• 1
    Gerend M, Erchull M, Aiken L, Maner J. Reasons and risk: factors underlying women's perceptions of susceptibility to osteoporosis. Maturitas 2006; 55(3):227237.
  • 2
    Delmas P. Treatment of postmenopausal osteoporosis. Lancet 2002; 359(9322):20182026.
  • 3
    Rubin M, Bilezikian J. New anabolic therapies in osteoporosis. Current Opinion in Rheumatology 2002; 14(4):433440.
  • 4
    Black D, Greenspan S, Ensrud K, Palermo L, McGowan J, Lang T, Garnero P, Bouxsein M, Bilezikian J, Rosen C. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. New England Journal of Medicine 2003; 349(13):12071215.
  • 5
    Amgen Inc., 2011. Available from: [Accessed 29 July 2013].
  • 6
    Boyce B, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Archives of Biochemistry and Biophysics 2008; 473(2):139146.
  • 7
    Martin R, Burr D, Sharkey N. Skeletal Tissue Mechanics. Springer Verlag: New York, USA, 1998.
  • 8
    Bekker P, Holloway D, Rasmussen A, Murphy R, Martin S, Leese P, Holmes G, Dunstan C, DePaoli A. A single-dose placebo-controlled study of AMG 162, a fully human monclonal antibody to RANKL, in postmenopausal women. Journal of Bone and Mineral Research 2004; 19(7):10591066.
  • 9
    McClung M, Lewiecki E, Cohen S, Bolognese M, Woodson G, Moffett A, Peacock M, Miller P, Lederman S, Chesnut C, et al. Denosumab in postmenopausal women with low bone mineral density. New England Journal of Medicine 2006; 354(8):821831.
  • 10
    Body JJ, Facon T, Coleman R, Lipton A, Geurs F, Fan M, Holloway D, Peterson M, Bekker P. A study of the biological receptor activator of nuclear factor- κB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clinical Cancer Research 2006; 12(4):12211228.
  • 11
    Lewiecki E, Miller P, McClung M, Cohen S, Bolognese M, Liu Y, Wang A, Siddhanti S, Fitzpatrick L. Two-year treatment with denosumab (AMG162) in a randomized phase 2 study of postmenopausal women with low BMD. Journal of Bone and Mineral Research 2007; 22(12):18321841.
  • 12
    Ellis G, Bone H, Chlebowski R, Paul D, Spadafora S, Smith J, Fan M, Jun S. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. Journal of Clinical Oncology 2008; 26(30):48754882.
  • 13
    U.S. Food and Drug Administration, 2011. Available from: [Accessed 29 July 2013].
  • 14
    Holford N, Kimko H, Monteleone J, Peck C. Simulation of clinical trials. Annual Review of Pharmacology and Toxicology 2000; 40:209234.
  • 15
    Mould D, Sweeney K. The pharmacokinetics and pharmacodynamics of monoclonal antibodies – mechanistic modeling applied to drug development. Current Opinion in Drug Discovery and Development 2007; 10(1):8496.
  • 16
    Post T, Cremers S, Kerbusch T, Danhof M. Bone physiology, disease and treatment – towards disease system analysis in osteoporosis. Clinical Pharmacokinetics 2010; 49(2):89118.
  • 17
    Sheiner L. Learning versus confirming in clinical drug development. Clinical Pharmacology and Therapeutics 1997; 61(3):275291.
  • 18
    Sharma A, Jusko W. Characterization of four basic models of indirect pharmacodynamic responses. Journal of Pharmacokinetics and Biopharmaceutics 1996; 24(6):611635.
  • 19
    Post T, Freijer J, DeJongh J, Danhof M. Disease system analysis: basic disease progression models in degenerative disease. Pharmaceutical Research 2005; 22(7):10381049.
  • 20
    Marathe A, Peterson M, Mager D. Integrated cellular bone homeostasis model for denosumab pharmacodynamics in multiple myeloma patients. Journal of Pharmacology and Experimental Therapeutics 2008; 326(2):555562.
  • 21
    Pivonka P, Zimak J, Smith D, Gardiner B, Dunstan C, Sims N, Martin T, Mundy G. Theoretical investigation of the role of the RANK-RANKL-OPG system in bone remodeling. Journal of Theoretical Biology 2010; 262(2):306316.
  • 22
    Peterson M, Riggs M. Predicting nonlinear changes in bone mineral density over time using a multscale systems pharmacology model. Pharmacometrics & Systems Pharmacology 2012; 1:18.
  • 23
    Robling A, Castillo A, Turner C. Biomechanical and molecular regulation of bone remodeling. Annual Review of Biomedical Engineering 2006; 8:455498.
  • 24
    Scheiner S, Pivonka P, Hellmich C. Coupling systems biology with multiscale mechanics, for computer simulations of bone remodeling. Computer Methods in Applied Mechanics and Engineering 2013; 254:181196.
  • 25
    Shargel L, Wu-Pong S, Yu A. Applied Biopharmaceutics & Pharmacokinetics, 5th ed. McGraw-Hill: New York, USA, 2005.
  • 26
    Lewiecki E. Treatment of osteoporosis with denosumab. Maturitas 2010; 66(2):182186.
  • 27
    Murray J. Mathematical Biology – I: An Introduction, 3rd ed. Springer Science and Business Media, Inc.: Berlin, Germany, 2002.
  • 28
    Schwefel HP. Numerische Optimierung von Computer-Modellen mittels der Evolutionsstrategie [Numerical Optimization of Computer Models by means of the Evolution Strategy]. Birkhäuser Verlag: Basel, Switzerland and Stuttgart, Germany, 1977. In German.
  • 29
    McDowell M, Fryar C, Ogden C, Flegal K. Anthropometric reference data for children and adults: United states, 2003–2006, National Health Statistics Reports, No. 10, Centers for Disease Control and Prevention, 2008.
  • 30
    Cirillo M, Laurenzi M, Tervisan M, Stamler J. Hematocrit, blood pressure, and hypertension: the Gubbio population study. Hypertension 1992; 20(3):319326.
  • 31
    Lemaire V, Tobin F, Greller L, Cho C, Suva L. Modeling of the interactions between osteoblast and osteoclast activities in bone remodeling. Journal of Theoretical Biology 2004; 229(3):293309.
  • 32
    Pivonka P, Zimak J, Smith D, Gardiner B, Dunstan C, Sims N, Martin T, Mundy G. Model structure and control of bone remodeling: a theoretical study. Bone 2008; 43(2):249263.
  • 33
    Pivonka P, Buenzli P, Scheiner S, Hellmich C, Dunstan C. The influence of bone surface availability in bone remodelling – a mathematical model including coupled geometrical and biomechanical regulations of bone cells. Engineering Structures 2013; 47:134147.
  • 34
    Janssens K, ten Dijke P, Janssens S, Van Hul W. Transforming growth factor- β1 to the bone. Endocrine Reviews 2005; 26(6):743774.
  • 35
    Erlebacher A, Filvaroff E, Ye JQ, Derynck R. Osteoblastic responses to TGF- β during bone remodeling. Molecular Biology of the Cell 1998; 9(7):19031918.
  • 36
    Jones D, Nolte H, Scholübbers JG, Turner E, Veltel D. Biochemical signal transduction of mechanical strain in osteoblast-like cells. Biomaterials 1991; 12(2):101110.
  • 37
    Owan I, Burr D, Turner C, Qiu J, Tu Y, Onyia J, Duncan R. Mechanotransduction in bone: osteoblasts are more responsive to fluid forces than mechanical strain. American Journal of Physiology - Cell Physiology 1997; 273(3):C810C815.
  • 38
    Kaspar D, Seidl W, Neidlinger-Wilke C, Beck A, Claes L, Ignatius A. Proliferation of human-derived osteoblast-like cells depends on the cycle number and frequency of uniaxial strain. Journal of Biomechanics 2002; 35(7):873880.
  • 39
    Weyts F, Bosmans B, Niesing R, Van JL, Weinans H. Mechanical control of human osteoblast apoptosis and proliferation in relation to differentiation. Calcified Tissue International 2003; 72(4):505512.
  • 40
    Fuller K, Lean J, Bayley K, Wani M, Chambers T. A role for TGF- β1 in osteoclast differentiation and survival. Journal of Cell Science 2000; 113(13):24452453.
  • 41
    Pitsillides A, Rawlinson S, Suswillo R, Bourrin S, Zaman G, Lanyon L. Mechanical strain-induced NO production by bone cells: a possible role in adaptive bone (re)modeling? FASEB Journal 1995; 9(15):16141622.
  • 42
    Mullender M, El Haj A, Yang Y, van Duin M, Burger E, Klein-Nulend J. Mechanotransduction of bone cells in vitro: mechanobiology of bone tissue. Medical and Biological Engineering and Computing 2004; 42(1):1421.
  • 43
    Fan X, Roy E, Zhu L, Murphy T, Ackert-Bicknell C, Hart C, Rosen C, Nanes M, Rubin J. Nitric oxide regulates receptor activator of nuclear factor- κB ligand and osteoprotegerin expression in bone marrow stromal cells. Endocrinology 2004; 145(2):751759.
  • 44
    Liu C, Zhao Y, Cheung WY, Gandhi R, Wang L, You L. Effects of cyclic hydraulic pressure on osteocytes. Bone 2010; 46(5):14491456.
  • 45
    Alon U. An Introduction to Systems Biology: Design Principles of Biological Circuits. Chapman & Hall: London, UK, 2007.
  • 46
    Wergedal J, Baylink D. Electron microprobe measurements of bone mineralization rate in vivo. American Journal of Physiology 1974; 226(2):345352.
  • 47
    Grynpas M. Age and disease-related changes in the mineral of bone. Calcified Tissue International 1993; 53(S1):5764.
  • 48
    Busa B, Miller L, Rubin C, Qin YX, Judex S. Rapid establishment of chemical and mechanical properties during lamellar bone formation. Calcified Tissue International 2005; 77(6):386394.
  • 49
    Hellmich C, Kober C, Erdmann B. Micromechanics-based conversion of CT data into anisotropic elasticity tensors, applied to FE simulations of a mandible. Annals of Biomedical Engineering 2008; 36(1):108122.
  • 50
    Zaoui A. Continuum micromechanics: survey. Journal of Engineering Mechanics (ASCE) 2002; 128(8):808816.
  • 51
    Riggs B, Khosla S, MeltonIII L. A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. Journal of Bone and Mineral Research 1998; 13(5):763773.
  • 52
    Manolagas S. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocrine Reviews 2000; 21(2):115137.
  • 53
    Garnero P, Sornay-Rendu E, Chapuy MC, Delmas P. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. Journal of Bone and Mineral Research 1996; 11(3):337349.
  • 54
    Hofbauer L, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. Journal of the American Medical Association 2004; 292(4):490495.
  • 55
    Riggs B. The mechanisms of estrogen regulation of bone resorption. The Journal of Clinical Investigation 2000; 106(10):12031204.
  • 56
    Tomkinson A, Gevers E, Wit J, Reeve J, Noble B. The role of estrogen in the control of rat osteocyte apoptosis. Journal of Bone and Mineral Research 1998; 13(8):12431250.
  • 57
    Kostenuik P, Nguyen H, McCabe J, Warmington K, Kurahara C, Sun N, Chen C, Li L, Cattley R, Van G, et al. Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases BMD in knock-out mice that express chimeric (murine/human) RANKL. Journal of Bone and Mineral Research 2009; 24(2):182195.
  • 58
    Atkins P. Physical Chemistry, 6th ed. Oxford University Press: Oxford, UK, 1998.
  • 59
    Green W. Denosumab (Prolia) injection – a new approach to the treatment of women with postmenopausal osteoporosis. Pharmacy and Therapeutics 2010; 35(10):553559.
  • 60
    Bonnet N, Ferrari S. Exercise and the skeleton: how it works and what it really does. IBMS BoneKey 2010; 7(7):235248.
  • 61
    Lekhnitskii S. Theory of Elasticity of an Anisotropic Elastic Body. Holden-Day, Inc.: San Francisco, USA, 1963.
  • 62
    Looker A, Bauer D, Chesnut III C, Gundberg C, Hochberg M, Klee G, Kleerekoper M, Watts N, Bell N. Clinical use of biochemical markers of bone remodeling: current status and future directions. Osteoporosis International 2000; 11(6):467480.
  • 63
    Eastell R, Christiansen C, Grauer A, Kutilek S, Libanati C, McClung M, Reid I, Resch H, Siris E, Uebelhart D, Wang A, Weryha G, Cummings S. Effects of denosumab on bone turnover markers in postmenopausal osteoporosis. Journal of Bone and Mineral Research 2011; 26(3):530537.
  • 64
    Lu Y, Genant HK, Sheperd J, Zhao S, Mathur A, Fuerst T, Cummings SR. Classification of osteoporosis based on bone mineral densities. Journal of Bone and Mineral Research 2001; 16(5):901910.
  • 65
    Bone H, Bolognese M, Yuen C, Kendler D, Wang H, Liu Y, Martin J. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. Journal of Clinical Endocrinology and Metabolism 2008; 93(6):21492157.
  • 66
    Kendler D, Roux C, Benhamou C, Brown J, Lillelstol M, Siddhanti S, Man HS, Martin J, Bone H. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy. Journal of Bone and Mineral Research 2010; 25(1):7281.
  • 67
    Miller P. Denosumab: anti-RANKL antibody. Current Osteoporosis Reports 2009; 7(1):1822.
  • 68
    Miller P, Wagman R, Peacock M, Lewiecki E, Bolognese M, Weinstein R, Ding B, Martin J, McClung M. Effect of denosumab on bone mineral density and biochemical markers of bone turnover: six-year results of a phase 2 clinical trial. Journal of Clinical Endocrinology and Metabolism 2011; 96(2):394402.
  • 69
    Bala Y, Farlay D, Delmas P, Meunier P, Boivin G. Time sequence of secondary mineralization and microhardness in cortical and cancellous bone from ewes. Bone 2010; 46(4):12041212.
  • 70
    Vuong J, Hellmich C. Bone fibrillogenesis and mineralization: quantitative analysis and implications for tissue elasticity. Journal of Theoretical Biology 2011; 287:115130.
  • 71
    Chavassieux P, Arlot M, Reda C, Wei L, Yates A, Meunier P. Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. The Journal of Clinical Investigation 1997; 100(6):14751480.
  • 72
    Stepan J, Alenfeld F, Boivin G, Feyen J, Lakatos P. Mechanisms of action of antiresorptive therapies of postmenopausal osteoporosis. Endocrine Regulations 2003; 37(4):225238.
  • 73
    Seeman E. Reduced bone formation and increased bone resorption: rational targets for the treatment of osteoporosis. Osteoporosis International 2003; 14(S2-S8).
  • 74
    Boivin G, Meunier P. The mineralization of bone tissue: a forgotten dimension in osteoporosis research. Osteoporosis International 2003; 14:S19S24.
  • 75
    Bone H, Hosking D, Devogelaer JP, Tucci J, Emkey R, Tonino R, Rodriguez-Portales J, Downs R, Gupta J, Santora A, Liberman U. Ten years' experience with alendronate for osteoporosis in postmenopausal women. The New England Journal of Medicine 2004; 350(12):11891199.
  • 76
    Lewiecki E, Silverman S. Redefining osteoporosis treatment: who to treat and how long to treat. Arquivos Brasileiros de Endocrinologia & Metabologia 2006; 50(4):694704.
  • 77
    Fuchs R, Faillace M, Allen M, Phipps R, Miller L, Burr D. Biphosphonates do not alter the rate of secondary mineralization. Bone 2011; 49(4):701705.
  • 78
    Muschitz C, Kocijan R, Fahrleitner-Pammer A, Lung S, Resch H. Antiresorptives overlapping ongoing teriparatide treatment result in additional increases in bone mineral density. Journal of Bone and Mineral Research 2013; 28(1):196205.
  • 79
    Fritsch A, Hellmich C. ‘Universal’ microstructural patterns in cortical and trabecular, extracellular and extravascular bone materials: micromechanics-based prediction of anisotropic elasticity. Journal of Theoretical Biology 2007; 244(4):597620.
  • 80
    Bonewald L, Johnson M. Osteocytes, mechanosensing and Wnt signaling. Bone 2008; 42(4):606615.
  • 81
    Bonewald L. The amazing osteocyte. Journal of Bone and Mineral Research 2011; 26(2):229238.
  • 82
    Jacobs C, Temiyasathit S, Castillo A. Osteocyte mechanobiology and pericellular mechanics. Annual Review of Biomedical Engineering 2010; 12: 369400.
  • 83
    Moroz A, Crane M, Smith G, Wimpenny D. Phenomenological model of bone remodeling cycle containing osteocyte regulation loop. Biosystems 2006; 84(3):183190.
  • 84
    Rieger R, Hambli R, Jennane R. Modeling of biological doses and mechanical effects on bone transduction. Journal of Theoretical Biology 2011; 274(1):3642.
  • 85
    Hambli R, Rieger R. Physiologically based mathematical model of transduction of mechanobiological signals by osteocytes. Biomechanics and Modeling in Mechanobiology 2012; 11(1-2):8393.
  • 86
    Graham J, Ayati B, Holstein S, Martin J. The role of osteocytes in targeted bone remodeling: a mathematical model. PLoS ONE 2013; 8(5):e63884, 110.
  • 87
    Klein-Nulend J, Van der Plas A, Semeins C, Ajubi N, Frangos J, Nijweide P, Burger E. Sensitivity of osteocytes to biomechanical stress in vitro. FASEB Journal 1995; 9(5):441445.
  • 88
    Klein-Nulend J, Bacabac R, Bakker A. Mechanical loading and how it affects bone cells: the role of the osteocyte cytoskeleton in maintaining our skeleton. European Cells and Materials 2012; 24:278291.
  • 89
    Ashman R, Cowin S, VanBuskirk W, Rice J. A continuous wave technique for the measurement of the elastic properties of cortical bone. Journal of Biomechanics 1984; 17(5):349361.
  • 90
    Cowin S, Mehrabadi M. The structure of the linear anisotropic elastic symmetries. Journal of the Mechanics and Physics of Solids 1992; 40(7):14591471.