True Gold or Pyrite: A Review of Reference Point Indentation for Assessing Bone Mechanical Properties In Vivo

Although the gold standard for determining bones' mechanical integrity is the direct measure of mechanical properties, clinical evaluation has long relied on surrogates of mechanical properties for assessment of fracture risk. Nearly a decade ago, reference point indentation (RPI) emerged as an innovative way to potentially assess mechanical properties of bone in vivo. Beginning with the BioDent device, and then followed by the newer generation OsteoProbe, this RPI technology has been utilized in several publications. In this review we present an overview of the technology and some important details about the two devices. We also highlight select key studies, focused specifically on the in vivo application of these devices, as a way of synthesizing where the technology stands in 2015. The BioDent machine has been shown, in two clinical reports, to be able to differentiate fracture versus nonfracture patient populations and in preclinical studies to detect treatment effects that are consistent with those quantified using traditional mechanical tests. The OsteoProbe appears able to separate clinical cohorts yet there exists a lack of clarity regarding details of testing, which suggests more rigorous work needs to be undertaken with this machine. Taken together, RPI technology has shown promising results, yet much more work is needed to determine if its theoretical potential to assess mechanical properties in vivo can be realized. © 2015 American Society for Bone and Mineral Research.

[1]  P. Thurner Atomic force microscopy and indentation force measurement of bone. , 2009, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[2]  平野 徹 Anabolic effects of human biosynthetic parathyroid hormone fragment (1-34), LY333334, on remodeling and mechanical properties of cortical bone in rabbits , 1999 .

[3]  Alexander J. Makowski,et al.  Identifying Novel Clinical Surrogates to Assess Human Bone Fracture Toughness , 2015, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[4]  J. Nyman,et al.  Increasing duration of type 1 diabetes perturbs the strength-structure relationship and increases brittleness of bone. , 2011, Bone.

[5]  Adam C. Abraham,et al.  Multiscale Predictors of Femoral Neck In Situ Strength in Aging Women: Contributions of BMD, Cortical Porosity, Reference Point Indentation, and Nonenzymatic Glycation , 2015, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[6]  I. Jasiuk,et al.  Towards a standardized reference point indentation testing procedure. , 2014, Journal of the mechanical behavior of biomedical materials.

[7]  D. Burr,et al.  Raloxifene enhances material-level mechanical properties of femoral cortical and trabecular bone. , 2007, Endocrinology.

[8]  Toru Hirano,et al.  Anabolic Effects of Human Biosynthetic Parathyroid Hormone Fragment (1–34), LY333334, on Remodeling and Mechanical Properties of Cortical Bone in Rabbits , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[9]  A. Díez-Pérez,et al.  Microindentation for in vivo measurement of bone tissue material properties in atypical femoral fracture patients and controls , 2013, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[10]  P. K. Zysset,et al.  Indentation of bone tissue: a short review , 2009, Osteoporosis International.

[11]  P. Thurner,et al.  Toughness and damage susceptibility in human cortical bone is proportional to mechanical inhomogeneity at the osteonal-level. , 2015, Bone.

[12]  D. Burr,et al.  Skeletal changes associated with the onset of type 2 diabetes in the ZDF and ZDSD rodent models. , 2009, American journal of physiology. Endocrinology and metabolism.

[13]  B. Bhushan,et al.  A Review of Nanoindentation Continuous Stiffness Measurement Technique and Its Applications , 2002 .

[14]  Thomas D Brown,et al.  Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Second Report of a Task Force of the American Society for Bone and Mineral Research , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[15]  G. Schitter,et al.  The Effect of NaF In Vitro on the Mechanical and Material Properties of Trabecular and Cortical Bone , 2009 .

[16]  Morton B. Brown,et al.  The bone diagnostic instrument II: indentation distance increase. , 2008, The Review of scientific instruments.

[17]  P. Hansma,et al.  The bone diagnostic instrument III: testing mouse femora. , 2009, The Review of scientific instruments.

[18]  A. Díez-Pérez,et al.  The tissue diagnostic instrument. , 2009, The Review of scientific instruments.

[19]  C. Cooper,et al.  Variability in reference point microindentation and recommendations for testing cortical bone: maximum load, sample orientation, mode of use, sample preparation and measurement spacing. , 2015, Journal of the mechanical behavior of biomedical materials.

[20]  M. Allen,et al.  Variability of in vivo reference point indentation in skeletally mature inbred rats. , 2014, Journal of biomechanics.

[21]  C. Cooper,et al.  Variability in reference point microindentation and recommendations for testing cortical bone: location, thickness and orientation heterogeneity. , 2015, Journal of the mechanical behavior of biomedical materials.

[22]  P. Hansma,et al.  Bone diagnostic instrument , 2006 .

[23]  S. Papapoulos,et al.  Bone material strength as measured by microindentation in vivo is decreased in patients with fragility fractures independently of bone mineral density. , 2015, The Journal of clinical endocrinology and metabolism.

[24]  Wen Du,et al.  Review of research on the mechanical properties of the human tooth , 2014, International Journal of Oral Science.

[25]  Joseph M. Wallace,et al.  In vivo reference point indentation measurement variability in skeletally mature inbred mice. , 2015, BoneKEy reports.

[26]  Jan L. Bruse,et al.  Reference point indentation is not indicative of whole mouse bone measures of stress intensity fracture toughness , 2014, Bone.

[27]  Daniel C Bridges,et al.  A new device for performing reference point indentation without a reference probe. , 2012, The Review of scientific instruments.

[28]  K. Jepsen,et al.  Biomechanical Mechanisms: Resolving the Apparent Conundrum of Why Individuals With Type II Diabetes Show Increased Fracture Incidence Despite Having Normal BMD , 2014, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[29]  Ian Pyrah,et al.  Denosumab, a fully human RANKL antibody, reduced bone turnover markers and increased trabecular and cortical bone mass, density, and strength in ovariectomized cynomolgus monkeys. , 2011, Bone.

[30]  Ego Seeman,et al.  Differing effects of denosumab and alendronate on cortical and trabecular bone. , 2014, Bone.

[31]  Bryan G Beutel,et al.  Characterization of damage mechanisms associated with reference point indentation in human bone. , 2015, Bone.

[32]  W. Bonfield,et al.  Fracture toughness of compact bone. , 1976, Journal of biomechanics.

[33]  A. Díez-Pérez,et al.  Bone Tissue Properties Measurement by Reference Point Indentation in Glucocorticoid‐Induced Osteoporosis , 2015, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[34]  P. Kostenuik,et al.  Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody. , 2011, Bone.

[35]  M. Delp,et al.  Altered bone mass, geometry and mechanical properties during the development and progression of type 2 diabetes in the Zucker diabetic fatty rat. , 2008, The Journal of endocrinology.

[36]  J. Nyman,et al.  Insights into reference point indentation involving human cortical bone: sensitivity to tissue anisotropy and mechanical behavior. , 2014, Journal of the mechanical behavior of biomedical materials.

[37]  Joseph M. Wallace,et al.  In vivo reference point indentation reveals positive effects of raloxifene on mechanical properties following 6 months of treatment in skeletally mature beagle dogs. , 2013, Bone.

[38]  R. Ritchie,et al.  Multi-level characterization of human femoral cortices and their underlying osteocyte network reveal trends in quality of young, aged, osteoporotic and antiresorptive-treated bone. , 2015, Biomaterials.

[39]  Matthew R Allen,et al.  Reference-point indentation correlates with bone toughness assessed using whole-bone traditional mechanical testing. , 2013, Bone.

[40]  Daniel C Bridges,et al.  Microindentation for In Vivo Measurement of Bone Tissue Mechanical Properties in Humans , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[41]  D. Burr,et al.  Bisphosphonate effects on bone turnover, microdamage, and mechanical properties: what we think we know and what we know that we don't know. , 2011, Bone.

[42]  S. Khosla Surrogates for Fracture Endpoints in Clinical Trials , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[43]  Daniel C Bridges,et al.  Applications of a New Handheld Reference Point Indentation Instrument Measuring Bone Material Strength. , 2013, Journal of medical devices.

[44]  S. Khosla,et al.  In Vivo Assessment of Bone Quality in Postmenopausal Women With Type 2 Diabetes , 2014, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[45]  G. Pharr,et al.  An improved technique for determining hardness and elastic modulus using load and displacement sensing indentation experiments , 1992 .