Finite Elements in Analysis and Design 104 (2015) 16–25

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Finite Elements in Analysis and Design

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

Review

A microscale bone remodeling simulation method considering

the influence of medicine and the impact of strain on osteoblast cells
Wei Yi a, Cheng Wang b, Xiaohu Liu a,n
a
Department of Mechanics, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, China
b
Lanzhou University, Lanzhou 730000, China

art ic l e i nf o a b s t r a c t

Article history: Bone remodeling is an evolutionary process of microstructure configuration that occurs under a variety of
Received 4 July 2014 external stimulations. Critical to the process are the osteoblast and osteoclast cells, which relate to bone
Received in revised form formation and absorption. Unlike osteoclast cells, the osteoblast cells are sensitive to mechanical strain,
15 April 2015
which indicates that mechanical strain plays a key role in the bone remodeling process. In this paper, a
Accepted 17 April 2015
modified governing equation for bone remodeling is proposed to simulate the remodeling process at a
Available online 2 June 2015
microscale. Equivalent strain was used as the stimulus, and the influence of medicine was taken into account.
Keywords: A forward Euler integration method and a strain distribution solver, Abaqus/standard, were used to solve the
Bone remodeling governing equation. Three sets of simulations were conducted based on the idealized microstructure
Microscale
configuration, the semi-idealized microstructure configuration (the space truss structure) and the actual
Medicine influences
bone microstructure configuration derived from a Micro-CT scan experiment. The results indicate that
mechanical load eventually determines the microstructure configuration as bone structure attempts to
support the mechanical load with minimal mass. The simulation confirms that Denosumab, which has been
wildly used to treat osteoporosis, effectively increased bone density and decreased porosity. Furthermore,
bone microstructure samples were obtained through the simulation to provide the elastic module – porosity
data points. All of the simulations indicated that the proposed method was reasonable and effective.
& 2015 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2. Material and method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2.1. Governing equation of microscale bone remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2.2. Solving scheme . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.2.1. Boundary element search algorithm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.2.2. Mass variation rate allocation algorithm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.1. Idealized microstructure configuration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.2. Semi-idealized microstructure configuration (space truss structure) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.3. Real microstructure configuration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3.3.1. Micro CT experiment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
3.3.2. Simulations and application . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Appendix A. Supplementary information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25

n
Corresponding author. Tel.: þ 86 27 87543538; fax: þ 86 27 87543501.
E-mail addresses: Yiwei_hust@qq.com (W. Yi),
wangchen@hhu.edu.cn (C. Wang), xhliu@mail.hust.edu.cn (X. Liu).

http://dx.doi.org/10.1016/j.finel.2015.04.007
0168-874X/& 2015 Elsevier B.V. All rights reserved.
 W. Yi et al. / Finite Elements in Analysis and Design 104 (2015) 16–25
1. Introduction
In the human body, cancellous bones are spongy-like structures
consisting of interlaced rod-type or plate-type trabecular bone [1].
This type of bone is the primary component of pressure-bearing
bones such as the spinal bones and the femoral head. The
evolution of bone microstructure is a process wherein stimuli
affect the osteoclast cells and osteoblast cells, which are closely
associated with bone resorption and formation, respectively [2].
The bone microstructure evolution process is also often referred to
as the bone remodeling process. The bone remodeling process is
an important physiological mechanism that helps keep the bone
structure functional and stable [3]. Once the dynamic balance of
bone remodeling is broken, the patient may suffer osteoporosis or
sclerosis. Mechanical stimulus plays a very important role in the
remodeling process [4]. When the mechanical stimulus, known as
strain, drops below a certain threshold, the osteoclast cells are
activated and begin to absorb bone. Conversely, when the stimulus
becomes higher than the threshold but remains within the
physiological range, the activated osteoblast cells begin to format
new bone [5]. Under some extreme circumstances when the
stimulus is within a pathologic range, the bone matrix cracks,
and a bone fracture occurs.
The bone remodeling simulation method can be divided into
two categories: macroscale and microscale according to the size of
the simulation object. Macroscale bone remodeling [6,7] mainly
focuses on the density redistribution inside the bone structure.
Assuming the relationship between the density and elastic mod-
ule, the density variation is calculated in accordance with the
mechanical stimulus, which in this case, is the strain energy
density. This method was frequently used to predict bone remo-
deling long after an orthopedic surgery [8,9] or implant [10–12].
Because the macroscale bone remodeling method only updated
the density, it was incapable of simulating the morphological
evolution of the bone structure. Concurrently, the microscale bone
remodeling method deals primarily with the microstructure con-
figuration [13,14], which is continuously evolving during remodel-
ing. Depending on the mechanical stimulus, the bone matrix
surfaces were either swallowed or grew outward. This resorption
and formation mechanism led to a microstructure evolution.
In macroscale bone remodeling simulation, the relationship
between the mechanical stimulus and resorption/formation is
relatively simple. A piecewise linear function is usually applied
to describe the relationship [15,16]. More specifically, a ‘lazy zone’
[17] represents the interval at which the resorption rate and the
formation rate remain in equilibrium. At the same time, increased
mechanical stimulus enhances the formation, and decreased
mechanical stimulus leads to local bone resorption. As density is
used to represent the local microstructure and the mechanical
stimulus distribution in the bone matrix (trabecular bone) is
unattainable, the piecewise function involving the mechanical
stimulus of each element is a successful simplification. However,
in microscale bone remodeling simulation method, the mechanical
stimulus distribution in the bone matrix (trabecular bone) is
available, and a more complicated function based on remodeling
mechanism is adopted [13,18–20].
Scholars have proposed disparate mechanical stimuli as the
basis for bone remodeling simulation methods. These include
strain energy density (SED) [10–12], strain energy density rate
(SED-R) [13,14], non-uniformity of the stress/strain distribution
[21], etc. However, many osteoblast in vitro experiments [22] have
shown that strain is the mechanical stimulus that influences
proliferation [23] and differentiation [24]. Additionally, a low-
frequency (0.2–1 Hz) alternating strain stimulus was more effec-
tive than a constant strain stimulus [25].
17
In this study, a microscale bone remodeling simulation method
was proposed, and a corresponding governing equation was
established. The equivalent strain was used as the mechanical
stimulus; the proliferation and differentiation effect of the osteo-
blast cells affected by the equivalent strain were also considered,
as was the influence of the different physiological conditions on
the formation/resorption rate.
This paper is organized as follows: a description of the governing
equation and the solving scheme are given in Section 2. Several
different numerical examples are presented in Section 3. The discus-
sion and conclusions follow in Sections 4 and 5, respectively.
2. Material and method
In this section, the governing equation and solving scheme are
detailed.
2.1. Governing equation of microscale bone remodeling
Based on different mechanical strain, bone remodeling reveals
varying characteristics in different stages. When the stimulus is
lower than a threshold, the formation speed is lower than the
absorption speed, and bone mass decreases. When the stimulus
reaches a certain magnitude, the formation speed is higher than
the absorption speed, and bone mass increases [4]. The threshold
strain is equivalent to the very strain at which the formation speed
equates to the absorption speed. Moreover, each bone inner
boundary element is considered (Fig. 2) as a virtual
remodeling site.
At any time t, the bone mass variation rate in each remodeling
site of the current micro-structure configuration is the combina-
tion of the formation and resorption, as outlined below
dmtot dmbl dmcl
¼ þ ð1Þ
dt dt dt
where dmcl and dmbl are the contribution of resorption and
formation to the bone mass variation, respectively. Because
resorption has nothing to do with mechanical strain,
dmcl
¼ r cl ð2Þ
dt
where rcl is the resorption rate in each virtual remodeling site. And Eq.
(2) was identical to the work of [13]. However, the osteoclast cells are
sensitive to specific medicine (Denosumab) and hormones (Testoster-
one), so an impact factor η is introduced into Eq. (2):
dmcl
¼ ð1 þ ηÞr cl and r cl ¼ nP cl ρ ð3Þ
dt
The value of η is in the range of [  1, þ1), theoretically, and the
upper and lower bounds represent infinitely enhancing and
completely inhibiting bone resorption, respectively. According to
the different types of medicine and the condition of the patient, η
should be set to an appropriate value. n is the osteoclast cell
density (the osteoclast cell number per a virtual remodeling site),
Pcl is the resorption rate per each osteoclast cell. ρ is the true
density of the bone material.
When the strain of the osteoblast cell is larger than the
threshold strain Ktr and less than the failure strain Kf, the forma-
tion rate in each virtual remodeling site is
dmbl
¼ ð1 þ λÞτi NP K tr ρ and τi ¼ Pðεi Þ U Nðεi Þ K f Z εi Z K tr ð4Þ
dt
where εi is the mechanical strain of the osteoblast cell i caused by
the adhesion bone matrix. PKtr is the formation rate of a single
osteoblast cell under threshold strain Ktr. N is the number of
18 W. Yi et al. / Finite Elements in Analysis and Design 104 (2015) 16–25

osteoblast cells per the virtual remodeling site. τi is the ratio of the
formation rate between the current strain and the threshold strain.
And τi includes two parts: differentiation and proliferation. The
osteoblast cell differentiates to osteocytes when it matures; during
this process, the osteoblast cell secretes matrix and fiber, which
turn into bone matrix. Thus, the differentiation factor P(εi) can be
used to represent the formation rate ratio of a single osteoblast cell
between the current strain εi and the threshold strain Ktr. More-
over, the total osteoblast cell numbers increase because of pro-
liferation. Accordingly, N(εi) is defined as the ratio of total
osteoblast cells between the current εi strain and the threshold
strain Ktr. Based on the study of Yang [22], proliferating cell
nuclear antibody (PCNA) and alkaline phosphatase (ALP) activities
are chosen as the indexes for proliferation and differentiation,
respectively. Two normalized piecewise functions are used to
describe these effects based on the experiment data.
Similar to η, λ is the theoretical medicine influence on the
osteoblast cell in the range of [  1,þ1). The upper and lower
bounds represent the infinitely enhancing and completely inhibit-
ing bone formation, respectively. According to the different types
of medicine and the condition of the patient, λ should be set to an
appropriate value.
When the mechanical strain of the basal bone matrix is larger
than the failure strain Kf, the matrix is damaged.
When the mechanical strain is lower than the threshold strain
Ktr, the osteogenesis effect is still active but is always less than the
formation effect under the threshold strain. This concept is out-
lined as follows:
dmbl ε As previously mentioned, the two collections, {Ei} and {E0i }, are
¼ ð1 þ λÞ i NP K tr ρ and εi oK tr :
dt K tr
2.2. Solving scheme
calculated based on the strain of the adhesion bone matrix as
determined by the Abaqus/standard; (2) based on dmtot/dt, it can be
determined whether the current bone matrix element will be
swallowed by the osteoclast cells and become void or if it will
grow to form new bone matrix elements. In the microstructure
evolution subprocedure, the resorption phase and the formation
phase co-exist. The resorption phase deals primarily with the bone
matrix inner boundary element {Ei} of the current configuration,
and the formation phase focuses on the outer boundary of the void
elements {E0i }, which is connected with the bone matrix element
and has the potential of becoming a bone matrix element. Thus,
for every microstructure alteration, two collections {Ei} and {E0i }
need to be updated by iterating all elements. Fig. 2 gives a visual
representation of the inner boundary and outer boundaries. There
are only two types of elements, i.e., bone matrix elements and void
elements. Furthermore, there are only three different ways for any
two elements to be directly connected, i.e., concurrent, collinear
and coplanar (existing in 3D). Thus, the void elements which
directly connect with the bone matrix are both the inner boundary
of the void element and the outer boundary of the bone matrix
elements, marked with a slash in the figure. The boundary element
search algorithm is outlined below. It is worth mentioning that
subscript i, j and k all represent element labels in the following
sections.
2.2.1. Boundary element search algorithm
ð5Þ
the inner boundary of the bone matrix elements and the inner
boundary of the void elements, both of which require updating for
each configuration. This search algorithm is valid for both

The bone remodeling governing equation is a function of time

and strain. A forward Euler integration method was implemented
to solve the equation. At the current time tn, the strain field can be
calculated through the Abaqus/standard using the microstructure
configuration under certain mechanical loading. The resorption
and formation is calculated per the governing equation. Then, a
time step Δtn is determined based on the average single element
resorption/formation period, as in Eq. (8). The microstructure
configuration at time tn þ 1 ¼ Δtn þtn is updated. Until the config-
uration is stable, the process outlined above is repeated. See the
flow chart below for the solving scheme in Fig. 1.
The microstructure evolution simulation is the most important
subprocedure. There are two main steps in this subprocedure:
(1) According to Eq. (1), the mass variation rate dmtot/dt is Fig. 2. Inner and outer boundaries (2D for convenient expression).

Fig. 1. Flow chart of the governing equation solving scheme. The subfigures below each subprocedure demonstrate the entire process more intuitively: (a) the configuration
of step n, i.e., 2; (b) the equivalent strain contour; (c) the configuration of step nþ 1, i.e., 3.
 W. Yi et al. / Finite Elements in Analysis and Design 104 (2015) 16–25 19

collections because they are complementary, as seen in Fig. 2. The
search process for the inner boundary of the void elements is as
follows:
(1) Assigning a flag value for each element ei, as
( swallowed, the element remains bone matrix. More specifically,
1 if ei is void
F ei ¼
1 if ei is bone matrix
(2) For any element ei with a flag value Fei ¼  1, all of the
connected elements ei,j can be determined. Then, if the flag
value of any of the related elements is opposite to the element
ei, i.e., Fei,j ¼1, then the element ei belongs to the inner
boundary of the void elements.
where M is the total number of bone matrix elements in collection
{Ei}, mvoxel is the bone mass of a single element (voxel), and Pi is
the mass variation rate of element Ei. Eq. (7) shows that when the
element Ei is completely swallowed, the element changed from
bone matrix to void. However, when element Ei is partially
ð6Þ each element has a status flag value of either 1 (bone matrix) or
 1 (void). Thus, the flag value must be switched to identify the
element as void or bone matrix. Moreover, in Abaqus/standard, if
the element has flag value  1, it will not appear in the finite
element mesh model. Therefore, only the bone matrix elements
are included in the calculation file for Abaqus/standard.
A unified step time must be determined. In this study, the step
time Δtn of current step tn was determined by Eq. (8)

Δt n ¼ maxðΔt rn ; Δt fn  1 Þ ð8Þ
The resorption phase is relatively simple. A temporary config-
where Δt rn and Δt fn  1 are the resorption step time of the current
uration should be obtained by deleting the bone matrix elements
time tn and the formation step time of the last time tn  1,
that were swallowed by the osteoclast cells from the current
respectively.
configuration. The discriminant of the bone matrix inner boundary
The formation phase then proceeds according to the temporary
element Ei whether swallowed or not is
configuration. Initially, the new collections of {Ei} and {E0i } are
(
if P i U Δt þmvoxel 4 0 M   updated according to the temporary configuration. Then the mass
F Ei ¼ 1 1 X mvoxel
and Δt ¼ variation rate Pi can be calculated for each bone matrix inner
F Ei ¼  1 if P i U Δt þ mvoxel r 0 2M i ¼ 1 Pi
boundary element Ei. And for each void element E0i , the mass
ð7Þ variation rate P 0i is the summation of all contributions from the

Fig. 3. Idealized microstructure configuration and remodeling process under isometric triaxial stimulus: (a) multi-cells structure; (b) single cell structure; (c) form I; (d) form
II; (e) remodeling process of form I; and (f) remodeling process of form II.
20 W. Yi et al. / Finite Elements in Analysis and Design 104 (2015) 16–25
connected bone matrix element Ek, i.e., P 0i ¼ Σ P 0i;k , where P 0i;k is
partial of Pk which stands for the element Ek. Thus, the new
configuration can be updated after every potential void element is
processed. The allocation algorithm of the mass variation rate will
be listed in the following paragraph.
2.2.2. Mass variation rate allocation algorithm
The allocation algorithm is used to distribute the total mass
variation rate of the current bone elements (the inner boundary
element of the bone matrix) to the related void elements for
further calculation. The main concept underlying this method is
that the allocated mass variation rate is related to the distance
between the void elements and the bone elements. As seen in
Eq. (9), Pi is the total mass variation rate of the bone matrix inner
boundary element Ei, which can be calculated with Eqs. (4) and
(5). Wj is the weight of the connected void element E0j , WT is the
total weight of all related void elements, li,j is the distance between
void element E0j and the bone matrixpinner ffiffiffi boundary
pffiffiffi element Ei.
There are only three values for li,j: 1, 2and 3, which represent
the coplanar, collinear and concurrent relations between Ei and E0j .
X
W j ¼ 1=li;j W T ¼ W j P 0j;i ¼ P i U W j =W T : ð9Þ
3. Results
In this section, the idealized microstructure configuration, the
semi-idealized microstructure configuration, and the real micro-
structure configuration simulations are carried out.
Three different types of microstructure were used: an idealized
microstructure, a space truss (semi ideal microstructure), and real
bone microstructure, the latter being derived from Micro CT
images through the proposed domain separated method (DSM).
Four types of circumstances were simulated, and the results
showed the rationality and efficiency of the proposed remodeling
simulation method. In addition, the equivalent elastic modulus
was calculated using the microstructure configurations obtained in
real bone microstructure remodeling stimulations under different
Fig. 4. Simulations of semi-idealized configurations under different external stimuli; the applied loads are shown in the bottom right corner: (a) initial configuration;
(b) under torque stimulus; (c) single shear; (d) compress and single shear 0.002 GPa; (e) compress and single shear 0.001 GPa; and (f) triaxial compress with lower value
along the lateral direction.
external loads. Data points expressing the relationship between
porosity and elastic modulus were thus obtained.
3.1. Idealized microstructure configuration
The idealized microstructure configuration has various char-
acteristics that are consistent with real bone microstructure
configurations: (1) the bone matrix microstructure configuration
has a similarity with different porosity; (2) the bone matrix
microstructure and pore microstructure configurations are com-
plementary, and they should fill the entire space; (3) the bone
microstructure and the pore microstructure are similar in that the
bone microstructure is formed by the trabecular connected with
each other, and the cavity is connected and filled with soft tissue.
Two remodeling simulations are carried out against two forms
of the idealized microstructure under isometric triaxial stimulus
(see Fig. 3 for partial results). Fig. 3(e) and (f) shows the evolution
of form I (Fig. 3(c)) and II (Fig. 3(d)) of the idealized microstruc-
ture. When the porosities are equal, the evolution results of form I
and form II are actually the same structure. When the summation
of the two porosities equals 1, the remodeling result of form I and
form II remain complementary. Thus, the simulation microstruc-
ture adheres to the description of the idealized microstructure.
3.2. Semi-idealized microstructure configuration (space truss
structure)
An orthogonal space truss configuration formed with a multi-
ple semi-idealized microstructure is calculated using the proposed
method under a different stimulus. Fig. 4 shows some interesting
results.
The initial microstructure configuration can be seen in Fig. 4(a).
The other sub-figures are the stable final configurations under
different stimuli. When under torque stimulus (Fig. 4(b)), the
microstructure evolved into a hollow cylinder. The corresponding
overall porosity increased as the radius increased. Under the shear
stimulus (Fig. 4(c)), the microstructure eventually evolved into
parallel surfaces with several pores. When under stimulus of the
same form with different magnitude, the final configurations
 W. Yi et al. / Finite Elements in Analysis and Design 104 (2015) 16–25
Fig. 5. Micro-CT scan experiment and element discrete with DSM: (a) experimental specimen; (b) scan image data; (c) reconstruction in Mimics; (d) division into cubes;
(e) one cube; (f) pre-discrete domain; and (g) separated domain. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of
this article.)
varied greatly (Fig. 4(d) and (e)): the strain stimulus magnitude
decreased, and the plate-like trabecular bone, after becoming
thinner, gradually formed into the rod-like trabecular bone with
a hollow section in the middle of the plate-like trabecular. When
under triaxial stimulus, which is lower along the lateral direction,
the microstructure eventually evolved into a parallel plate
arrangement [26]. Because stimuli are simple, the final steady
microstructure configurations can be predicted and show the
applicability of the proposed method from another side.
3.3. Real microstructure configuration
3.3.1. Micro CT experiment
The Micro CT experiment is a commonly used method to
determine the micro-structure configuration without damaging
the specimen. The specimens were prepared via the following
steps. First, a femur was cut into small pieces with a manual bone
saw, and the soft tissue was eliminated through a high-purity
alcohol and distilled water rinse. The pieces were then soaked in a
liquid of formalin and alcohol for two weeks. Finally, the pieces
were removed and air-dried. The experiment was carried out in
Wuhan University Stomatological Hospital on a CT50 SCANCO
Micro CT scanner with 20 μm resolution. One of the specimens is
shown in Fig. 5(a).
Each slice image file has a 1024  1024 voxel, and one slice
image is shown in Fig. 5(b). With the Mimics software, a triangle
discrete 3D model (Fig. 5(c)) was constructed from the slice
21
images. Then, the entire model was cut into cubes with lengths
of 1 mm, shown as in Fig. 5(d). DSM was used to discrete the cubes
with orthogonal hexahedron elements. The main principle of DSM
is to establish a pre-discrete domain first, followed by separation
of the domain into two parts: bone and void.
The key phase of DSM is to separate the pre-discrete domain
with the 3D STL model. For example, for the cube marked in red in
Fig. 5(d), a pre-discrete domain with 1003 hexahedron elements
was initially established (Fig. 5(f)). Then, a self-coding intersection
detection program was used to mark the hexahedron elements
which intersected with the triangle elements in the 3D STL model.
Then, it was simple to divide the remaining hexahedron elements
into two collections, bone and void, as shown in Fig. 5(g). The red
and blue elements represent bone and void, respectively. If the
element sizes need adjustment, the domain simply needs to be
pre-meshed with the appropriate elements in advance.
3.3.2. Simulations and application
Three sets of simulations were carried out based on realistic
bone micro-structure. The simulation focused on the impact of the
strain stimulus with different intensities. The second set focused
on the impact of different physiological conditions, which can
reveal the influence of drugs on the bone remodeling process. The
third set focused on generating a large amount of samples to
provide data points for the elastic modulus – porosity curve.
22 W. Yi et al. / Finite Elements in Analysis and Design 104 (2015) 16–25

Table 1
Parameter settings for the simulation without drug influence.

Variable Symbol Unit Value

Elastic module [14] E GPa 15

Poisson's ratio [14] ν 0.3
Volume V mm3 1
Threshold strain [27] Ktr με 200
Failure strain [22,28] Kf με 6000
Drag influence on resorption η 0
Drag influence on formation λ 0
Number of osteoclast per virtual remodeling site n 0.005
Number of osteoblast per virtual remodeling site N 1
Formation rate of a single osteoblasts cell under the threshold strain PKtr mm3 day  1 1.0  10  6
Resorption rate of a single osteoclast cell [29] Pcl mm3 day  1 2.0  10  4

Fig. 6. Simulations of real bone microstructure configuration evolution: (a) Initial configuration; (b) porosity versus time; (c) under 0.001 GPa distributed tangential stress
on the top; (d) under 0.001 GPa distributed tangential stress on the top with treatment of Denosumab; and (e) under 0.002 GPa distributed tangential on the top.

3.3.2.1. Simulation I. The simulation parameters used to determine When under a threshold strain stimulus, the formation rate and
the impact of the strain stimulus intensity on the bone remodeling resorption rate of each virtual remodeling site are balanced
process are available in Table 1. because n  Pcl ¼N  PKtr.
 W. Yi et al. / Finite Elements in Analysis and Design 104 (2015) 16–25
In this section, the impact of the strain stimulus on the bone
microstructure remodeling is discussed. The drug influences
represented by λ and η are set to 0. The initial configuration is
shown in Fig. 6(a); some configurations and their apparent time in
the remodeling process are shown in Fig. 6(c)–(e).
When compared to the initial microstructure, the overall bone
mass increased and the porosity decreased under 0.002 GPa
stimulus. More specifically, the overall bone mass first increased
before reaching a peak value on day 135. This overshoot phenom-
enon was consistent with a morphological study of bone devel-
opment in pigs [30]. At the same time, the 0.001 GPa stimuli could
cause bone loss and an increase in porosity. In this instance, the
overshoot phenomenon did not occur during the simulation
period, and the bone mass variation rate gradually slowed.
After the bone mass variation rate decreased significantly on
day 700, the porosity slightly increased under both types of
stimuli. This suggests that the microstructure configuration
evolved towards an optimal configuration containing less mass
but identical stiffness. The evolution variation rate in this phase is
very low because the microstructure configuration already
adapted to the specific external load and continued to optimize.
Taken together, these findings indicate that real human bone
microstructure is not the theoretical minimum flexibility struc-
ture. Rather, this is the evolutionary process moving towards an
optimized configuration. This simulation occurs under a constant
stimulus, but the microstructure configuration did not achieve the
minimum compliance structure, even on day 1200. Moreover, the
stimulus inside the human body is vibrational, and the internal
physiological environment is not stable. These factors mean that
the microstructure configuration of human bone is always under-
going a dynamic evolutionary process.
Table 2
Computational cost of different cases.
Cases 0.001 GPa 0.002 GPa 0.001 GPa with treatment of
Denosumab
Computational 154 min 224 min 175 min
cost
Fig. 7. Elastic module – porosity data. (For interpretation of the references to color
in this figure, the reader is referred to the web version of this article.)
23
The total computational cost was compared for each config-
uration in simulation I and II with 44 steps. The computational
software environment is Microsoft Visual Studio 2008 with an
Intel Visual Fortran Compiler, Professional Edition 11.1 and Aba-
qus/standard 6.10-1. The hardware environment is an Intel Core i5-
2410 2.3 GHz CPU with 8 Gb of memory. The results are listed in
Table 2. It is clear that the lower the porosity, the more time it
costs because the most computational cost was spent in solving
the strain/stress distribution; the computational costs were
directly determined by the total element numbers in the FE
mesh model.
3.3.2.2. Simulation II. In the second simulation, the influence of the
drug on the bone remodeling process was investigated. Two
circumstances with different physiological conditions were
simulated. Denosumab, the commonly used drug for treating
osteoporosis, was considered. A fully human monoclonal
antibody, Denosumab binds to RANKL by lowering the chance of
RANKL binding with RANK receptors on osteoclasts and osteoclast
precursors. This, in turn, inhibits the synthesis, activity, and
lifespan of the existing osteoclasts [31].
The influence of the drug on the resorption was represented by
the parameter η, as in Eq. (3). When its value was equal to 0, no
drug was used; when the value was greater than 0, the drug
enhanced the resorption efficacy of osteoclast cells; when the
value was less than 0, the drug inhibited resorption. The value was
set to  0.5 in this section to show that the Denosumab treatment
could decrease the resorption rate to half of the original level.
As shown in Fig. 6(b), the Denosumab treatment significantly
increased the bone mass. The porosity decreased from 70.9%,
which represents the no-drug case, to 62.2% for the Denosumab
treatment case on day 1000. The porosity differential between the
two cases reached 8% on day 400, and then it remained stable. This
finding was consistent with clinical statistical studies of Denosu-
mab [32,33]. Although the bone mineral density (BMD) variations
were the focused measurement in those studies, they are compar-
able to the porosity used in this study because the BMD is directly
proportional to the CT value, and the CT value is directly propor-
tional to the apparent density related to porosity.
3.3.2.3. Simulation III. Another application of the microscale bone
remodeling simulation method is the generation of enough
random bone microstructure samples to provide a significant
amount of data for stochastic study. Using the equivalent elastic
module as an example Many relationship models for the elastic
module and porosity had been proposed. The most widely used
models were the power and exponential models [34], which were
used for Eqs. (10) and (11), respectively:
E ¼ E0 ð1  ϕÞ2 ð10Þ
 
 2ϕ
E ¼ E0 exp ð11Þ
1ϕ
The porosity distribution areas of the bone specimen used in
the mechanical experiment were comparatively concentrated [35],
and the quantity was also limited in reality, shown with marks ‘ þ’,
‘  ’ and ‘n’ in Fig. 7. The elastic module-porosity data points
obtained from the mechanical experiments based on bone speci-
mens share the same disadvantage. However, enough microstruc-
ture samples with different porosities could be obtained through
microscale bone remodeling simulating based on real microstruc-
tures by adjusting the external load. Because widely distributed
porosity data points are desired, a total of 16 different initial
configurations were obtained through DSM and simulated under
two different magnitude displacement loads on the top: one load
24 W. Yi et al. / Finite Elements in Analysis and Design 104 (2015) 16–25
was 0.00001 mm, which led to serious bone mass loss; the other
load was 0.003 mm, which ensured bone mass growth without
bone matrix failure. Based on the obtained microstructure sam-
ples, enough representative volume elements (RVEs) could be
established. RVE [36,37] analysis is a commonly used method for
equalization and homogenization, and it is capable of acquiring
the equivalent elastic module of a material with the acknowl-
edgement of its microstructure configuration. By applying a strain
boundary condition, the equivalent elastic module could be
obtained through RVE analysis.
The bone remodeling simulation under microscale data was
distributed in the interval [0, 1]. The power model (black line) and
exponential model (red line) match the partial data points in the
[0, 0.3] and [0.5, 1.0] intervals, respectively. Overall, however, these
two models are not reasonably accurate.
4. Discussion
In this paper, the effects of strain on the proliferation and
differentiation of osteoblast cells was introduced; the influence of
the drug on the formation/resorption rate was also introduced into
the remodeling simulation. According to the equivalent strain for
the bone matrix, the remodeling was divided into three phases.
(1) In the physiological phase (200–6000 με) the formation rate
was calculated with the strain stimulus impact on the proliferation
and differentiation of the osteoblast cells based on the experi-
mental data. (2) In the disuse phase (0–200 με), the formation rate
is linear to the equivalent strain. (3) In the pathologic phase
(4 6000 με), the bone matrix element was damaged. Using
Abaqus/standard as a strain/stress distribution solver, the Euler
forward method was implemented to solve the governing
equations.
The trabecular bone grows along the direction perpendicular to
the principal stresses in order to adapt to the stresses [3], and it
strives to achieve an optimal structure. An optimization algorithm
combined with a macroscale bone remodeling method was used
by other researchers to calculate the optimal density distribution
of the bone structure [38]. This method did not correlate with real
time. When the convergence criteria were satisfied after appro-
priate iterations, the solution was deemed to be optimal. Thus, the
microstructure configurations obtained through the optimization
algorithm are the optimal structure adapted to the specified load.
This, however, does not reflect the randomness of the bone
microstructure. Furthermore, the randomness is not reflected
because the stiffness of the optimal microstructure configuration
is always higher when the porosity is the same.
Concurrently, the proposed method correlates with real time.
The step time of each increment was determined by the element
(voxel) size and the mass variation (formation/resorption) rate.
The microstructure configurations obtained through this method
show that the configuration evolved during the entire bone
remodeling process. Thus, these configurations can reflect the
characteristics of real bone microstructure. At the same time, the
stabilized configuration (obtained through the Euler forward
method) and the optimal configuration (obtained with an optimi-
zation algorithm) shared the same characteristic: a compliance-
minimized structure.
The signal attenuation function involved in many bone remo-
deling simulation studies [13,18–20] is not appropriate for this
study. In those studies, the mechanical stimulus (strain energy
density, strain energy density rate, the asymmetry of stress
distribution, etc.) of a point on the bone matrix surface is the
summation of all signals created by sensors (osteocyte) within a
certain range. The mechanical stimulus used in this study is the
equivalent strain of the bone matrix, which, it should be noted,
only affects the local osteoblast cells. However, during the forma-
tion of a new bone matrix, the osteogenesis rate of a specific void
element is related to all of the adjacent bone matrix elements.
Likewise, the contribution weight is inversely proportional to the
distance.
5. Conclusions
Based on three different types of microstructure, the idealized
microstructure, the semi-idealized structure (space truss struc-
tures) and the actual bone microstructure, the remodeling pro-
cesses under different external loads were simulated. The
following conclusions have been made:
(1) Under an equal triaxial stress external load, the idealized
structure maintained its topological characteristics during
the entire remodeling period.
(2) Under a different external load, the space truss structure
remodeling revealed a strong adaptability to the external load.
The microstructure was always evolving to withstand the
external load with minimum mass by disconnecting the old
trabeculae and reconstructing new trabeculae to form a new
structure.
(3) Through the remodeling simulation of the real bone micro-
structure, it was found that (a) the bone microstructure
evolved over a long process into an optimal structure. After
3 years, the structure continues to evolve in the optimal
structure, even under a single load. It is not hard to imagine
that because of the diversity of the external load and internal
metabolism perpetually changing in the human body, the bone
microstructure will always continue along the evolutionary
path to an optimal structure. (b) Denosumab, which is an
inhibitor to osteoclast cell activity, can effectively improve
bone mineral density and reduce porosity. These findings
show that the method proposed can accommodate drug
treatment effects. (c) The proposed method can be used to
generate enough random specimens for statistical analysis.
These specimens involve a wide porosity distribution range
because of the diversity of the external load. This range
compensates for the bone material experiment disadvantages
to specifically include the number limitation and the compara-
tively concentrated porosity of the real bone specimens.
The main difference between microscale and macroscale bone
remodeling simulation is the size of the structure and the discrete
element. The resolution of the image data obtained from the CT
scan experiments is at the millimeter level. The resolution of the
image data obtained from the micro CT experiments, which, unlike
the CT, contain too much radiation for the human body and can
only scan an in vitro sample at the micrometer level. High-
resolution peripheral quantitative computed tomography (HR-
pQCT) allows for the quantification of the trabecular and cortical
structure in vivo, and it includes a capability for generating images
at a hundred micron resolution. This makes the bone remodeling
simulation method under microscale suitable for macro structures,
which is the future research of this study.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China through the Project no. 11172110.
 W. Yi et al. / Finite Elements in Analysis and Design 104 (2015) 16–25
Appendix A. Supplementary information
Supplementary data associated with this article can be found in
the online version at http://dx.doi.org/10.1016/j.finel.2015.04.007.
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