modeling bone remodeling - the influence of microcracks

Modeling Bone-Remodeling

21.04.2015 1UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de21.04.2015


The Influence of Microcracks

Tom Theile


21.04.2015 2UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de21.04.2015 2

Bone RemodelingIntroduction – The Bone Remodeling Process

The human skeleton serves many functions:

For all these functions, the remodeling-process plays an important role

Remodeling repairs damages and microdamages and lets the bone adapt to changing loads

~10% turnaround every year in adults (Heaney et al. 1978)

Pathologic changes may lead to osteoporosis and fractures

Mechanical functions Chemical functions Biological functions

• Carry loads

• Protect the body

• Allow movements

• Store calcium and iron

• Produce blood cells

• Release hormons

21.04.2015 UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de 3

Bone Remodeling – How is it done?Introduction – The Bone Remodeling Process

Osteoclasts resorp mineralized bone

Osteoblasts synthesize mineralized bone

Osteocytes are former osteoblasts, build into the mineralized matrix.

Osteocytes

Image-source: york.ac.uk


Bone Remodeling – How is it done?Introduction – The Bone Remodeling Process

Osteoclasts resorp mineralized bone

Osteoblasts synthesize mineralized bone

Osteocytes are former osteoblasts, build into the mineralized matrix.

Osteocytes

Image-source: york.ac.uk


21.04.2015 5UNIVERSITÄT ROSTOCK | Institut für Informatik | Dept. Of Systems Biology and Bioinformatics | www.sbi.uni-rostock.de

Osteocytes

Osteocytes form a network to exchange

nutrients and waste (Aarden et al. 1994)

This Network may also be used for

intercellular communication

Osteocytes secrete RANKL

Osteocytes initiate bone remodeling events

Osteocytes control the bone remodeling

process (Nakashima et al. 2011)



Microcracks

• Microcracks are tiny fractures

• Microcracks arise after many cycles of high (but not too

high) loads

• Accumulation and growth of microcracks leads to material

failure

• Bone remodeling repairs microcracks

• First evidence for higher remodeling rates at locations with

more microcracks (Mori et. al)



Microcracks – Our Objective

(afaik) no direct evidence, that osteocytes can really sense mechanical

or electrical fields

Our hypothesis:

• Osteocytes can (only) sense microcracks

• Local bone remodeling is only steered by microcracks

• Adaption to changing loads only by excessive repair of

microcracks

Our model

• We build a model, that tests this hypothesis quantitatively



Methods – Microcrack Simulation

Spatio-temporal, agent-based Monte Carlo simulation

Input:

• Micro-computer comography data of bone microstructure ( Fazzalari 2012)

• Parameters from the literature

• Remodeling volume fraction per year (usually 10% in adults)

• Remodeling volume per event

• New cracks per volume per year (hard to obtain)

Model

Output

• Number of microcracks per volume

• Mean length of microcracks

• Length of the biggest microcrack



Methods – Microcrack Simulation –The Model

Cracks• Add microcracks to the microstructure

Signals

• Send out signals at the positions of microcracks

• Spread signals by diffusion simulation

Remodel

• Find a remodel position

• Remove all microcracks and signals around theposition

1 time step

x 100 years



Mineralized bone (trabecula)

Marrow tissue



Cracks• Add microcracks to the microstructure



Signals

• Send out signals at the positions of microcracks

• Spread signals by diffusion simulation



Remodel• Find a remodel position



Remodel

• Remove all microcracks and signals around the remodel position


21.04.2015 15UNIVERSITÄT ROSTOCK | Institut für Informatik | Systems Biology and Bioinformatics Rostock | www.sbi.uni-rostock.de

Remodel

• Remove all microcracks and signals around the remodel position



repeat



Methods – Microcrack Simulation – Variants

With osteocytes and signal-steered remodeling

Remodeling events with higher probability near

microcracks

Without osteocytes and signal-steered remodeling

Random positions of remodeling events

• Two different versions of the simulation – to be able to compare the results



Results


1

10

100

1000

10000

100000

0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4

crac

klen

gth

su

m in

mm

/mm

^3

remodeling volume fraction per year

mean cracklength over remodeling volume fraction

Random

Steered


Results

~3 times more remodeling events are necessary to keep the bone on the same health without directed remodeling


1

1001

2001

3001

4001

5001

6001

0 0.05 0.1 0.15 0.2 0.25 0.3 0.35

mea

n m

axim

um

cra

ckle

ng

th in

m

m/m

m^

3


mean maximum cracklength over remodeling volume fraction

Random

Steered


Results

The effect is even more extreme on the maximum crack-length ~6 times more efficient



Discussion 1

1

10

100

1000

10000

100000

0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4


mean cracklength over remodeling volume fraction

Random

Steered

Strange artifact in the steered simulation:

Especially good bone health at remodeling rates

of 10% per year!

Why?

• Random result?

• No. Simulation was repeated often

• Error in simulation?

• …probably not

• Negative influence of remodeling events on signal distribution – 10% rate may be an

optimum value?

10%/year is assumed as the actual turnover rate in adult humans – but that is probably a

coincidence

Needs further investigation



Discussion 2 & Conclusion

We showed: Guided bone remodeling is much more efficient than random bone remodeling!

Widely believed: The role of osteocytes is to guide the remodelling process. Our simulation shows why guidance is

needed.

It remains unclear wether osteocytes can sense mechanical strain

We showed: Microcrack-sensing is a sufficient mechanism to steer the remodeling locations



Outlook – What to do next

Combine with FE-Analysis

• Do osteocytes sense mechanical strain?

• Will the remodeling be even more efficient

compared to microcrack-sensing?



Outlook

• Investigate strange behaviour at 10% turnover rate

• Include variable parameters over lifetime

• Compare results to FE-coupled modell

• Include spatial remodeling into the model

• Compare spatial structure to experimental data



Thank you

for your attention and useful ideas!

Bibliography

Aarden, E.M., Nijweide, P.J. & Burger, E.H., 1994. Function of osteocytes in bone. Journal of

cellular biochemistry, 55(3), pp.287–299.

Heaney, R.P., Recker, R. & Saville, P., 1978. Menopausal changes in bone remodeling. The

Journal of laboratory and clinical medicine, 92(6), pp.964–970.

Lanyon, L., 1993. Osteocytes, strain detection, bone modeling and remodeling. Calcified tissue

international, 53(1), pp.S102–S107.

Nakashima, T. et al., 2011. Evidence for osteocyte regulation of bone homeostasis through

RANKL expression. Nature medicine, 17(10), pp.1231–1234.

Verborgt, O., Gibson, G.J. & Schaffler, M.B., 2000. Loss of osteocyte integrity in association with

microdamage and bone remodeling after fatigue in vivo. Journal of Bone and Mineral Research,

15(1), pp.60–67.

Nicola L. Fazzalari 2012, , Brianna L. Martin, Murk J. Bottema, Tammy M. Cleek, Arash Badiei. A

model for the change of cancellous bone volume and structure over time. Mathematical

Biosciences. 240 132–140


modeling bone remodeling - the influence of microcracks

Science

mineralized matrix

mineralized boneosteocytes

systems biology

rankl osteocytes

osteocytes imagesource

layers of collagen type

ossificated osteoblast

growth of microcracks