 2003; 32: 273-84
306. Tanko LB, Bagger YZ, Alexandersen P, et al. Safety and efficacy of a novel salmon calcitonin (sCT) technology-based oral formulation in healthy postmenopausal women: acute and 3-month effects on biomarkers of bone turnover. J Bone Miner Res 2004; 19: 1531-1538
307. Ettinger B,San MJ, Crans G,et al. Differential effects of teriparatide onBMD after treatment with raloxifene or alendronate. J Bone Miner Res 2004; 19: 745-751
308. Bilezikian JP, Rubin MR. Combination/sequential therapies for anabolic and antiresorptive skelet al agents for osteoporosis. Curr Osteoporos Rep 2006; 4: 5-13
309. Boonen S, Marin F, Obermayer-Pietsch B, et al. Effects of previous anti-resorptive therapy on the bone mineral density response to two years of teriparatide treatment in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2008; 93: 852-860
310. Bilezikian JP, Rubin MR, Finkelstein JS. Parathyroid hormone as an ana-bolic therapy for women and men. J Endocrinol Invest 2005; 28: 41-49
311. Bradbeer JN, Arlot ME, Meunier PJ, et al. Treatment of osteoporosis with parathyroid peptide (hPTH 1-34) and oestrogen: increase in volumetric density ofiliac cancellous bone may depend onreduced trabecular spacing as wellas increased thickness of packets of newly formed bone. Clin Endocrinol (Oxf) 1992; 37: 282-289
312. Chen P, Satterwhite JH, Licata AA, et al. Early changes in biochemical markers of bone formation predict BMD response to teriparatide in post-menopausal women with osteoporosis. J Bone Miner Res 2005; 20: 962-970
313. Chen P, Miller PD, Delmas PD, et al. Change in lumbar spine BMD and vertebral fracture risk reduction in teriparatide-treated postmenopausal women with osteoporosis. J Bone Miner Res 2006; 21: 1785-1790
314. Finkelstein JS, Leder BZ, Burnett SM, et al. Effects of teriparatide, alen-dronate, or both on bone turnover in osteoporotic men. J Clin Endocrinol Metab 2006; 91: 2882-2887
315. Neer RM, Arnaud CD, ZanchettaJR,et al.Effectofparathyroid hormone(1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001; 344: 1434-1441
316. Tashjian Jr AH, Gagel RF. Teriparatide [human PTH(1-34)]: 2.5 years of experience on the use and safety of the drug for the treatment of osteoporosis. J Bone Miner Res 2006; 21: 354-365
317. Lane NE, Kelman A. A review of anabolic therapies for osteoporosis. Arthritis Res Ther 2003; 5: 214-222
318. Marie PJ. Strontium ranelate: a dual mode of action rebalancing bone turn-over in favour of bone formation. Curr Opin Rheumatol 2006; 18 Suppl. 1: S11-5
319. Marie PJ. Strontium ranelate: a physiological approach for optimizing bone formation and resorption. Bone 2006; 38: S10-4
320. Marie PJ. Strontium as therapy for osteoporosis. Curr Opin Pharmacol 2005; 5: 633-636
321. Marie PJ. Strontium ranelate: a novel mode of action optimizing bone for-mation and resorption. Osteoporos Int 2005; 16 Suppl. 1: S7-10
322. Meunier PJ, Slosman DO, Delmas PD, et al. Strontium ranelate: dose-dependent effects in established postmenopausal vertebral osteoporosis: a 2-year randomized placebo controlled trial. J Clin Endocrinol Metab 2002; 87: 2060-2066
323. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med 2004; 350: 459-468 (Pubitemid 38133766)
324. Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab 2005; 90: 2816-2822
325. Reginster JY, Felsenberg D, Boonen S, et al. Effects of long-term strontium ranelate treatment on the risk of nonvertebral and vertebral fractures in postmenopausal osteoporosis: results of a five-year, randomized, placebo-controlled trial. Arthritis Rheum 2008; 58: 1687-1695
326. Khosla S, Westendorf JJ, Oursler MJ. Building bone to reverse osteoporosis and repair fractures. J Clin Invest 2008; 118: 421-428
327. Ebeling PR, Wark JD, Yeung S, et al. Effects of calcitriol or calcium on bone mineral density, bone turnover, and fractures in men with primary osteoporosis: a two-year randomized, double blind, double placebo study. J Clin Endocrinol Metab 2001; 86: 4098-4103
328. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supple-mentation and the risk of fractures. N Engl J Med 2006; 354: 669-683 (Pubitemid 43247138)
329. Prestwood KM, Pannullo AM, Kenny AM, et al. The effect of a short course of calcium and vitamin D on bone turnover in older women. Osteoporos Int 1996; 6: 314-319
330. Scopacasa F, Need AG, Horowitz M, et al. Effects of dose and timing of calcium supplementation on bone resorption in early menopausal women. Horm Metab Res 2002; 34: 44-47
331. Storm D, Eslin R, Porter ES, et al. Calcium supplementation prevents sea-sonal bone loss and changes in biochemical markers of bone turnover in elderly New England women: a randomized placebo-controlled trial. J Clin Endocrinol Metab 1998; 83: 3817-3825
332. Wishart JM, Scopacasa F, Horowitz M, et al. Effect of perimenopause on calcium absorption: a longitudinal study. Climacteric 2000; 3: 102-108
333. Dawson-HughesB, Harris SS, Krall EA, et al. Effectofwithdrawal of calcium and vitamin D supplements on bone mass in elderly men and women. Am J Clin Nutr 2000; 72: 745-750
334. Dawson-Hughes B, Harris SS, Krall EA, et al. Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older. N Engl J Med 1997; 337: 670-676
335. Garnero P,Munoz F, Sornay-Rendu E, et al. Associations of vitamin D status with bone mineral density, bone turnover, bone loss and fracture risk in healthy postmenopausal women: the OFELY study. Bone 2007; 40: 716-722
336. Heikkinen AM, Parviainen M, Niskanen L, et al. Biochemical bone markers and bone mineral density during postmenopausal hormone replacement therapy with and without vitamin D3: a prospective, controlled, randomized study. J Clin Endocrinol Metab 1997; 82: 2476-2482
337. Jesudason D, Need AG, Horowitz M, et al. Relationship between serum 25-hydroxyvitamin D and bone resorption markers in vitamin D insufficiency. Bone 2002; 31: 626-630
338. Komulainen M, Tuppurainen MT, Kroger H, et al. Vitamin D and HRT: no benefit additional to that of HRT alone in prevention of bone loss in early postmenopausal women. A 2.5-year randomized placebo-controlled study. Osteoporos Int 1997; 7: 126-132
339. Lips P. Relative value of 25(OH)D and 1,25(OH)2D measurements. J Bone Miner Res 2007; 22: 1668-1671
340. Murphy S, Khaw KT, Prentice A, et al. Relationships between parathyroid hormone, 25-hydroxyvitamin D, and bone mineral density in elderly men. Age Ageing 1993; 22: 198-204
341. Dawson-Hughes B, Chen P, Krege JH. Response to teriparatide in patients with baseline 25-hydroxyvitamin D insufficiency or sufficiency. J Clin Endocrinol Metab 2007; 92: 4630-4636
342. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment ofpostmenopausal osteoporosis. N EnglJMed 2007; 356: 1809-1822
343. Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 2003; 349: 1207-1215
344. Cosman F, Nieves J, Zion M, et al. Daily and cyclic parathyroid hormone in women receiving alendronate. N Engl J Med 2005; 353: 566-575
345. Wasnich RD, Bagger YZ, Hosking DJ, et al. Changes in bone density and turnover after alendronate or estrogen withdrawal. Menopause 2004; 11: 622-630
346. Bagger YZ, Tanko LB, Alexandersen P, et al. Alendronate has a residual effect on bone mass in postmenopausal Danish women up to 7 years after treatment withdrawal. Bone 2003; 33: 301-307
347. Tremollieres FA, Pouilles JM, Ribot C. Withdrawal of hormone replacement therapy is associated with significant vertebral bone loss in postmenopausal women. Osteoporos Int 2001; 12: 385-390
348. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stop-ping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-Term Extension (FLEX): a randomized trial. JAMA 2006; 296: 2927-2938
349. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996; 348: 1535-1541
350. Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab 2000; 85: 4118-4124
351. Ensrud KE, Barrett-Connor EL, Schwartz A, et al. Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial Long-Term Extension. J Bone Miner Res 2004; 19: 1259-69
352. Martin RB. Toward a unifying theory of bone remodeling. Bone 2000; 26: 1-6
353. van der Linden JC, Verhaar JA, Pols HA, et al. A simulation model at tra-becular level to predict effects of antiresorptive treatment after menopause. Calcif Tissue Int 2003; 73: 537-544
354. Hernandez CJ, Gupta A, Keaveny TM. A biomechanical analysis of the effects of resorption cavities on cancellous bone strength. J Bone Miner Res 2006; 21: 1248-1255
355. Martin MJ, Buckland-Wright JC. A novel mathematical model identifies potential factors regulating bone apposition. Calcif Tissue Int 2005; 77: 250-260
356. Martin MJ, Buckland-Wright JC. Sensitivity analysisof a novel mathematical model identifies factors determining bone resorption rates. Bone 2004; 35: 918-928
357. Pioletti DP, Rakotomanana LR. Can the increase of bone mineral density following bisphosphonates treatments be explained by biomechanical considerations? Clin Biomech (Bristol, Avon) 2004; 19: 170-174
358. Ruffoni D, Fratzl P, Roschger P, et al. The bone mineralization density distribution as a fingerprint of the mineralization process. Bone 2007; 40: 1308-1319
359. Hernandez CJ, Hazelwood SJ, Martin RB. The relationship between basic multicellular unit activation and origination in cancellous bone. Bone 1999; 25: 585-587
360. Hernandez CJ, Beaupre GS, Marcus R, et al. A theoretical analysis of the contributions of remodeling space, mineralization, and bone balance to changes in bone mineral density during alendronate treatment. Bone 2001; 29: 511-516
361. Hernandez CJ, Beaupre GS, Marcus R, et al. Long-term predictions of the therapeutic equivalence of daily and less than daily alendronate dosing. J Bone Miner Res 2002; 17: 1662-1666
362. Hernandez CJ, Beaupre GS, Carter DR. A theoretical analysis of the relative influences of peak BMD, age-related bone loss and menopause on the development of osteoporosis. Osteoporos Int 2003; 14: 843-847
363. Beaupre GS, Orr TE, Carter DR. An approach for time-dependent bone modeling and remodeling-application: a preliminary remodeling simulation. J Orthop Res 1990; 8: 662-670
364. Hazelwood SJ, Bruce MR, Rashid MM, et al. A mechanistic model for in-ternal bone remodeling exhibits different dynamic responses in disuse and overload. J Biomech 2001; 34: 299-308
365. Fleming DE, Chettle DR, Webber CE, et al. The O'Flaherty model of lead kinetics: an evaluation using data from a lead smelter population. Toxicol Appl Pharmacol 1999; 161: 100-109
366. O'Flaherty EJ. A physiologically based kinetic model for lead in children and adults. Environ Health Perspect 1998; 106 Suppl. 6: 1495-1503
367. Moroz A, Crane MC, Smith G, et al. Phenomenological model of bone remodeling cycle containing osteocyte regulation loop. Biosystems 2006; 84: 183-190
368. Moroz A, Wimpenny DI. Allosteric control model of bone remodelling containing periodical modes. Biophys Chem 2007; 127: 194-212 (Pubitemid 46441625)
369. Wimpenny DI, Moroz A. On allosteric control model of bone turnover cycle containing osteocyte regulation loop. Biosystems 2007; 90: 295-308
370. Komarova SV, Smith RJ, Dixon SJ, et al. Mathematical model predicts a critical role for osteoclast autocrine regulation in the control of bone remodeling. Bone 2003; 33: 206-215
371. Komarova SV. Mathematical model of paracrine interactions between os-teoclasts and osteoblasts predicts anabolic action of parathyroid hormone on bone. Endocrinology 2005; 146: 3589-3595
372. Komarova SV. Bone remodeling in health and disease: lessons from mathe-matical modeling. Ann N Y Acad Sci 2006; 1068: 557-559
373. Rattanakul C,Lenbury Y, Krishnamara N, et al. Modelingof bone formation and resorption mediated by parathyroid hormone: response to estrogen/PTH therapy. Biosystems 2003; 70: 55-72
374. Stepan JJ. Prediction of bone loss in postmenopausal women. Osteoporos Int 2000; 11 Suppl. 6: S45-54
375. Garnero P, Darte C, Delmas PD. A model to monitor the efficacy of alen-dronate treatment in women with osteoporosis using a biochemical marker of bone turnover. Bone 1999; 24: 603-609
376. EastellR,Hannon RA, Garnero P,et al. Relationship of early changesinbone resorption to the reduction in fracture risk with risedronate: review of statistical analysis. J Bone Miner Res 2007; 22: 1656-1660
377. Melsen F, Mosekilde L. Tetracycline double-labeling of iliac trabecular bone in 41 normal adults. Calcif Tissue Res 1978; 26: 99-102
378. Melsen F, Melsen B, Mosekilde L, et al. Histomorphometric analysis of normal bone from the iliac crest. Acta Pathol Microbiol Scand A 1978; 86: 70-81
379. Mosekilde L, Melsen F. Effect of antithyroid treatment on calcium-phos-phorus metabolism in hyperthyroidism: II. Bone histomorphometry. Acta Endocrinol (Copenh) 1978; 87: 751-758
380. Mosekilde L, Melsen F. A tetracycline-based histomorphometric evaluation of bone resorption and bone turnover in hyperthyroidism and hyperpara- thyroidism. Acta Med Scand 1978; 204: 97-102
381. Deacon AC, Hulme P, Hesp R, et al. Estimation of whole body bone re-sorption rate: a comparison of urinary total hydroxyproline excretion with two radioisotopic tracer methods in osteoporosis. Clin Chim Acta 1987; 166: 297-306
382. Reeve J, Arlot ME, Chavassieux PM, et al. The assessment of bone formation and bone resorption in osteoporosis: a comparison between tetracycline-based iliac histomorphometry and whole body 85Sr kinetics. J Bone Miner Res 1987; 2: 479-489
383. Eastell R, Riggs BL. Calcium homeostasis and osteoporosis. Endocrinol Metab Clin North Am 1987; 16: 829-842
384. Frost ML, Fogelman I, Blake GM, et al. Dissociation between global markers of bone formation and direct measurement of spinal bone formation in osteoporosis. J Bone Miner Res 2004; 19: 1797-1804
385. Sheiner LB, Steimer JL. Pharmacokinetic/pharmacodynamic modeling in drug development. Annu Rev Pharmacol Toxicol 2000; 40: 67-95
386. Sheiner LB, Ludden TM. Population pharmacokinetics/dynamics. Annu Rev Pharmacol Toxicol 1992; 32: 185-209
387. Breimer DD, Danhof M. Relevance of the application of pharmacokinetic-pharmacodynamic modelling concepts in drug development: the 'wooden shoe' paradigm. Clin Pharmacokinet 1997; 32: 259-267
388. Danhof M, de Lange EC, la Pasqua OE, et al. Mechanism-based pharma-cokinetic-pharmacodynamic (PK-PD) modeling in translational drug research. Trends Pharmacol Sci 2008; 29: 186-191
389. Holford N, Nutt JG. Disease progression, drug action and Parkinson's dis-ease: why time cannot be ignored. Eur J Clin Pharmacol 2008; 64: 207-216
390. Holford NH, Sheiner LB. Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 1981; 6: 429-453
391. Pillai G, Gieschke R, Goggin T, et al. A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis. Br J Clin Pharmacol 2004; 58: 618-631
392. Holford N, Pillai G, Kamel S, et al. PKPD model for cathepsin K inhibition with balicatib and changes in bone turnover biomarkers, in particular NTx [abstract no. 1015]. 15th Meeting, Population Approach Group in Europe; 2006 Jun 14-16; Bruges [online]. Available from URL: http://www.page-meeting. org/default.asp?abstract=1015 [Accessed 2009 Nov 13]
393. Cremers S, Sparidans R, den HJ, et al. A pharmacokinetic and pharmaco-dynamic model for intravenous bisphosphonate (pamidronate) in osteoporosis. Eur J Clin Pharmacol 2002; 57: 883-890
394. Cremers SC, Papapoulos SE, Gelderblom H, et al. Skelet al retention of bisphos-phonate (pamidronate) and its relation to the rate of bone resorption in patients with breast cancer and bone metastases. J Bone Miner Res 2005; 20: 1543-1547
395. Zierhut ML, Peterson MC, Gastonguay MR, et al. Development and evaluation of a population PK/PD model for Fc-OPG in healthy postmenopausal women [abstract no. 483]. 15th Meeting, Population Approach Group in Europe; 2004 Jun 17-18; Uppsala [online]. Available from URL: http://www.page-meet ing.org/default.asp?abstract = 483 [Accessed 2009 Nov 13]
396. Girard P, Claret L, Ebling W, et al. Evaluation of an osteoporosis biomarker model for simulation using posterior predictive check technique [abstract no. 460]. 12th Meeting, Population Approach Group in Europe; 2003 Jun 12-13; Verona [online]. Available from URL: http://www.page-meeting.org/default. asp?abstract = 460 [Accessed 2009 Nov 13]
397. Gieschke R, Pillai G, Goggin T, et al. Population PD and clinical trial simulation: investigating oral dosing regimens for a new bisphosphonate drug for treatment of osteoporosis [abstract no. 198]. 10th Meeting, Population Approach Group in Europe; 2001 Jun 7-8; Basel [online]. Available from URL: http://www.page-meeting.org/default.asp?abstract= 198 [Accessed 2009 Nov 13]
398. Earp JC, Dubois DC, Molano DS, et al. Modeling corticosteroid effects in a rat model of rheumatoid arthritis I: mechanistic disease progression model for the time course of collagen-induced arthritis in Lewis rats. J Pharmacol Exp Ther 2008; 326: 532-545
399. Zierhut ML, Gastonguay MR, Martin SW, et al. Population PK-PD model for Fc-osteoprotegerin in healthy postmenopausal women. J Pharmacokinet Pharmacodyn 2008; 35: 379-399
400. Garnett C, Holford N. Bone mineral density progression to dropout and time-to-fracture: application to postmenopausal women taking hormone replacement therapy [abstract]. 5th International Symposium on Measurement and Kinetics of In Vivo Drug Effects; 2006 Apr 26-29; Leiden
401. Holford NHG, Baathe S, Karlsson M. Auckland bones and summer sun [ab-stract no. 231]. 10th Meeting, Population Approach Group in Europe; 2001 Jun 7-8; Basel [online]. Available from URL: http://www.page-meeting.org/default. asp?abstract=231 [Accessed 2009 Nov 13]
402. Defranoux NA, Stokes CL, Young DL, et al. In silico modeling and simu-lation of bone biology: a proposal. J Bone Miner Res 2005; 20: 1079-84
403. NONMEM® users' guides. Ellicott City (MD): Icon Development Solutions, 1989 Chan PL, Holford NH. Drug treatment effects on disease progression. Annu Rev Pharmacol Toxicol 2001; 41: 625-659
404. Bhattaram VA, Bonapace C, Chilukuri DM, et al. Impact of pharmacometric reviews on new drug approval and labeling decisions:asurvey of 31 new drug applications submitted between 2005 and 2006. Clin Pharmacol Ther 2007; 81: 213-221
405. Lalonde RL, Kowalski KG, Hutmacher MM, et al. Model-based drug de-velopment. Clin Pharmacol Ther 2007; 82: 21-32
406. Miller R, Ewy W, Corrigan BW, et al. How modeling and simulation have enhanced decision making in new drug development. J Pharmacokinet Pharmacodyn 2005; 32: 185-197
407. Gieschke R, Steimer JL. Pharmacometrics: modelling and simulation tools to improve decision making in clinical drug development. Eur J Drug Metab Pharmacokinet 2000; 25: 49-58
408. Steimer JL, Holford NHG, Kaila N, et al. Population PK model of balicatib, a cathepsin K inhibitor, and a PKPD model for changes in rapid and slow bone biomarkers [abstract]. Pharmacokinetics UK; 2006 Nov 15-17; Sheffield [online]. Available from URL: http://www.pkuk.org.uk/ContentImages/PKUK20 06ABSTRACTS.pdf [Accessed 2009 Nov 13]
409. Peterson MC, Riggs MM. A physiologically based mathematical model of in-tegrated calcium homeostasis and bone remodeling. Bone. Epub 2009 Sep 2