Applied Mathematical Modelling 39 (2015) 35253534

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Applied Mathematical Modelling

journal homepage: www.elsevier.com/locate/apm

A theory for internal bone remodeling based on interstitial uid

velocity stimulus function
Ridha Hambli , Azeddine Kourta
Univ. Orlans, INSA-CVL, PRISME, EA 4229, Orlans, France
Polytech Orlans, 8, Rue Lonard de Vinci 45072 Orlans, France

a r t i c l e i n f o a b s t r a c t

Article history: Internal bone remodeling subjected to coupled axial force and radial loading is studied in
Received 22 March 2013 this paper. A theoretical model is developed based on a novel stimulus function expressed
Received in revised form 31 March 2014 in terms of a relation between radial strain applied to the pericellular matrix and the
Accepted 20 November 2014
interstitial uid velocity in the lacunar-canalicular system. An assumption of homogeneity
Available online 11 December 2014
is made in order to obtain a continuum representation. Theoretical results are presented to
verify the proposed remodeling theory.
Keywords:
2014 Elsevier Inc. All rights reserved.
Internal bone remodeling
Fluid ow velocity
Stimulus

1. Introduction

Bone continuously adjusts its mass, architecture and properties to a changing mechanical environment under internal
and/or external loads. Generally, there are two kinds of bone remodeling: internal and surface [1] (Frost, 1964). Internal
remodeling refers to the resorption or reinforcement of an existing bone by respectively decreasing or increasing the bulk
density of the bone within xed external boundaries. Surface remodeling refers to the resorption or deposition of bone
material on the external surface of the bone. Many internal bone adaptation theories have been proposed by several authors
[210]. Most of them are based on the concept of adaptive elasticity using an empirical remodeling rate equation expressed
in terms of rate change in the volume fraction of bone from its reference value. It does not describe, however, how local
mechanical signals are detected and how they are translated to bone formation and resorption. Several authors, Weinbaum
et al., 1994; Knothe Tate, 2003; Cowin, 2007 [1113] have suggested that when a whole bone is deformed, the deformation-
induced pressure gradient will cause bone uid to ow in the pericellular matrix (PCM) space of the lacunar-canalicular sys-
tem, inducing a drag force on the matrix bers. The ow is considered as a stimulus that drives osteocyte response, since
pressure variation within the bone uid can lead to shear stress forces, hydrostatic pressure and electric eld at the cell
membrane of the osteocytes. These mechanisms stimulate osteocytes to produce and secrete hormonal and biochemical
messengers such as cytokines and growth factors which affect cell differentiation and proliferation. In You et al. and Han
et al. [14,15] a model describing the uid ow of bone through the lacunar-canalicular system leading to strain amplication
in the osteocytic cell process membrane was developed.
In general, bone strain adaptation approaches are based on the phenomenological relationship between the rate of
deposition or resorption of the bone matrix and a macroscopic mechanical stimulus. Currently, no theories describing inter-
nal bone remodeling in response to mechanical stimulus expressed in terms of uid ow velocity in the PCM are available.

Corresponding author at: Univ. Orlans, INSA-CVL, PRISME, EA 4229, F45072 Orlans, France. Tel.: +33 (0)2 38 49 40 55.

http://dx.doi.org/10.1016/j.apm.2014.11.050
0307-904X/ 2014 Elsevier Inc. All rights reserved.
3526 R. Hambli, A. Kourta / Applied Mathematical Modelling 39 (2015) 35253534

In this work, an isotropic theory of internal bone remodeling is presented to study the effect of mechanical loads on the
bone remodeling process. The rate of remodeling is described using a stimulus function which expresses the relation
between the applied external strain in the PCM and the interstitial uid velocity which triggers the cell responses. In addi-
tion, a sensitivity analysis was performed to investigate the impact of the model factors sensitivities on the predicted
remodeling results.

2. Theory of internal bone remodeling

The proposed theoretical model has been built based on work by You et al. [14]. Following You, the idealized canaliculus
model consists of a hollow circular cylinder with its central cell process containing a centrally positioned osteocyte process
and its surrounding uid annulus. The inner radius is equal to Rw and the outer radius is equal to Rcan . Rm is the membrane
process radius (Fig. 1).
The dimensions of the model are discussed in detail in [11,16,17]. Cooper et al. [18], Marotti et al. [19] suggested a range
of dimension values depending on species, age and several factors.
The uid ow is generated by radial pressure. Therefore one can consider in the present paper that the cylindrical PCM is
subjected to radial external strain err due to daily mechanical loading which generates an applied external pressure on the
canalicular wall (Pcan ) and an internal pressure in the pericellular space of the lacunar-canalicular system (P w ). The boundary
conditions are:
rrr Pw ; rrh rrz rhz 0; at r Rw ; 1

rrr Pcan ; rrh rrz rhz 0; at r Rcan ; 2

and
Z
F
rzz dS Paxial ) rzz  2 axial 2  : 3
S p Rcan  Rw
In vitro experiments have found that bone cells respond to a uid shear stress of 0.26 Pa [2023].
The initial conditions are:
At t 0; err 0; V V 1 : 4
V 1 can be regarded as the initial condition for uid velocity in the case of disuse. V 1 is related to uid ow generated by
osmosis and electro-osmosis elds.
Bone is a heterogeneous material; an assumption of homogeneity is nevertheless made in the present work to achieve
smoothing over features such as osteons, lamellae, bers, and other structural elements, so that a continuum representation
can be obtained. The idealized model of the PCM consists of a hollow circular cylinder made of deformable bone matrix sat-
urated with an interstitial uid subjected to radial strain. An axisymmetric solid can be represented as shown in Fig. 1 using a
cylindrical coordinates system (r, z, h) with r and z denoting respectively the radial and axial coordinates of a point and with
u and v being the corresponding displacements.
In the (r, z) plane, where z is the axis of symmetry, the displacement eld of an axisymmetric solid is given by:
 
u
U ; 5
v
In this case, the strain tensor of a solid subjected to radial loading is given by:
 @u   T
e f err ezz ehh erz gT @r
@v
@z
u
r
1 @u
2 @z
@@rv : 6

( rr )2
Pericellular matrix
(space for fluid flow) ( rr )1
Canalicular wall
er
e
Canaliculus
M S1, P1 V1 V2 S2, P2
ez

R can
Cell process
Rw
Rm
( rr )1 Lost ( rr )2
Fig. 1. Idealized geometry of the theoretical model for PCM and uid ow model in the PCM space.
 R. Hambli, A. Kourta / Applied Mathematical Modelling 39 (2015) 35253534 3527

For quasi-stationary behavior, in the absence of a heat source and body forces, the set of equations for the elastic theory of
bones is completed by the following equations of equilibrium:
@ rrr @ rrz rrr  rhh
0; 7a
@r @z r

@ rzz @ rrz rrz

0; 7b
@z @r r

1 @ rhh
0: 7c
r @h
The behavior law derived from the continuum mechanics laws in [3,6] in the cylindrical coordinate system are:
rrr a11 err a12 ehh a13 ezz ; 8a

rhh a12 err a11 ehh a13 ezz ; 8b

rzz a13 err a13 ehh a33 ezz ; 8c

rrz a44 erz ; 8d

aij are elastic stiffness given by Cowin and Buskirk [6]:
e 1 
aij aij e a0ij a  a0ij ; 9
n0 ij
a0ij and a1ij are material constants, and e and n0 denote respectively the bone volume fraction and reference volume fraction of
bone material.
The remodeling rate equation of the theory of adaptive elasticity proposed by Cowin and Hegedus [3] in cylindrical coor-
dinates is given by:
e_ Ae Ar e err ehh Az eezz ; 10
where e_ is a change in the volume fraction of bone matrix material from its reference value e0 , Ae, Ar e and Az are material
parameters dependent upon the volume fraction e.
Very few data are available for material properties. A polynomial approximation of the data functions is given by Cowin
and Hegedus [3]:

Am e A0m A1m e; m r; z; 11
A0m and A1m are constants representing the material properties.

3. Proposition of uid ow based stimulus function

The Cowin and Hegedus [3] model considers that the mechanical stimulus for bone adaptation is a function depending on
strain components and some material parameters expressed by Eq. (10) which describes the change in the volume fraction of
the bone matrix in relation to applied strain. However, it has been postulated that interstitial uid ow through the lacuno-
canalicular system plays an important role in the regulation of bone adaptation [11,17]. McGarry et al. [24] developed a nite
element model of an idealized osteocyte cell body and conducted an in vivo experimental study to investigate cellular defor-
mation due to uid shear stress. The results obtained demonstrated a relationship between interstitial uid velocity and cell
responses. Based on these ndings, one can assume that the rate of remodeling equation is governed by a stimulus function
depending on the interstitial uid velocity stimulus rather than by a stimulus function expressed in terms of strain/stress
components. The objective in this paper is to develop a relationship between the change in the volume fraction of the bone
matrix from its reference value e0 and the interstitial uid velocity in the PCM.
Integration of (7a-b) leads to the expression of the radial displacement of the tubular bone matrix:
B
u Ar ; 12
r
and
v C z; 13
where A, B and C are unknown parameters which can be determined by introducing boundary conditions.
Applying Eq. (6) leads to:
B
err A  ; 14
r2
3528 R. Hambli, A. Kourta / Applied Mathematical Modelling 39 (2015) 35253534

B
ehh A ; 15
r2

ezz C; 16

erz 0: 17
Substituting the strain eld (14)(17) into stressstrain relations (8a-d), we obtain:
B
rrr Aa11 a12  a11  a12 a13 C; 18a
r2

B
rhh Aa11 a12 a11  a12 a13 C; 18b
r2

rzz 2Aa13 a33 C: 18c

Applying boundary conditions (1)(3), we obtain:
B
Aa11 a12  a11  a12 a13 C Pw ; 19a
R2w

B
Aa11 a12  a11  a12 a13 C Pcan ; 19b
R2can

pR2can  R2w 2Aa13 a33 C F axial : 19c

The unknown parameters are obtained from the system (19a-c):

pa33 R2can P
 can
Pw a13 F axial
A Pw 
; 20
p R2w  R2can a33 a11 a12  2a213

R2can R2w Pcan Pw

B ; 21
a11  a12 R2w  R2can

F axial a11 a12 2a13 p R2can Pcan Pw 2a13

C Pw : 22
pR2can  R2w a33 a11 a12  2 a213  a33

To describe the uid ow within the PCM space, a converging duct model was used in the investigation (Fig. 1). We con-
sider a uid movement located between areas S1 and S2 corresponding to the canaliculus length Lcan. The canaliculus was
subjected to a radial strain gradient err 1 and err 2 at areas S1 and S2 . Strain gradient generates pressures and velocity values
(P1 , V 1 ) at S1 and (P 2 ; V 2 ) at S2 locations.
In the case of steady ow of a constant density uid in a converging duct without losses due to friction, and if elevation
and gravity are neglected, the ow satises all the restrictions governing the use of Bernoullis equation expressed by:
1
P1  P2 q V 22  V 21 : 23
2
If we consider the steady ow of a constant density and incompressible uid, the continuity equation expressed in terms
of uid mass conservation is given by:
Q V 1 S1 V 2 S2 ; 24
3
Q is the volumetric ow rate expressed in mm /s, S1 and S2 are the cross sectional areas of the annular uid space at locations
1 and 2 of the pericellular space. By rearranging Eq. (24), we obtain:
S1 Q
V2 V1 : 25
S 2 S2
Substituting V 2 in Eq. (23), we obtain:
" #
2
1 S1
P1  P2 q V 21 1 : 26
2 S2

Interstitial uid ow through the PCM annular space can be treated as ow through a porous medium which can be
described by Darcys law:
 R. Hambli, A. Kourta / Applied Mathematical Modelling 39 (2015) 35253534 3529

K K dP
V  rP  ; 27
l l dz
l and K denote respectively uid viscosity and the permeability of bone which can determined by the bones microstruc-
ture and depend on the spacing of the transverse elements in the annular space and the ber spacing [14].
Eq. (27) can be written in discrete form:
K P2  P1
V  : 28
l Lcan
Substituting (23) into (25), we obtain:
" #
2
K 1 q V 21 S1
V  1 : 29
l 2 Lcan S2

The annular uid ow space for a location i (i = 1, 2) (Fig. 1) is expressed by:

h i
Si p R2w i  R2m : 30

Applying Eq. (14) at the pericellular wall (r Rw ), radial strain can be expressed by:
B
err w A  : 31
R2w
This leads to a wall radius position under radial strain load:
 12
B
Rw : 32
A  err w
The equation is nally injected into Eq. (27):
2 !2 3
1 K q V 21 4
B
Aerr w1
 R2m
V   15: 33
2 l Lcan B
Aerr w2
 R2m

The theory of adaptive elasticity [4] describes internal bone remodeling based on the idea of linearizing the elasticity
components and adapting their values iteratively depending on a variable describing the volume fraction of bone. The pro-
posed rate of volume fraction evolution referred to the remodeling equation is expressed empirically as a function of some
material parameters and applied strain. It is generally admitted that there are three main mechanosensory mechanisms in
bone: the cell system stimulated by mechanical loading, the system that translates mechanical loading into a signal, and the
systems that transmit that signal to the BMU cells for adaptation of the bone structure.
An increase in the strain gradient leads to an increase in uid velocity and hence, osteocytes respond by mechanotrans-
duction, releasing the local factors nitric oxide and prostaglandin E2. These local factors act as the signaling recruitment sig-
nals for bone cell progenitors and inuence the coupling activity among osteoblasts and osteoclasts during the process of
bone remodeling.
When bone tissue is exposed to a mechanical load, extracellular uid movement occurs in the canaliculi as a result of
spatial variation in the hydrostatic pressure. The ow generates shear stress on bone cell (osteocyte) membranes [11,17].
However, it is well admitted that initial mechanosensory events occur at the osteocytic and/or canalicular processes. Theo-
retical studies directed at understanding the cellular mechanism for bone remodeling have suggested that the prime mover
is the bone strain rate driven motion of the bone uid whose signal is translated by osteocytes. You et al., and Han et al.
[14,15] suggested that mechanotransduction is related to the tension exerted by the bers connecting the wall of the can-
aliculus to the cell process cytoskeleton rather than to the shear stress on the cell process. Gross et al. [25] showed that bone
deposition is related to strain gradients.
Based on these remarks, it can be suggested that a more realistic remodeling equation has to be expressed in terms of
interstitial uid velocity which triggers a number of events. To propose a relationship between the change in the volume
fraction of bone matrix from its reference value e0 and the interstitial uid velocity in the PCM, one can assume that the
interstitial uid velocity, which acts on the osteocyte network within the bone, can be linked to the variation in the bone
volume fraction:
e_ f V: 34
The non-linear form of Eq. (34) can be written:
2 !2 3b
B
Aerr w1
 R2m
e_ a V 21 4  15 ; 35
B
Aerr w2
 R2m
3530 R. Hambli, A. Kourta / Applied Mathematical Modelling 39 (2015) 35253534

a and b m2 sec4 are bone material parameters with:

1 Kq
a : 36
2 l Lcan

4. Results

To illustrate the proposed internal remodeling theory, a hollow, homogeneous circular cylindrical bone subjected to cyclic
quasi-static axial load P axial , an external pressure gradient Pcan 1 ; P can 2 at S1 and S2 and an internal pressure Pw was con-
sidered (Fig. 2). The boundary conditions are:

rrr Pw ; rrh rrz rhz 0; at r Rw ; 37

rrr Pcan ; rrh rrz rhz 0; at r Rcan : 38

Different axisymmetric loading cases were applied to the canaliculus corresponding to superimposed internal and exter-
nal pressure with:

Pw 1  n; n 1; 2; 3; 4; 5;

Pcan 2  m; m 1; 2; 3:
The material properties assumed for the bone and the remodeling rate coefcients are given in Table 1.
The elastic stiffness parameters assumed for the bone are [10]:

a11 151 e GPa; a12 a13 6:71 e GPa; a33 121 e GPa
The canaliculus length, initial inner and outer radii are given by You et al. [26]:

Lcan 50 nm; Rw 130 nm; Rcan 300 nm

The evolution of the normalized uid velocity in the PCM obtained by Eq. (33) is plotted in Fig. 3 as a function of the


amplitude of applied radial strain amplitude abs err 1  err 2 for different values of applied internal pressure Pw in the
PCM. The results show that uid velocity is strongly inuenced by the internal uid pressure.
It can be noticed that the shapes of the curves in Fig. 3 are similar to the one obtained experimentally by Guillaume et al.
[27] representing the variation of reacting osteoblasts versus applied strain during an in vivo experiment. A similar shape
was obtained theoretically by Han et al. [15] who described the evolution of hoop strain in the osteocytic process versus
the loading frequency with tissue loaded at different amplitudes.
Changes in bone volume fraction (VF) are plotted in Figs. 4 (a) and (b) obtained iteratively by the remodeling equations
for different applied internal pressures P w and external pressures Pcan . It can be seen that the VF increases or decreases
depending on the applied load amplitudes.

(Pan )1 (Pan )2

S1, P1 V1 Pw V2 S2, P2
ez

(Pan )1 Lost (Pan )2

Fig. 2. Boundary conditions and applied external (P can ) and internal (P w ) pressures.

Table 1
Material parameters used for the example [26].

E (GPa) m K (m2) l (Pa.s) e0 b V1 (m.s1)

18 3
15 0.3 10 10 0.2 1 107
 R. Hambli, A. Kourta / Applied Mathematical Modelling 39 (2015) 35253534 3531

Fig. 3. Normalized uid velocity in the PCM versus the amplitude of applied radial strain for different values of internal uid pressure P w .

0,3 0,35

0,25 0,3

0,25
0,2
0,2
VF
VF

0,15
0,15
0,1
0,1
0,05 Pw=1MPa Pw=2MPa Pw=3MPa 0,05
Pw=4MPa Pw=5MPa
0 0
0,0E+00 5,0E+05 1,0E+06 1,5E+06 2,0E+06 2,5E+06 0,0E+00 5,0E+05 1,0E+06 1,5E+06 2,0E+06 2,5E+06
Time (s) Time (s)

(a) Pcan = 2 MPa (b) Pcan = 4 MPa

Fig. 4. Variation of volume fraction VF with time t for different loads.

The bone volume fraction as a function of the external applied pressure P can is plotted in Fig. 5 for different internal pres-
sure values P w . One can notice the strong sensitivity of the response to external pressure which triggers the interstitial uid
velocity and hence the adaptive remodeling process.

4.1. Model parameters sensitivity analysis

The application of the proposed remodeling model requires 7 model factors (Table 1) which depend on aging, gender,
pathologies, drug intake, etc. Therefore, a sensitivity analysis (SA) was performed to investigate the impact of these factors
sensitivities on the predicted variation of bone volume fraction VF.
A preliminary one-factor SA analysis was performed in which only one model parameter value was varied by a given
amount while the other parameters were kept at their reference values. For each parameter change, a remodeling simulation
was performed for a duration of 2.5E6 cycles under normal daily loading with (Pw 2 MPa and P can 4 MPa) and the bone
volume fraction VF variation was predicted for each run. Each of the remodeling input parameters listed in Table 1 was var-
ied by 50% and +50% with respect to its reference values. A single run of the reference parameter values of the model was
compared to single runs of the model with each parameter changed individually. The SA analysis consisted of 7 runs
altogether.
The results of the SA are plotted in Fig. 6 which shows the impact that a xed change in each model parameter has on the
variation of the bone volume fraction.
3532 R. Hambli, A. Kourta / Applied Mathematical Modelling 39 (2015) 35253534

0,35

0,30

0,25

0,20
VF
0,15

0,10

0,05 Pw=1MPa Pw=2MPa Pw=3MPa

Pw=4MPa Pw=5MPa
0,00
1,50 2,50 3,50 4,50 5,50 6,50
External applied pressure (Pcan in MPa)

Fig. 5. Variation of volume fraction VF with applied external pressure P can for different values of internal pressure P w .

Fig. 6. Relative percentage change of the predicted bone volume fraction. Model parameters were varied between 50% and +50%.

The results of the SA underscore the inuence of each parameter on the resulting bone volume fraction. The results indi-
cate that variations in the permeability, uid viscosity and Youngs modulus density have a signicant inuence on bone var-
iation during the remodeling process. This can be related to the fact that these properties explicitly affect bone
mechanosensitivity and bone stiffness. Therefore, the higher deformation signals trigger the bone formation process
[12,21,28,29]. Note that the SA analysis showed that the Poisson ratio, initial volume fraction, initial uid velocity and
the material factor b have a moderate impact compared to the other parameters.
The present one-factor SA showed in particular that the bone mechanotransduction factors play signicant roles in the
bone adaptation process which may be modulated by specic bone drugs. Nevertheless, for future general SA analysis, it
is necessary to consider the full factorial parameters variation simultaneously.

5. Discussion

Several models have been developed to describe the adaptive behavior of bone based on the mechanical stimulus func-
tion [25,30]. It has been hypothesized that bone acts as a control system in which bone functional adaptation is driven by
the error between a mechanical set point and a mechanical stimulus [9,10,3033]. These models are phenomenological and
are not based on physical mechanisms related to interstitial uid velocity. In their work, Han et al. [15] investigated the par-
adox in bone tissue, namely the fact that tissue-level strains due to animal and human locomotion are too small to initiate
intracellular chemical responses directly. They put forward the idea that the uid ow through the PCM in the lacunar-
canalicular porosity due to mechanical loading can induce strains in the actin lament bundles of the cytoskeleton that
are more than one order of magnitude larger than tissue level strains. They suggested that mechanical stress increases
the ow of interstitial bone through canalicular and osteonal uid ow in the osteocyte network which generates strain-
amplication. Such mechanisms can provide a more realistic hypothesis for the excitation of osteocytes since the osteocyte
network embedded in the lacuna-canalicular system has shown sensitivity to shear stresses induced by uid ow [21]. The
ow is considered as a potent stimulus for osteocyte response. Pressure variation within the bone uid can translate to shear
stress forces, hydrostatic pressure and electric eld at the cell membrane of the osteocytes. These mechanisms stimulate
 R. Hambli, A. Kourta / Applied Mathematical Modelling 39 (2015) 35253534 3533

osteocytes to produce and secrete hormonal and biochemical messengers such as cytokines and growth factors which affect
cell differentiation and proliferation.
Despite these conclusions, the relation between the rate of bone volume fraction evolution and the interstitial uid
velocity has not yet been determined. Based on the previous remarks, we postulated that mechanotransduction signals
for adaptive bone remodeling are triggered by interstitial uid ow. Therefore, a modication of Cowins theory has been
proposed in this paper to describe the internal remodeling process with a mechanical stimulus expressed in relation to uid
velocity rather than a stress/strain phenomenological stimulus function.
As can be observed in Figs. 4 and 5, the proposed model predicted a saturation effect of the volume fraction. This is in
agreement with established results which suggested that the osteogenic response saturates quickly in response to mechan-
ical loading, and that cells require a recovery period to re-establish their mechanical sensitivity before they can fully respond
again to their mechanical environment. Rubin and Lanyon [34] and Umemura et al. [35] showed that the magnitude of the
bone response was not enhanced by additional loading cycles beyond a limited number of loading cycles, around 36 cycles/
day, implying that the cellular response to mechanical loading saturates quickly. Similar results were obtained by Klein-
Nulend et al. [21] and Ajubi et al. [36] which showed that intermittent hydrostatic compression had less effect than uid
ow in stimulating osteocyte proliferation.
It has been shown that the cascades of internal bone remodeling mechanisms triggered by mechanotransduction signals
for bone remodeling are linked to uid ow [12,21,28,29]. Osteocytes buried in the lacuna-canalicular porosity of the bone
matrix are sensitive to shear stresses induced by cyclic uid ow generated by the pressure gradient. It has been observed
that bone mass increases when osteocytes are cyclically loaded [37], indicating that bone remodeling is a response to mech-
anotransduction. Despite progress in the elds of bone mechanotransduction and adaptation processes, there is a lack of
integrated and coupled transduction-remodeling models. Such models would be very useful in helping to explain bone tissue
behavior and in developing enhanced computer simulations to investigate the determinant factors of bone strength by
considering the cascades of mechanobiological mechanisms that occur during bone organ adaptation to its mechanical
and biological environment.
A review of the literature showed that the classical mathematical remodeling models currently available are generally
based on principles of continuum mechanics, which establishes a phenomenological relationship between mechanical load
and bone remodeling, without considering the physical process of mechanotransduction. Developing physically based
mechanistic models that take the real cascades of bone remodeling mechanisms into consideration is of great importance
to investigate the determinant of bone strength and related diseases such as osteoporosis and to design bone implants
because it enables monitoring of bone tissue behavior during postoperative implanted conditions where loading conditions
change.
In the present work, the problem of internal bone remodeling has been addressed within the framework of adaptive elas-
tic theory, assuming a homogeneous bone material. At the canalicular scale, the present model proposes a theory of adaptive
remodeling coupled with a mechanotransduction function expressed in relation to interstitial uid velocity in the PCM. Fluid
velocity at the macroscopic scale is important since it represents the average uid velocity through the canaliculi and can be
linked to the mechanotransduction of bone remodeling signals [26].
We have proposed here a coupled transduction-remodeling theory which combines the geometrical model developed by
You et al. [14] and a novel remodeling model based on work by Cowin and Hegedus [3]. From a computer simulation point of
view, the present theory may be implemented into nite element (FE) codes to perform remodeling predictions at bone
organ level. Nevertheless, a validation step is needed to assess the reliability of the model. In general, due to the lack of
specic experimental data related to the human femur remodeling process, complete validation of human remodeling FE
models is hard to achieve. Therefore, one can compare the results obtained by the proposed theory with those obtained
by the classic phenomenological remodeling approaches of Huiskes [38] considered as the gold standard for the simulation
of bone remodeling [39].
Beyond the mathematical development, a practical clinical question of utility will hinge on the specic role of the
transduction process in the occurrence of specic diseases such as osteoporosis. For example, the proposed model may be
implemented into nite element codes to perform simulations to explore the effects of different transduction and remodel-
ing activities on the human proximal femur adaptation process, in particular for osteoporotic people. Nevertheless, in order
to perform numerical simulations consistent with real phenomena, it is crucial to develop specic experiments to character-
ize the parameters involved in the present model and perform experimental validation, which is beyond the scope of the
current study.

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