In Vivo Validation of Predictive Models for Bone Remodeling and Mechanobiology

  • Alina Levchuk
  • Ralph Müller
Conference paper


In silico modeling is a powerful tool for the prediction of bone remodeling and mechanobiology. As the method is gaining popularity a standardized measure for the in vivo validation of the quality of the produced simulations is required. In this review, we discuss current validity assessment approaches, as well as the validation ‘gold standard’, in which the experimental and computational parts are carried out concomitantly, and by the same research team. A novel validation framework for the tissue level model, based on the true geometry is introduced.


Fracture Healing Strain Energy Density Bone Adaptation Morphometric Index Bone Mineralization Density Distribution 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors gratefully acknowledge funding from the European Union for the Osteoporotic Virtual Physiological Human project (VPHOP FP7-ICT2008-223865) and computational time from the Swiss National Supercomputing Center (CSCS, Manno, Switzerland).


  1. Adachi T, Tsubota K, Tomita Y, Hollister SJ (2001) Trabecular surface remodeling simulation for cancellous bone using microstructural voxel finite element models. J Biomech Eng 123:403–409 CrossRefGoogle Scholar
  2. Anderson AE, Ellis BJ, Weiss JA (2007) Verification, validation and sensitivity studies in computational biomechanics. Comput Methods Biomech Biomed Eng 10:171–184 CrossRefGoogle Scholar
  3. Anderson EJ, Knothe Tate ML (2008) Idealization of pericellular fluid space geometry and dimension results in a profound underprediction of nano-microscale stresses imparted by fluid drag on osteocytes. J Biomech 41:1736–1746 CrossRefGoogle Scholar
  4. Bonivtch AR, Bonewald LF, Nicolella DP (2007) Tissue strain amplification at the osteocyte lacuna: a microstructural finite element analysis. J Biomech 40:2199–2206 CrossRefGoogle Scholar
  5. Brekelmans W, Slooff T, Poort H (1972) New method to analyze mechanical behavior of skeletal parts. Acta Orthop Scand 43:301–317 CrossRefGoogle Scholar
  6. Carter DR, Beaupré GS, Giori NJ, Helms JA (1998) Mechanobiology of skeletal regeneration. Clin Orthop Relat Res S355:S41–S55 CrossRefGoogle Scholar
  7. Coelho PG, Fernandes PR, Rodrigues HC, Cardoso JB, Guedes JM (2009) Numerical modeling of bone tissue adaptation—a hierarchical approach for bone apparent density and trabecular structure. J Biomech 42:830–837 CrossRefGoogle Scholar
  8. Engh CA, Mcgovern TF, Bobyn JD, Harris WH (1992) A quantitative-evaluation of periprosthetic bone-remodeling after cementless total hip-arthroplasty. J Bone Jt Surg, Am Vol 74:1009–1020 Google Scholar
  9. Feldkamp LA, Goldstein SA, Parfitt AM, Jesion G, Kleerekoper M (1989) The direct examination of three-dimensional bone architecture in vitro by computed tomography. J Bone Miner Res 4:3–11 CrossRefGoogle Scholar
  10. Frisch T, Thoumine O (2002) Predicting the kinetics of cell spreading. J Biomech 35:1137–1141 CrossRefGoogle Scholar
  11. Fritton SP, McLeod KJ, Rubin CT (2000) Quantifying the strain history of bone: spatial uniformity and self-similarity of low-magnitude strains. J Biomech 33:317–325 CrossRefGoogle Scholar
  12. Frost HM (1964) The laws of bone structure. Thomas, Springfield Google Scholar
  13. Gerhard FA, Webster DJ, van Lenthe GH, Müller R (2009) The relative significance of trabecular and cortical bone-density as a diagnostic index for osteoporosis. Philos Trans R Soc A 367:2011–2030 CrossRefGoogle Scholar
  14. Goldstein SA, Matthews LS, Kuhn JL, Hollister SJ (1991) Trabecular bone remodeling—an experimental model. J Biomech 24:135–150 CrossRefGoogle Scholar
  15. Guldberg RE, Richards M, Caldwell NJ, Kuelske CL, Goldstein SA (1997) Trabecular bone adaptation to variations in porous-coated implant topology. J Biomech 30:147–153 CrossRefGoogle Scholar
  16. Hartmann MA, Dunlop JW, Brechet YJ, Fratzl P, Weinkamer R (2011) Trabecular bone remodelling simulated by a stochastic exchange of discrete bone packets from the surface. J Mech Beh Biomed Mat 4:879–887 CrossRefGoogle Scholar
  17. Huiskes R (1997) Validation of adaptive bone-remodeling simulation models. Stud Health Technol Inform 40:33–48 Google Scholar
  18. Huiskes R, Chao EYS (1983) A survey of finite element analysis in orthopedic biomechanics: the first decade. J Biomech 16:385–409 CrossRefGoogle Scholar
  19. Huiskes R, Ruimerman R, van Lenthe GH, Janssen JD, (2000) Effects of mechanical forces on maintenance and adaptation of form in trabecular bone. Nature 405:704–706 CrossRefGoogle Scholar
  20. Isaksson H (2012) Recent advances in mechanobiological modeling of bone regeneration. Mech Res Commun 42:22–31 CrossRefGoogle Scholar
  21. Isaksson H, Wilson W, van Donkelaar CC, Huiskes R, Ito K (2006) Comparison of biophysical stimuli for mechano-regulation of tissue differentiation during fracture healing. J Biomech 39:1507–1516 CrossRefGoogle Scholar
  22. Jacobs CR, Kelly DJ (2011) Cell mechanics: the role of simulation. In: Fernandes PR, Bártolo PJ (eds) Advances on modeling in tissue engineering. Computational methods in applied sciences, vol. 20, pp 1–14 CrossRefGoogle Scholar
  23. Kelly K (1998) The third culture. Science 279:992–993 CrossRefGoogle Scholar
  24. Kerner J, Huiskes R, van Lenthe GH, Weinans H, van Rietbergen B, Engh CA, Amis AA (1999) Correlation between pre-operative periprosthetic bone density and post-operative bone loss in THA can be explained by strain-adaptive remodelling. J Biomech 32:695–703 CrossRefGoogle Scholar
  25. Knothe Tate ML, Niederer P (1998) A theoretical FE-based model developed to predict the relative contribution of convective and diffusive transport mechanisms for the maintenance of local equilibria within cortical bone. In: Clegg S (ed) Advances in heat and mass transfer in biotechnology. The American Society of Mechanical Engineers, New York, pp 133–142 Google Scholar
  26. Lacroix D, Prendergast PJ (2002) A mechano-regulation model for tissue differentiation during fracture healing: analysis of gap size and loading. J Biomech 35:1163–1171 CrossRefGoogle Scholar
  27. Landsberg C, Stenger F, Deutsch A, Gelinsky M, Rosen-Wolff A, Voigt A (2011) Chemotaxis of mesenchymal stem cells within 3D biomimetic scaffolds—a modeling approach. J Biomech 44:359–364 CrossRefGoogle Scholar
  28. Leichter I, Bivas A, Giveon A, Margulies JY, Weinreb A (1987) The relative significance of trabecular and cortical bone-density as a diagnostic index for osteoporosis. Phys Med Biol 32:1167–1174 CrossRefGoogle Scholar
  29. Lemaire V, Tobin FL, Greller LD, Cho CR, Suva LJ (2004) Modeling the interactions between osteoblast and osteoclast activities in bone remodeling. J Theor Biol 229:293–309 MathSciNetCrossRefGoogle Scholar
  30. Lengsfeld M, Gunther D, Pressel T, Leppek R, Schmitt J, Griss P (2002) Validation data for periprosthetic bone remodelling theories. J Biomech 35:1553–1564 CrossRefGoogle Scholar
  31. Lengsfeld M, Burchard R, Gunther D, Pressel T, Schmitt J, Leppek R, Griss P (2005) Femoral strain changes after total hip arthroplasty–patient-specific finite element analyses 12 years after operation. Med Eng Phys 27:649–654 CrossRefGoogle Scholar
  32. Lio P, Merelli E, Paoletti N, Viceconti M (2011) A combined process algebraic and stochastic approach to bone remodeling. Electron Notes Theor Comput Sci 277:41–52 CrossRefGoogle Scholar
  33. Loosli Y, Luginbuehl R, Snedeker JG (2010) Cytoskeleton reorganization of spreading cells on micro-patterned islands: a functional model. Philos Trans R Soc, Math Phys Eng Sci 368:2629–2652 CrossRefGoogle Scholar
  34. McGarry JG, Klein-Nulend J, Mullender MG, Prendergast PJ (2005) A comparison of strain and fluid shear stress in stimulating bone cell responses—a computational and experimental study. FASEB J 19:482–484 Google Scholar
  35. Müller R (2005) Long-term prediction of three-dimensional bone architecture in simulations of pre-, peri- and post-menopausal microstructural bone remodeling. Osteoporos Int 16:S25–S35 CrossRefGoogle Scholar
  36. Müller R, Hayes WC (1997) Biomechanical competence of microstructural bone in the progress of adaptive bone remodeling. Proc SPIE 3149:69–81 CrossRefGoogle Scholar
  37. Müller R, Rüegsegger P (1996) Analysis of mechanical properties of cancellous bone under conditions of simulated bone atrophy. J Biomech 29:1053–1060 CrossRefGoogle Scholar
  38. Pivonka P, Zimak J, Smith DW, Gardiner BS, Dunstan CR, Sims NA, Martin TJ, Mundy GR (2008) Model structure and control of bone remodeling: a theoretical study. Bone 43:249–263 CrossRefGoogle Scholar
  39. Potter LK, Greller LD, Cho CR, Nuttall ME, Stroup GB, Suva LJ, Tobin FL (2005) Response to continuous and pulsatile PTH dosing: a mathematical model for parathyroid hormone receptor kinetics. Bone 37:159–169 CrossRefGoogle Scholar
  40. Roux W (1881) Der Kampf der Theile im Organismus. Ein Beitrag zur Vervollständigung der mechanischen Zweckmässigkeitslehre. Leipzig Google Scholar
  41. Ruffoni D, Fratzl P, Roschger P, Klaushofer K, Weinkamer R (2007) The bone mineralization density distribution as a fingerprint of the mineralization process. Bone 40:1308–1319 CrossRefGoogle Scholar
  42. Ruimerman R, Hilbers P, van Rietbergen B, Huiskes R (2005a). A theoretical framework for strain-related trabecular bone maintenance and adaptation. J Biomech 38:931–941 CrossRefGoogle Scholar
  43. Ruimerman R, van Rietbergen B, Hilbers P, Huiskes R (2005b). The effects of trabecular-bone loading variables on the surface signaling potential for bone remodeling and adaptation. Ann Biomed Eng 33:71–78 CrossRefGoogle Scholar
  44. Sangiorgio SN, Longjohn DB, Dorr LD, Ebramzadeh E (2011) Challenges in relating experimental hip implant fixation predictions to clinical observations. J Biomech 44:235–243 CrossRefGoogle Scholar
  45. Santos L, Romeu JC, Canhao H, Fonseca JE, Fernandes PR (2010) A quantitative comparison of a bone remodeling model with dual-energy X-ray absorptiometry and analysis of the inter-individual biological variability of femoral neck T-score. J Biomech 43:3150–3155 CrossRefGoogle Scholar
  46. Schmitz MJ, Clift SE, Taylor WR, Hertig D, Warner MD, Ploeg HL, Bereiter H (2004) Investigating the effect of remodelling signal type on the finite element based predictions of bone remodelling around the thrust plate prosthesis: a patient-specific comparison. Proc Inst Mech Eng, H J Eng Med 218, pp 417–424 CrossRefGoogle Scholar
  47. Schulte FA (2011) In silico bone biology in a murine model of bone adaptation. Diss. ETH No. 19679, Zurich Google Scholar
  48. Schulte FA, Lambers FM, Webster DJ, Kuhn G, Müller R (2011) In vivo validation of a computational bone adaptation model using open-loop control and time-lapsed micro-computed tomography. Bone 49:1166–1172 CrossRefGoogle Scholar
  49. Silva MJ, Gibson LJ (1997) Modeling the mechanical behavior of vertebral trabecular bone: effects of age-related changes in microstructure. Bone 21:191–199 CrossRefGoogle Scholar
  50. Sumner DR, Turner TM, Urban RM, Galante JO (1992) Remodeling and ingrowth of bone at two years in a canine cementless total hip-arthroplasty model. J Bone Jt Surg, Am Vol 74:239–250 Google Scholar
  51. Taylor D, Hazenberg JG, Lee TC (2007) Living with cracks: damage and repair in human bone. Nat Mater 6:263–268 CrossRefGoogle Scholar
  52. Testi D, Cappello A, Sgallari F, Rumpf M, Viceconti M (2004) A new software for prediction of femoral neck fractures. Comput Methods Programs Biomed 75:141–145 CrossRefGoogle Scholar
  53. Van der Linden JC, Verhaar JAN, Weinans H (2001) A three-dimensional simulation of age-related remodeling in trabecular bone. J Bone Miner Res 16:688–696 CrossRefGoogle Scholar
  54. Van der Meulen MCH, Huiskes R (2002) Why mechanobiology? A survey article. J Biomech 35:401–414 CrossRefGoogle Scholar
  55. Webster D, Müller R (2011) In silico models of bone remodeling from macro to nano-from organ to cell. Wires Syst Biol Med 3:241–251 CrossRefGoogle Scholar
  56. Weinbaum S, Cowin SC, Zeng Y (1994) A model for the excitation of ostecytes by mechanical loading-induced bone fluid shear stresses. J Biomech 27:339–360 CrossRefGoogle Scholar
  57. Wolff J (1892) Das Gesetz der Transformation der Knochen. Hirschwald, Berlin Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.ETH ZurichZurichSwitzerland

Personalised recommendations