Handheld microindentation - a direct assessment of bone fracture risk

Lead Research Organisation: University of Southampton
Department Name: Faculty of Engineering & the Environment

Abstract

Osteoporotic fractures are a major and increasing problem for both patients and society as a whole. The NHS is already spending well over a £1bn a year for treating patients with osteoporotic fractures and with the ever increasing life expectancy more and more patients will need treatment. It is estimated that 1 in 3 women over fifty and 1 in 5 men will suffer from an osteoporotic fracture. Yet an effective diagnosis is lacking to this point and the most commonly used assessment of bone mineral density or bone mass using X-ray techniques is seemingly inaccurate for individual patients. In part the problem is originating from the fact that bone mass is a surrogate and dose not account for the quality of bone and changes in material properties, which may be independent of bone mineral density. Therefore complementary tests could improve the diagnosis significantly and help in early identification and treatment of osteoporosis and osteopenia. Recently a microindentation was used in a pilot study on a cohort of patients. Indenting patient's tibiae that could clearly identify patients that had a recent osteoporotic fracture from a group of controls. While this is informative, further research is required to understand the correlation between bone mass, microindentation measurements and conventional assessment of in vitro bone tissue fragility. We propose ot acquire a microindentation device, which would be the first one in the UK to conduct further studies with the aim to judge potential future use for screening of patients and for laboratory studies.

Planned Impact

Potential future developments and overall impact of the proposed research
We are proposing to establish microindentation as novel tool for the assessment of bone quality. In particular we aim to validate microindentation against more conventional fracture toughness experiments. Given successful validation microindentation would be a promising step towards a bone fragility assessment tool that is easy to use. In a first instance the validation would benefit researchers in the medical, biological and biomedical engineering fields. Conventional fracture toughness tests on bone are complicated, require careful sample preparation and post-hoc fractography to determine areas created during stable and instable crack growth. In contrast, microindentation using the indentation distance increase parameter needs little preparation and does not require any post-hoc assessment. Given the so far encouraging results there is even the potential of this technique to advance to the bedside for screening of patient. It would truly be a breakthrough for patients at risk if instead of using a surrogate, i.e. bone mass, a real mechanical parameter could be used to diagnose their fracture risk. If the technique proves to be too invasive for regular use on patients, there is still huge benefit for development of drugs and better therapies. Usually most of these efforts are employing bone mass assessment as the most important endpoint. Yet, with the questionable value of this endpoint, it seems evident that treatments should also be tested against real mechanical parameters. There is true potential that drugs having an effect on bone quality complementary to bone quantity can be developed by targeting osteoblasts rather than osteoclasts. Also, microindentation may only be the first step. Surely the use of this technique and careful assessment of the parameters it delivers will likely also inspire other technological approaches, which may even be able to deliver similar parameters in a less invasive fashion.
Beyond academic beneficaries the proposed research would in the long run also benefit surgeons and potential patients alike, i.e. lowering the number of patients requiring total hip replacement due to hip fracture. Patients would also benefit, from better drugs from lowered incidence of back pain, which is often associated with osteoporosis of the spine. In addition, to the improvement of the situation for patients, society as a whole would benefit due to lowered costs in healthcare. For comparison the NHS spent about £1 billion per year on osteoporosis related fractures in 2000. This figure has likely risen substantially ever since and with the increasing life-expectancy and average age of our society is due to rise even further in the future if we do not fin more effective ways to diagnose, treat and prevent osteoporosis.
In addition, Professor Oreffo is Associate Dean Enterprise, Faculty of Medicine and was appointed as a Director, in 2008, on the Board of Southampton Asset Management and thus, is aware of the need to exploit and protect IP. Professor Cooper is part of a consortium EPIGEN, including the MRC, University of Southampton, University of Auckland, AgResearch New Zealand, and National University of Singapore involved in translating findings in developmental origins of disease as appropriate. Information gained from this study will be disseminated at the earliest appropriate opportunity at relevant bioengineering, chemical, mathematical, biophysical, and orthopaedic forums as well as in peer-reviewed journals. In addition, we are planning to establish a web site with information on the current project available for scientific and public access, the distribution of code for modelling as well as recorded datasets.

Publications

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Coutts LV (2017) Local Variation in Femoral Neck Cortical Bone: In Vitro Measured Bone Mineral Density, Geometry and Mechanical Properties. in Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry

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Jenkins T (2016) Site-Dependent Reference Point Microindentation Complements Clinical Measures for Improved Fracture Risk Assessment at the Human Femoral Neck. in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

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Thurner PJ (2014) The role of nanoscale toughening mechanisms in osteoporosis. in Current osteoporosis reports

 
Title ASBMR slide kit and videos 
Description ASBMR slide kit and videos 
Type Of Art Film/Video/Animation 
Year Produced 2016 
Impact ASBMR slide kit and videos 
 
Title ASBMR slide kit and videos 2017 
Description ASBMR slide kit and videos 2017 
Type Of Art Film/Video/Animation 
Year Produced 2017 
Impact ASBMR slide kit and videos 
 
Title WCO slide kit and videos 2016 
Description WCO slide kit and videos 2016 
Type Of Art Film/Video/Animation 
Year Produced 2016 
Impact WCO slide kit and videos 2016 
 
Title WCO slide kit and videos 2017 
Description WCO slide kit and videos 2017 
Type Of Art Film/Video/Animation 
Year Produced 2017 
Impact WCO slide kit and videos 2017 
 
Description During the grant we finally collected and characterized cortical femoral bone from 46 osteoporotic donors, 47 osteoarthritic donors and 16 cadaveric (healthy) controls.

Comparing results from reference point microindentation (RPI) and bone mineral density (BMD) measurements, which are the current gold standard we (developed,) discovered or concluded the following:

- best practices for how and where to test bone with RPI (Development)

-RPI delivers complementary information in comparison to BMD

- in the cohorts tested RPI did show significant differences between osteoporotic and non-osteoporotic (healthy) controls after adjustments for confounding factors

- RPI achieved an area under the curve of 0.89 by itself and combing it with BMD and / or FRAX this rose to up to 0.99 (1 would be a perfect identifier)

- Still, it is not entirely clear what RPI actually measures - from imaging studies we so far conclude that it is a mix of elasto-plastic properties, damage formation and porosity in the intend vicinity

- in the cohorts tested RPI did show significant differences between osteoarthritic and non-osteoarthritic (healthy) controls after adjustment for confounding factors

- Fracture toughness of bone at the inferomedial femoral neck was not found to be different between healthy, osteoporotic or osteoarthritic bone - therefor differences in RPI measurements stem mostly from other bone quadrants

- whether our results (obtained at the fracture site, i.e. the femoral neck) can be extended to the clinical measurement site for RPI (the tibia) remains to be shown - this is an important task to reveal whether such measurement truly give a picture of developments at another bone site. Due to legal restrictions it was not possible to perform such measurements on patients during the time of the grant.

- BMD currently delivers only one value - revisiting the results from our RPI measurements we are considering whether there is more unused information in BMD data that could provide a better diagnostic sensitivity and specificity in terms of a receiver operator characteristic (ROC)

- in the cohorts tested RPI did show significant differences between osteoarthritic and non-osteoarthritic (healthy) controls after adjustments for confounding factors

- some of the RPI measures did correlate with severity of osteoarthritis as per the Croft score cortical collapse, narrowing every or osteophyte severity


Beyond our studies on human bone, we also applied RPI (amongst other techniques) to evaluate the mechanical properties of animal bones from a study investigating the impact of Vitamin D deficiency during gestation. Here bones from offspring animals were investigated. Through RPI (and other techniques) we concluded that Vitamin D deficiency during gestation is no longer detectable in offspring bones, which are fed a normal diet (normal Vitamin D intake). This study was underpinned through an adjacent collaboration (including a PhD student) with Prof. Richard O. C. Oreffo (University of Southampton).
Exploitation Route Our research will provide important input into the use of reference point indentation in vitro and in vivo for mechanical characterization of bone tissue related to bone fragility. Our oral presentation at the 2015 congress of the American Society for Bone and Mineral Research did put our results into the spotlight and raised important questions and discussion within the bone community as a whole.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description We have disseminated most results in the course of scientific peer-reviews publications notably also in the highest-ranking journal for bone research (Journal of Bone and Mineral Research). Further we are currently considering to protect possible IP relating to improving conventional diagnostics from BMD measurements by extracting complementary information.
First Year Of Impact 2015
Sector Healthcare
Impact Types Economic

 
Description MRC Capital Award
Amount £134,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 03/2018 
End 03/2019
 
Description Wellcome Trust Collaborative Award
Amount £1,600,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2018 
End 09/2023
 
Description AUGMENT UK Biobank collaboration 
Organisation University of Bristol
Country United Kingdom 
Sector Academic/University 
PI Contribution AUGMENT UK Biobank collaboration
Collaborator Contribution AUGMENT UK Biobank collaboration
Impact AUGMENT UK Biobank collaboration
Start Year 2017
 
Description AUGMENT UK Biobank collaboration 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution AUGMENT UK Biobank collaboration
Collaborator Contribution AUGMENT UK Biobank collaboration
Impact AUGMENT UK Biobank collaboration
Start Year 2017
 
Description IOF CTF Webinar (NCH) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact IOF CTF Webinar
Year(s) Of Engagement Activity 2018
 
Description Invited ASBMR Webinar (NCH) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited ASBMR Webinar (NCH)
Year(s) Of Engagement Activity 2018
 
Description Plenary invited presentation at DOHAD World Congress (NCH) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Plenary invited presentation at DOHAD World Congress
Year(s) Of Engagement Activity 2017
 
Description Plenary presentation, International Conference on Children's Bone Health, Wurzburg (NCH) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Plenary presentation, International Conference on Children's Bone Health, Wurzburg (NCH)
Year(s) Of Engagement Activity 2017
 
Description Presentation at American Society for Bone and Mineral Research Annual Scientific meeting (EMC) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation at American Society for Bone and Mineral Research Annual Scientific meeting (EMC)
Year(s) Of Engagement Activity 2017
 
Description Presentation at American Society for Bone and Mineral Research Annual Scientific meeting (NCH) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation at American Society for Bone and Mineral Research Annual Scientific meeting (NCH)
Year(s) Of Engagement Activity 2017
 
Description Presentation at Association of Physicians Meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation at Association of Physicians Meeting
Year(s) Of Engagement Activity 2017
 
Description Presentation at DOHAD World Congress (EMC) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation at DOHAD World Congress (EMC)
Year(s) Of Engagement Activity 2017
 
Description Presentation at UK Association of Physicians Meeting (EMC) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentation at Association of Physicians Meeting
Year(s) Of Engagement Activity 2017
 
Description Presentation at World Congress in Osteoporosis (NCH) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation at World Congress in Osteoporosis (NCH)
Year(s) Of Engagement Activity 2017