Skip to main content
SpringerLink
Log in

Registered Micro-Computed Tomography Data as a Four-Dimensional Imaging Biomarker of Bone Formation and Resorption

  • Reference work entry
  • First Online:
Book cover Biomarkers in Bone Disease

Abstract

There are significant clinical reasons motivating scientists to better understand how loading conditions, diseases, synthetic implants, and drug treatments affect bone formation and resorption. Changes in bone turnover have enormous impact on the quality and mechanical competence of the skeleton. Until recently, bone formation and resorption were primarily measured using biochemical markers of bone turnover or histomorphometry. However, recent advances in computed tomography allow one to follow structural changes in the cortical and trabecular bone of living animals and human patients. The aim of this chapter is to describe recently developed methods that allow the monitoring of bone modeling and remodeling processes in vivo by using registered longitudinal micro-computed tomography data, which serves as an imaging biomarker of bone formation and resorption. The chapter provides an overview of bone modeling and remodeling processes and the standard methods that have been used in the past and present to assess bone formation and resorption. Micro-computed tomography-based imaging of the bone is then discussed. A detailed description is then given of recently developed computation methods that allow monitoring of bone modeling and remodeling using registered longitudinal micro-computed tomography data as an imaging biomarker of bone formation and resorption. The chapter ends with a discussion of how these imaging-based biomarkers of formation and resorption can be used to complement and in some cases replace conventional experimental and clinical methods of monitoring bone turnover.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 379.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AFR:

Activation, formation, and resorption

BALP:

Bone-specific alkaline phosphatase

BFR:

Bone formation rate

BMU:

Basic multicellular unit

BRR:

Bone resorption rate

BS:

Bone surface

BSP:

Bone sialoprotein

BV:

Bone volume

CTX:

Carboxy-terminal cross-linked telopeptide of type I collagen

DPD:

Deoxypyridinoline

ES:

Eroded surface

EV:

Eroded volume

HR-pQCT:

High-resolution peripheral quantitative computed tomography

LRP5/6:

Lipoprotein receptor-related protein 5 and 6

MAR:

Mineral apposition rate

microCT:

Micro-computed tomography

MRR:

Mineral resorption rate

MS:

Mineralizing surface

MV:

Mineralized volume

NTX:

Amino-terminal cross-linked telopeptide of type I collagen

OC:

Osteocalcin

PICP:

Procollagen type I C-terminal propeptide

PINP:

Procollagen type I N-terminal propeptide

PYD:

Pyridinoline

TRACP5b:

5b isoenzyme of tartrate-resistant acid phosphatase

TRAP:

Tartrate-resistant acid phosphatase

References

  • Birkhold AI, Razi H, Duda GN, et al. The influence of age on adaptive bone formation and bone resorption. Biomaterials. 2014a;35:9290–301.

    Article  CAS  PubMed  Google Scholar 

  • Birkhold AI, Razi H, Duda GN, et al. Mineralizing surface is the main target of mechanical stimulation independent of age: 3D dynamic in vivo morphometry. Bone. 2014b;66:15–25.

    Article  PubMed  Google Scholar 

  • Birkhold AI, Razi H, Weinkamer R, et al. Monitoring in vivo (re)modeling: a computational approach using 4D microCT data to quantify bone surface movements. Bone. 2015;75:210–21.

    Article  PubMed  Google Scholar 

  • Boone JM, Velazquez O, Cherry SR. Small-animal X-ray dose from micro-CT. Mol Imaging. 2004;3:149–58.

    Article  PubMed  Google Scholar 

  • Bouxsein ML, Boyd SK, Christiansen BA, et al. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J Bone Miner Res. 2010;25:1468–86.

    Article  PubMed  Google Scholar 

  • Boyd SK, Davison P, Mueller R, et al. Monitoring individual morphological changes over time in ovariectomized rats by in vivo micro-computed tomography. Bone. 2006;39:854–62.

    Article  PubMed  Google Scholar 

  • Buie HR, Campbell GM, Klinck RJ, et al. Automatic segmentation of cortical and trabecular compartments based on a dual threshold technique for in vivo micro-CT bone analysis. Bone. 2007;41:505–15.

    Article  PubMed  Google Scholar 

  • Buie HR, Moore CP, Boyd SK. Postpubertal architectural developmental patterns differ between the L3 vertebra and proximal tibia in three inbred strains of mice. J Bone Miner Res. 2008;23:2048–59.

    Article  PubMed  Google Scholar 

  • Burghardt AJ, Kazakia GJ, Majumdar S. A local adaptive threshold strategy for high resolution peripheral quantitative computed tomography of trabecular bone. Ann Biomed Eng. 2007;35:1678–86.

    Article  PubMed  Google Scholar 

  • Carlson SK, Classic KL, Bender CE, et al. Small animal absorbed radiation dose from serial micro-computed tomography imaging. Mol Imaging Biol. 2007;9:78–82.

    Article  PubMed  Google Scholar 

  • Chappard C, Basillais A, Benhamou L, et al. Comparison of synchrotron radiation and conventional x-ray microCT for assessing trabecular bone microarchitecture of human femoral heads. Med Phys. 2006;33:3568–77.

    Article  PubMed  Google Scholar 

  • Christen P, Ito K, Ellouz R, et al. Bone remodelling in humans is load-driven but not lazy. Nat Commun. 2014;5:4855.

    Article  CAS  PubMed  Google Scholar 

  • Cormack AM. Representation of a function by its line integrals, with some radiological applications. New York: American Institute of Physics; 1963.

    Google Scholar 

  • David V, Laroche N, Boudignon B, et al. Noninvasive in vivo monitoring of bone architecture alterations in hindlimb-unloaded female rats using novel three-dimensional microcomputed tomography. J Bone Miner Res. 2003;18:1622–31.

    Article  PubMed  Google Scholar 

  • Dempster DW, Compston JE, Drezner MK, et al. Standardized nomenclature, symbols, and units for bone histomorphometry. J Bone Miner Res. 2013;28:2–17.

    Article  PubMed  PubMed Central  Google Scholar 

  • Deserno TM. Biomedical image processing. Berlin/Heidelberg: Springer; 2011.

    Book  Google Scholar 

  • Dufresne T. Segmentation techniques for analysis of bone by three-dimensional computed tomographic imaging. Technol Health Care. 1998;6:351–9.

    CAS  PubMed  Google Scholar 

  • Duyar I, Pelin C. Body height estimation based on tibia length in different stature groups. Am J Phys Anthropol. 2003;122:23–7.

    Article  PubMed  Google Scholar 

  • Elliott JC, Dover SD. X-ray microtomography. J Microsc. 1982;126:211–3.

    Article  CAS  PubMed  Google Scholar 

  • Erben RG. Trabecular and endocortical bone surfaces in the rat: modeling or remodeling? Anat Rec. 1996;246:39–46.

    Article  CAS  PubMed  Google Scholar 

  • Erben RG, Glösmann M. Chapter 19: Histomorphometry in rodents. In: Bone research protocols. Methods in molecular biology. 2nd ed. New York: Springer; 2012.

    Google Scholar 

  • Eriksen EF. Normal and pathological remodeling of human trabecular bone: three dimensional reconstruction of the remodeling sequence in normals and in metabolic bone disease. Endocr Rev. 1986;7:379–408.

    Article  CAS  PubMed  Google Scholar 

  • Eriksen EF, Gundersen HJ, Melsen F, et al. Reconstruction of the formative site in iliac trabecular bone in 20 normal individuals employing a kinetic model for matrix and mineral apposition. Metab Bone Dis Relat Res. 1984a;5:243–52.

    Article  CAS  PubMed  Google Scholar 

  • Eriksen EF, Melsen F, Mosekilde L. Reconstruction of the resorptive site in iliac trabecular bone: a kinetic model for bone resorption in 20 normal individuals. Metab Bone Dis Relat Res. 1984b;5:235–42.

    Article  CAS  PubMed  Google Scholar 

  • Feldkamp LA, Goldstein SA, Parfitt AM, et al. The direct examination of 3D bone architecture in vitro by CT. J Bone Miner Res. 1989;4:3–11.

    Article  CAS  PubMed  Google Scholar 

  • Ford NL, Thornton MM, Holdsworth DW. Fundamental image quality limits for microcomputed tomography in small animals. Med Phys. 2003;30:2869–77.

    Article  CAS  PubMed  Google Scholar 

  • Franz-Odendaal TA, Hall BK, Witten PE. Buried alive: how osteoblasts become osteocytes. Dev Dyn. 2006;235:176–90.

    Article  CAS  PubMed  Google Scholar 

  • Frost HM. Tetracycline-based histological analysis of bone remodeling. Calcif Tissue Res. 1969;3:211–37.

    Article  CAS  PubMed  Google Scholar 

  • Gelaude F, Vander Sloten J, Lauwers B. Semi-automated segmentation and visualisation of outer bone cortex from medical images. Comput Methods Biomech Biomed Engin. 2006;9:65–77.

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez EA, Lund RJ, Martin KJ, et al. Treatment of a murine model of high-turnover renal osteodystrophy by exogenous BMP-7. Kidney Int. 2002;61:1322–31.

    Article  CAS  PubMed  Google Scholar 

  • Halloran BP, Ferguson VL, Simske SJ, et al. Changes in bone structure and mass with advancing age in the male C57BL/6J mouse. J Bone Miner Res. 2002;17:1044–50.

    Article  PubMed  Google Scholar 

  • Hattner R, Epker BN, Frost HM. Suggested sequential mode of control of changes in cell behaviour in adult bone remodelling. Nature. 1965;206:489–90.

    Article  CAS  PubMed  Google Scholar 

  • Herman GT. Fundamentals of computerized tomography: image reconstruction from projections. Dordrecht/New York: Springer; 2009.

    Book  Google Scholar 

  • Hernandez CJ, Hazelwood SJ, Martin RB. The relationship between basic multicellular unit activation and origination in cancellous bone. Bone. 1999;25:585–7.

    Article  CAS  PubMed  Google Scholar 

  • Hlaing TT, Compston JE. Biochemical markers of bone turnover – uses and limitations. Ann Clin Biochem. 2014;51:189–202.

    Article  PubMed  Google Scholar 

  • Hounsfield GN. Computerized transverse axial scanning (tomography). Br J Radiol. 1973;46:1016–22.

    Article  CAS  PubMed  Google Scholar 

  • Jaworski ZF, Lok E. The rate of osteoclastic bone erosion in Haversian remodeling sites of adult dog’s rib. Calcif Tissue Res. 1972;10:103–12.

    Article  CAS  PubMed  Google Scholar 

  • Kettenberger U, Ston J, Thein E, et al. Does locally delivered Zoledronate influence peri-implant bone formation? - Spatio-temporal monitoring of bone remodeling in vivo. Biomaterials. 2014;35:9995–10006.

    Article  CAS  PubMed  Google Scholar 

  • Klinck RJ, Campbell GM, Boyd SK. Radiation effects on bone architecture in mice and rats resulting from in vivo microCT scanning. Med Eng Phys. 2008;30:888–95.

    Article  PubMed  Google Scholar 

  • Kohler T, Stauber M, Donahue LR, et al. Automated compartmental analysis for high-throughput skeletal phenotyping in femora of genetic mouse models. Bone. 2007;41:659–67.

    Article  PubMed  Google Scholar 

  • Lukas C, Ruffoni D, Lambers FM, et al. Mineralization kinetics in murine trabecular bone quantified by time-lapsed in vivo microCT. Bone. 2013;56:55–60.

    Article  PubMed  Google Scholar 

  • Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000;21:115–37.

    CAS  PubMed  Google Scholar 

  • Martin RB, Burr DB, Sharkey NA. Skeletal tissue mechanics. New York: Springer; 1998.

    Book  Google Scholar 

  • Meganck JA, Kozloff KM, Thornton MM, et al. Beam hardening artifacts in microCT scanning can be reduced by X-ray beam filtration and the resulting images can be used to accurately measure BMD. Bone. 2009;45:1104–16.

    Article  PubMed  PubMed Central  Google Scholar 

  • Meijering E. Spline interpolation in medical imaging: comparison with other convolution-based approaches. Signal Processing X: Theories and Applications Proceedings of EUSIPCO; 2000. 2000:1989–1996

    Google Scholar 

  • Milch RA, Rall DP, Tobie JE. Fluorescence of tetracycline antibiotics in bone. J Bone Joint Surg Am. 1958;40-A:897–910.

    Article  CAS  PubMed  Google Scholar 

  • Nishiyama KK, Campbell GM, Klinck RJ, et al. Reproducibility of bone micro-architecture measurements in rodents by in vivo microCT is maximized with 3D image registration. Bone. 2010;66:155–61.

    Article  Google Scholar 

  • Nuzzo S, Lafage-Proust MH, Martin-Badosa E, et al. Synchrotron radiation microtomography allows the analysis of three-dimensional microarchitecture and degree of mineralization of human iliac crest biopsy specimens: effects of etidronate treatment. J Bone Miner Res. 2002a;17:1372–82.

    Article  CAS  PubMed  Google Scholar 

  • Nuzzo S, Peyrin F, Cloetens P, et al. Quantification of the degree of mineralization of bone in three dimensions using synchrotron radiation microtomography. Med Phys. 2002b;29:2672–81.

    Article  PubMed  Google Scholar 

  • Oliveira F, Tavares J. Medical image registration: a review. Comput Methods Biomech Biomed Engin. 2014;17:73–93.

    Article  PubMed  Google Scholar 

  • Parfitt AM. Age-related structural changes in trabecular and cortical bone: cellular mechanisms and biomechanical consequences. Calcif Tissue Int. 1984;36 Suppl 1:S123–8.

    Article  PubMed  Google Scholar 

  • Parfitt AM. Osteonal and hemi-osteonal remodeling: the spatial and temporal framework for signal traffic in adult human bone. J Cell Biochem. 1994;55:273–86.

    Article  CAS  PubMed  Google Scholar 

  • Parfitt AM. Osteoclast precursors as leukocytes: importance of the area code. Bone. 1998;23:491–4.

    Article  CAS  PubMed  Google Scholar 

  • Parfitt AM, Mathews CH, Villanueva AR, et al. Relationships between surface, volume, and thickness of iliac trabecular bone in aging and in osteoporosis. Implications for the microanatomic and cellular mechanisms of bone loss. J Clin Invest. 1983;72:1396–409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parfitt AM, Drezner MK, Glorieux FH, et al. Bone histomorphometry: standardization of nomenclature, symbols, and units. J Bone Miner Res. 1987;2:595–610.

    Article  CAS  PubMed  Google Scholar 

  • Pluim JPW, Maintz JBA, Viergever MA. Mutual-information-based registration of medical images: a survey. IEEE Trans Med Imaging. 2003;22:986–1004.

    Article  PubMed  Google Scholar 

  • Radon J. Über die Bestimmung von Funktionen durch ihre Integralwerte längs gewisser Mannigfaltigkeiten. Akad Wiss. 1971;69:262–77.

    Google Scholar 

  • Razi H, Birkhold AI, Weinkamer R, et al. Aging leads to a dysregulation in mechanically driven bone formation and resorption. J Bone Miner Res. 2015;30:1864–1873.

    Article  PubMed  Google Scholar 

  • Recker RR. Bone histomorphometry: techniques and interpretation. Boca Raton: CRC Press; 1983.

    Google Scholar 

  • Riggs BL, Melton LJ, Robb RA, et al. A population-based assessment of rates of bone loss at multiple skeletal sites: evidence for substantial trabecular bone loss in young adult women and men. J Bone Miner Res. 2008;23:205–14.

    Article  PubMed  Google Scholar 

  • Rueegsegger P, Koller B, Mueller R. A microtomographic system for the nondestructive evaluation of bone architecture. Calcif Tissue Int. 1996;58:24–9.

    Article  CAS  Google Scholar 

  • Schulte FA, Lambers FM, Kuhn G, et al. In vivo microCT allows direct 3D quantification of both bone formation and bone resorption parameters using time-lapsed imaging. Bone. 2011;48:433–42.

    Article  PubMed  Google Scholar 

  • Schulte FA, Ruffoni D, Lambers FM, et al. Local mechanical stimuli regulate bone formation and resorption in mice at the tissue level. PLoS One. 2013;8:e62172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slyfield CR, Tkachenko EV, Wilson DL, et al. Three-dimensional dynamic bone histomorphometry. J Bone Miner Res. 2012;27:486–95.

    Article  PubMed  PubMed Central  Google Scholar 

  • Somerville JM, Aspden RM, Armour KE, et al. Growth of C57BL/6 mice and the material and mechanical properties of cortical bone from the tibia. Calcif Tissue Int. 2004;74:469–75.

    Article  CAS  PubMed  Google Scholar 

  • Thévenaz P, Ruttimann UE, Unser M. A pyramid approach to subpixel registration based on intensity. IEEE Trans Image Process. 1998;7:27–41.

    Article  PubMed  Google Scholar 

  • Vasikaran S, Eastell R, Bruyere O, et al. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int. 2011;22:391–420.

    Article  CAS  PubMed  Google Scholar 

  • Waarsing JH, Day JS, van der Linden JC, et al. Detecting and tracking local changes in the tibiae of individual rats. Bone. 2004a;34:163–9.

    Article  CAS  PubMed  Google Scholar 

  • Waarsing JH, Day JS, Weinans H. An improved segmentation method for in vivo microCT imaging. J Bone Miner Res. 2004b;19:1640–50.

    Article  PubMed  Google Scholar 

  • Weinstein RS, Jilka RL, Parfitt A, et al. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. J Clin Investig. 1998;102:274–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weinstein RS, Chen JR, Powers CC, et al. Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J Clin Investig. 2002;109:1041–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wells WM, Viola P, Atsumi H, et al. Multi-modal volume registration by maximization of mutual information. Med Image Anal. 1996;1:35–51.

    Article  PubMed  Google Scholar 

  • Willie BM, Birkhold AI, Razi H, et al. Diminished response to in vivo mechanical loading in trabecular and not cortical bone in adulthood of female C57Bl/6 mice coincides with a reduction in deformation to load. Bone. 2013;55:335–46.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Continuum Biomechanics and Mechanobiology Research Group, Institute of Applied Mechanics, University of Stuttgart, Pfaffenwaldring 5a, 70569, Stuttgart, Germany

    Annette I. Birkhold

  2. Department of Pediatric Surgery, McGill University, Research Centre, Shriners Hospital for Children-Canada, 1003 Decarie Blvd, H4A 0A9, Montreal, QC, Canada

    Bettina M. Willie

Authors
  1. Annette I. Birkhold
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bettina M. Willie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bettina M. Willie .

Editor information

Editors and Affiliations

  1. Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, United Kingdom

    Vinood B. Patel

  2. Department of Nutrition and Dietetics, Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom

    Victor R. Preedy

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media Dordrecht

About this entry

Cite this entry

Birkhold, A.I., Willie, B.M. (2017). Registered Micro-Computed Tomography Data as a Four-Dimensional Imaging Biomarker of Bone Formation and Resorption. In: Patel, V., Preedy, V. (eds) Biomarkers in Bone Disease. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7693-7_7

Download citation

Publish with us

Policies and ethics

Search

Navigation