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Numerical simulation of apparent density evolution of trabecular bone under

fatigue loading: effect of bone initial properties

Article  in  Journal of Mechanics in Medicine and Biology · May 2019

DOI: 10.1142/S0219519419500416

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Numerical simulation of apparent density evolution of trabecular bone under
fatigue loading: effect of bone initial properties

Abdelwahed BARKAOUI 1*, Rabeb BEN KAHLA2, Tarek MERZOUKI3, Ridha HAMBLI4

1. Laboratoire des Energies Renouvelables et Matériaux Avancés (LERMA), Université

Internationale de Rabat, Rocade Rabat-Salé, 11100, Rabat-Sala El Jadida, Maroc.

2. Laboratoire de Systèmes et de Mécanique Appliquée (Lasmap-EPT), Ecole Polytechnique de

Tunis, Université de Carthage, 2078 La Marsa, TUNISIE.

3. Laboratoire Ingénierie des Systèmes de Versailles, Université de Versailles St Quentin en

Yvelines, 10 avenue de l’Europe, 78140 Velizy, FRANCE.

4. Laboratoire Prisme, EA4229, Ecole d’Ingénieurs Polytech Orléans, Université d’Orléans, 8 Rue
Léonard de Vinci, 45072 Orléans, FRANCE.

Corresponding author. Email: abdelwahed .barkaoui@uir.ac.ma

Abstract

Bone remodeling is a physiological phenomenon, coupling resorption and formation

processes that are mainly mediated by osteoclasts and osteoblasts, in response to mechanical
stimuli transduced by osteocytes to biochemical signals activating the bone multicellular unit.
Under normal loading conditions, bone resorption and formation are balanced by a
homeostasis process. When bone is subjected to overstress, microdamaging occurs, which
induces a modification of the structural integrity and microarchitecture. This has drawn
significant attention to the mechanical properties of bone. In this context, the current study
has been carried out, with the aim of numerically investigating the impact of the mechanical
properties on the remodeling process of the trabecular bone under cyclic loading, highlighting
the effects of different values of the mineral density and the Young’s modulus. This was
performed using a mechanobiological model, coupling mechanical and biological approaches,
allowing to numerically simulate the effect of the selected parameters for a 20-year-period of
cyclic loading for a 2D and 3D models of a human femur head. The current work is an
explorative numerical study, and the obtained results revealed the changes in the overall
stiffness of the bone according to the mechanical properties.

Keywords: Bone remodeling, finite element method, bone initial properties, apparent density
evolution.

Introduction

At the macroscopic level, bone seems to be a static organ. But at the microscopic level, it is a
highly dynamic tissue. As a living composite material, bone has the potential to constantly
reconstruct and adapt its mass and microarchitecture to changes and requirements in the
mechanical loading environment. Osteocytes are known to be mechanosensors, detecting
mechanical signals and transducing them to biochemical signals that are conducted to the
BMU (Bone Multicellular Unit), activating osteoclasts, which locally resorb old bone, and then
osteoblasts, which locally synthesize a new collagen matrix. The latter, known as osteoid
tissue, is then mineralized. By adding or removing bone according to the local mechanical
strains, the remodeling process confers to bone its load-supporting function, allowing to avoid
mechanical failure.
The outstanding mechanical properties of the bone are due to its particular unique structure,
which is hierarchically arranged from microscale to macroscale. However, a loss of the
mechano-responsiveness of the bone results in failing reconstructing processes, affecting its
structure, and leading to the manifestation of metabolic bone diseases.

The relationship between the bone structures and the applied loads was firstly stated by Wolff
(1986), who proposed that the remodeling process is ruled by the mechanical stress to which
the bone is subjected. Thereafter, several mathematical formulations were developed to
describe the bone response to mechanical stimuli. Some models greatly contributed to the
bone biomechanical understandings, such as the curvature model developed by Frost (1964),
formalizing clinical observations of bone turnover, the adaptive model developed by Cowin
and Hegedus (1976), modeling the adaptation of the bone structure to the applied mechanical
loading, and the self-optimization model developed by Carter et al. (1987), assuming that
bone mass is adjusted in response to the applied energy or strength. These models are based
on the stress/strain influence on bone apparent density.

With the development of the in vitro techniques, the identification of the autocrine and
paracrine signaling pathways led to the development of new models based on the biological
and chemical components of the remodeling process. The two main biological models were
developed by Komarova et al. (2003) and Lemaire et al. (2004). The first one (Komarova et al.
2003) investigated the cooperative roles of autocrine and paracrine signaling pathways in the
remodeling control, based on the hypothesis that osteoclast and osteoblast formation rates
are regulated by local effectors produced by these two bone cells. The second one (Lemaire
et al. 2004) includes a formulation of the regulation of the biochemical agents (RANK, RANKL,
OPG, TGFβ), taking into account the role of PTH (Parathyroid Hormone) on RANKL production,
and integrating a real paracrine communication between osteoclasts and osteoblasts.

Thereafter, the combination of these mechanical and biological approaches gave rise to a
more accurate description of the bone remodeling process. In this context, several
mechanobiological models have been developed, such as the model developed by Hambli
(2014) describing bone remodeling based on a coupled strain-damage stimulus function
controlling the levels of autocrine and paracrine factors, the model developed by Yi et al.
(2015) simulating bone remodeling at a microscale using equivalent strain as the stimulus, and
the model developed by Lerebours et al. (2016) allowing to simulate the spatio-temporal
evolution of a human midshaft femur scan.

The evolution of these mechanobiological models and the acceleration of scientific discovery
in orthopedic regenerative medicine have led to the development of adaptive computational
methods and strategies that are in evermore excessive use. Moreover, the usage of numerical
methods, such as the finite element method (FEM), in computational mechanics, allow not
only to estimate bone quality evolution under unloading conditions, but enable also to show
the changes taking place during the loading application, and predict the probable future
changings in strains and stress distributions. Furthermore, FE analysis allows to evaluate bone
mechanical competences for each specific individual in vivo, and enables to visualize
microstructural regions, such as trabecular and cortical bone. For these reasons, FE analysis
has been widely adopted, and is considered as a good predictor of bone strength and
remodeling, and is considered as a good predictor of bone strength (Tawara and Nagura 2017).

The finite element method is used in this study with the aim of simulating the effects of
changing of the mechanical properties of the trabecular bone subjected to fatigue damage
under cyclic loading over 20 years. This work provides a purely numerical explorative study,
and is performed based on a mathematical model coupling the mechanical behavior and the
cellular activities of the trabecular bone, using mathematical formulas from a previous study
(Barkaoui et al. 2016). Particularly, the current investigation highlights the influence of the
mineral density and the Young’s modulus on the remodeling process of human proximal
femurs, revealing the relationship between the fatigue damage and the overall stiffness of the
bone.

Methods and tools

Based on the assumption of an isotropic elastic material, the mechanical stimulus (Eq. 1) can
be given in terms of the reference stimulus (Eq. 2) and of the mechanical signal (Eq. 3)
detected by an osteocyte in its location. This signal is then transduced to a biochemical signal,
stimulating the cell activities and dynamics (Eq. 4) within the BMU.

𝑤(𝑥⃗ (𝑖) )
∆𝜓(𝑥⃗) = − 𝑊∗ (1)
𝜌
𝑊 ∗ = 𝑤(𝑥⃗ (𝑖) ) − (𝑤(𝑥⃗ (𝑖) ) − 𝑊0 )𝑒 −𝜏𝑡 (2)

1
𝑤(𝑥⃗ (𝑖) ) = 𝝈(𝑥⃗ (𝑖) ): 𝜺(𝑥⃗ (𝑖) ) (3)
2

𝑑𝑛1 𝑔 𝑔
= 𝛼1 𝑛1 11 𝑛2 21 − 𝛽1 𝑛1
{ 𝑑𝑡 (4)
𝑑𝑛2 𝑔 𝑔
= 𝛼2 𝑛1 12 𝑛2 22 − 𝛽2 𝑛2
𝑑𝑡

where, ∆𝜓(𝑥⃗) denotes the mechanical stimulus, 𝑤(𝑥⃗ (𝑖) ) the strain energy density, 𝜌 the bone
apparent density, 𝑤 the mechanical signal, 𝑖 the corresponding osteocyte, 𝑥⃗ (𝑖) the location of
the corresponding osteocyte, 𝑊 ∗ the balance stimulus, 𝑊0 the initial of the reference
stimulus, 𝝈 and 𝜺 are respectively the stress and strain tensors, 𝑛𝑖 the total cell number, 𝛼𝑖
and 𝛽𝑖 are respectively the production and removal rates, 𝑔𝑖𝑖 and 𝑔𝑖𝑗 are respectively the
autocrine and paracrine factor effects, the number 1 and 2 respectively denote the osteoclast
and osteoblast cell numbers.

The cell interactions are regulated by the expression of autocrine and paracrine factors (Eq.
5) and result in a variation in bone mass (Eq. 6). The latter is expressed in terms of the number
of active osteoclasts and osteoblasts (Eq. 7). This cell active number depends on the ramp
function (Eq. 8) and on the number of steady state inactive cells (Eq. 9).

𝑔 = 𝐴1 + 𝐵1 𝑒 −𝛾1 ∆𝜓
{ 12 (5)
𝑔21 = 𝐴2 + 𝐵2 𝑒 −𝛾2|∆𝜓|

𝑑𝑚
= 𝐾2 𝑁2 − 𝐾1 𝑁1 (6)
𝑑𝑡

𝑁𝑖 = 𝐻(𝑛𝑖 − 𝑛𝑖 ) (7)

(𝑥 − 𝑥0 ) + 𝑎𝑏𝑠(𝑥 − 𝑥0 )
𝐻(𝑥 − 𝑥0 ) = (8)
2
1
𝛽1 𝛽2 𝑔21 𝑔12 𝑔21−1
𝑛1 = ( )
𝛼1 𝛼2 𝑔21
1 (9)
𝑔12 𝑔 𝑔 −1
𝛽2 𝛽1 12 21
𝑛2 = ( )
{ 𝛼2 𝛼1 𝑔12

where 𝐴1 , 𝐴2 , 𝐵1, 𝐵2, 𝛾1 and 𝛾2 present the model parameters controlling the production of
the paracrine factors (𝐴1 = 1.6, 𝐴2 = −1.6, 𝐵1 = −0.49, 𝐵2 = 0.6, 𝛾1 = 16.67 𝑔⁄𝐽, 𝛾2 =
33.37 𝑔⁄𝐽), 𝑚 denotes the bone mass variation, 𝐾1 and 𝐾2 respectively denote the normalized
resorption and formation activities, 𝑁1 and 𝑁2 respectively denote the osteoclast and
osteoblast cell active numbers, 𝐻 is the ramp function, 𝑛𝑖 is the steady state inactive cell
number, 𝑥 and 𝑥0 are locations of the osteocyte.

Considering the existence of an empirical relationship between the bone density and the
Young’s modulus, the impact of the fatigue damage was added to the formulation established
by Bonfoh et al. (2011), which was inspired from the work developed by Jacobs (1996). Then,
the evolution of the Young’s modulus is formulated (Eq. 10, 11, 12, 13). The Poisson’s ratio
(Eq. 14) is described in terms of the initial Poisson’s ratios of the cortical and the trabecular
bone.

𝐸 = 𝐸0 (1 − 𝑑)2 𝜔 𝜉(𝜔) (10)

𝜌
𝜔= (11)
𝜌𝑙

𝜉(𝜔) = 𝜉𝑠 − (𝜉𝑠 − 𝜉𝑐 )𝑆(𝜔 − 1) (12)

𝐻(𝑥 − 𝑥0 )
𝑆(𝑥 − 𝑥0 ) = (13)
𝑥 − 𝑥0

ν(ω) = νs − (νs − νc )S(ω − 1) (14)

where 𝐸 denotes the elastic modulus, 𝐸0 the initial elastic modulus, 𝑑 the damage variable, 𝜔
the relative density, 𝜌𝑙 a particular variable separating the cortical and the trabecular bones
(𝜌𝑙 = 1.2 𝑔⁄𝑐𝑚3). 𝜉(𝜔) is a function that characterizes young's module variation based on
density, 𝜉𝑠 and 𝜉𝑐 are constants defining the evolution of Young’s modulus of the trabecular
and the cortical bones respectively (𝜉𝑠 = 2.5 and 𝜉𝑐 = 3.2), ν(ω) is is a function that
characterizes Poisson’s ratios variation based on density, νs and νc are the initial coefficients
of Poisson’s ration in the trabecular and the cortical bone respectively (νs = 0.2 and νc =
0.32).

To model the fatigue damage resulting from the cyclic loadings applied to the bone, the notion
of life cycle, suggest by Chaboche (1981), was adopted. Reaching a maximum value of up to 1,
which corresponds to the material failure, damage can be described by the number of failure
cycles (Eq. 15). The latter is expressed in terms of the amplitude of the applied microstrains,
which corresponds to the equivalent strain (Eq. 16), and in terms of constants obtained from
experimental data and depending on the nature of the solicitation (Eq. 17, 18). Over time, the
accumulation of damages by a given cycle is expressed as the damage at failure (Eq. 19), which
is given in terms of the incremental damage to the cycle (Eq. 20) which is formulated based
on a simplistic nonlinear evolution. In the case of an isotropic material, the incremental
damage can be given in terms of tensile and compressive loading cycles.

𝑁𝑓 = 𝐶∆𝜀 −𝜗 (15)

2
𝜀𝑒𝑞 = √ 𝜀𝑖𝑗 𝜀𝑖𝑗 (16)
3

𝑁𝑓,𝑐 = 1.479 ∗ 10−21 ∆𝜀𝑖−10.3 (17)

𝑁𝑓,𝑡 = 3.630 ∗ 10−32 ∆𝜀𝑖−14.1 (18)

𝑑 𝑛+1 = 𝑑 𝑛 + 𝛿𝑑 (19)

1
𝛿𝑑 = (20)
𝑁𝑓

where, 𝑁𝑓 denotes the failure cycle’s number, ∆𝜀 the applied microstrain amplitude
corresponding to the equivalent strain 𝜀𝑒𝑞 , while 𝐶 and 𝜗 denote constants obtained by
referring to experimental data. These two variables depend on the solicitation nature (tensile
or compressive loads). Equation 17 corresponds to the failure cycle’s number under
compressive loads, and Equation 18 to the failure cycle’s number under tensile loads. The
damage at failure (𝑑 = 1) represents the given cycle accumulation damage 𝑑 𝑛+1 , and 𝛿𝑑 is
the incremental damage to the cycle (𝑛 + 1).

Therefore, the total damage is the sum of both tensile and compressive damages (Eq. 21, 22,
23). The state of damage affecting the mechanical properties of bone is expressed by an
isotropic formulation based on the example given by Baste et al. (1989), allowing to describe
the evolution of the Young’s modulus (Eq. 24). Since the damage is only calculated for the
longitudinal directions, the shear moduli remain the same.

1 1
𝛿𝑑𝑖,𝑐 = = (21)
𝑁𝑓,𝑐 1.479 ∗ 10−21 ∆𝜀𝑖−10.3
 1 1
𝛿𝑑𝑖,𝑡 = = (22)
𝑁𝑓,𝑡 3.630 ∗ 10−32 ∆𝜀𝑖−14.1

𝛿𝑑𝑖 = 𝛿𝑑𝑖,𝑡 + 𝛿𝑑𝑖,𝑐 (23)

𝐸 = 𝐸𝑖0 (1 − 𝑑𝑖 )2 (24)

where 𝛿𝑑𝑖,𝑐 denotes the compressive damage, 𝛿𝑑𝑖,𝑡 the tensile damage, 𝛿𝑑𝑖 the total damage,
∆𝜀𝑖 the microstrain amplitude detected by each osteocyte 𝑖.

Below a certain level of mechanical solicitation, the rate of the resorption process in the
corresponding area is higher than the formation process. This induces a weakening of the
bone and the corresponding area (SR) is called the disuse zone. However, if the area is
sufficiently solicited, the formation rate exceeds the resorption one, resulting in an increase
in the bone strength, and the corresponding area (SF) is called the overuse zone. Between
these two behaviors, an inactive zone is identified, resulting from a solicitation level that is
low to generate bone formation, but high to generate resorption (S*). This area is called the
lazy zone (Fig 1). Above a certain threshold corresponding to an excessive physical activity,
the bone is damaged, which causes a significant accumulation microcracks, resulting in a local
deterioration of the structural integrity (SD) and then a bone resorption.

Figure 1| Different solicitation zone according to the mechanical stimulus intensity. (SR is the
resorption stimulus, it denotes the low mechanical stimulus resulting in bone resorption and
corresponding to the disuse zone. SF is the formation stimulus, it denotes the mechanical
stimulus exceeding the threshold, resulting in bone formation and corresponding to the
overuse zone. SD is the damage stimulus, it denotes the excessive mechanical stimulus
resulting in bone damage and corresponding to the damage zone. S* denotes the reference
stimulus corresponding to the lazy zone were no change in bone strength is recorded).
As in the previous work, the initial and boundary conditions are illustrated in Figure 2. The
deformation resulting from walking is represented by a resultant force applied to the femur
head, slewed 19 degrees right to the central axis of the 2D model. The succession of
charge/discharge is applied as a displacement in the femur head.

Figure 2| Initial and boundary conditions of the femur model.

A displacement of 1.58 mm is applied on the femur head. This value corresponds to a medium
physical activity, and is obtained from medical records. Evidently, each part of bone has its
specific initial characteristics that are grouped in Table 1 in addition to the biological
parameters used in the current investigation (𝑜𝑡𝑐 denotes the osteoclastic cells, 𝑜𝑡𝑏 the
osteoblastic cells, 𝜌0 the initial apparent density, 𝜐0 the initial coefficient of Poisson’s ratio, the rest
of the parameters are the same as in the above equations).
 Table 1| Biological parameters selected for the mechanobiological model.
Parameter Value Reference
𝛼1 3 𝑜𝑡𝑐⁄𝑑𝑎𝑦 (Komarova et al. 2003)
𝛼2 4 𝑜𝑡𝑏⁄𝑑𝑎𝑦 (Komarova et al. 2003)
𝛽1 0.2 𝑜𝑡𝑐⁄𝑑𝑎𝑦 (Komarova et al. 2003)
𝛽2 0.02 𝑜𝑡𝑏⁄𝑑𝑎𝑦 (Komarova et al. 2003)
𝑛1 (𝑡 = 0) 15 𝑜𝑡𝑐 (Barkaoui 2012)
𝑛2 (𝑡 = 0) 0 𝑜𝑡𝑏 (Barkaoui 2012)
𝐾1 0.24% 𝑜𝑡𝑐⁄𝑑𝑎𝑦 (Komarova et al. 2003)
𝐾2 0.0017% 𝑜𝑡𝑏⁄𝑑𝑎𝑦 (Komarova et al. 2003)
𝑔11 0 (Barkaoui 2012)
𝑔22 0 (Barkaoui 2012)
𝑊0 0.002 𝐽⁄𝑔 (Barkaoui 2012)
𝜌𝑙 1.2 𝑔⁄𝑐𝑚3 (Barkaoui 2012)
𝐴1 1.6 (Hambli et al., 2009)
𝐴2 −1,6 (Hambli et al., 2009)
𝐵1 0.49 (Hambli et al. 2009)
𝐵2 0.6 (Hambli et al., 2009)
𝛾1 16.67 𝑔⁄𝐽 (Barkaoui 2012)
𝛾2 33.37 𝑔⁄𝐽 (Barkaoui 2012)
𝜌0 (𝐶𝑜𝑟𝑡𝑖𝑐𝑎𝑙 𝑏𝑜𝑛𝑒) 1.2 𝑔⁄𝑐𝑚3 (Barkaoui 2012)
𝜌0 (𝑇𝑟𝑎𝑏𝑒𝑐𝑢𝑙𝑎𝑟 𝑏𝑜𝑛𝑒) 0.8 𝑔⁄𝑐𝑚3 (Barkaoui 2012)
𝜌0 (𝐵𝑜𝑛𝑒 𝑚𝑎𝑟𝑟𝑜𝑤) 0.08 𝑔⁄𝑐𝑚3 (Barkaoui 2012)
𝐸0 (𝐶𝑜𝑟𝑡𝑖𝑐𝑎𝑙 𝑏𝑜𝑛𝑒) 17000 𝑀𝑃𝑎 (Barkaoui 2012)
𝐸0 (𝑇𝑟𝑎𝑏𝑒𝑐𝑢𝑙𝑎𝑟 𝑏𝑜𝑛𝑒) 3767 𝑀𝑃𝑎 (Barkaoui 2012)
𝐸0 (𝐵𝑜𝑛𝑒 𝑚𝑎𝑟𝑟𝑜𝑤) 17 𝑀𝑃𝑎 (Barkaoui 2012)
𝜐0 (𝐶𝑜𝑟𝑡𝑖𝑐𝑎𝑙 𝑏𝑜𝑛𝑒) 0.3 (Barkaoui 2012)
𝜐0 (𝑇𝑟𝑎𝑏𝑒𝑐𝑢𝑙𝑎𝑟 𝑏𝑜𝑛𝑒) 0.3 (Barkaoui 2012)
𝜐0 (𝐵𝑜𝑛𝑒 𝑚𝑎𝑟𝑟𝑜𝑤) 0.3 (Barkaoui 2012)
The computational simulation is performed on the trabecular bone for over 20-year-period of
cyclic loading for different scenarios, in order to study the behavior of the femur head under
the selected parameters (Tab. 2).

Table 2| Selected parameters of the simulation scenarios

Initial Young’s Young’s modulus
Gender Age Loading amplitude Initial density
modulus of the mineral
Man 40 years Cortical bone 𝜌0 − 20% 𝐸0 − 20% 𝐸𝑚 = 60 𝐺𝑃𝑎
Trabecular bone 𝜌0 𝐸0 𝐸𝑚 = 100 𝐺𝑃𝑎
Bone marrow 𝜌0 + 20% 𝐸0 + 20% 𝐸𝑚 = 120 𝐺𝑃𝑎
𝐸𝑚 = 150 𝐺𝑃𝑎
The FE algorithm (Fig. 3) is programmed in FORTRAN language and implemented in ABAQUS
code, using UMAT as a subroutine, allowing to only focus on writing the behavior laws instead
of calculating the conservation ones and the steady state formulations. Thus, the only factors
to manage are the material properties, the stress updating, the stiffness matrix and the cell
population laws.

Figure 3| Organigram of the bone remodeling algorithm implemented in ABAQUS code with
UMAT subroutine.

The simulation series is performed on 2D and then on 3D virtual macroscopic femur volumes,
in order to highlight the impact of the initial mineral density, as well as the influence of the
mechanical properties of the bone on the remodeling process. At first, the simulation is
performed on 2D geometries in order to test and validate our model by comparing the
obtained results to other 2D simulation results from previous studies. Then, 3D geometries
are used in order to provide more realistic results regarding the influence of Young’s modulus
and initial mineral density on bone adaptation.

Previously (Barkaoui et al. 2016), the influence of age and gender on the bone apparent
density was investigated. In this paper, the focus is on the influence of the Young’s modulus
and the initial mineral density on the distribution of the apparent density.
Results

The computational simulation of the mechanobiological model is tested and validated by

comparing the obtained apparent density distribution, in a 2D proximal femur model, with
results from other studies (data not shown). Then, 3D geometries are used in the simulation
to provide more realistic results.

Initial density influence on bone adaptation

Figure 4 shows the distribution of the apparent density as a function of the variation of the
initial density over time.

Figure 4| Distribution of the apparent density of the trabecular bone over a 20-year-
remodeling period in terms of the initial density. (A): 𝜌0 = 0.64 𝑔⁄𝑐𝑚3, (B): 𝜌0 =
0.80 𝑔⁄𝑐𝑚3, (C): 𝜌0 = 0.96 𝑔⁄𝑐𝑚3 .

The initial density affects the apparent density distribution of the trabecular bone at the end
of the remodeling cycle. Indeed, the bone densification is better for a high initial density,
mainly for the less stressed regions in which the resorption process is more active (black
dashed circles in (A), (B) and (C)). In the formation zones, no significant difference is noticed
in the density distribution for both of the cases (B) and (C).

Figure 5 shows that both of the curves of the apparent density for an element in the formed
zone (Fig. 5 (c)) are almost coincident starting from 45th month.
 Figure 5| Apparent density evolution for different solicitation zones for an element of the
trabecular bone for different values of the initial density. (a): absorbed zone, (b) balanced
zone, (c) formed zone.

Indeed, the out-of-plan proximal femur properties cannot be represented by a 2D model. And,
as mentioned above, a more realistic simulation may be obtained with a 3D model.

Initial mineral density influence on bone adaptation

Figure 6 shows the impact of a perturbation of +/- 20% in the initial density on the distribution
and the evolution of the apparent density is studied.
Figure 6| Distribution of the apparent density of the trabecular bone during the remodeling
period in terms of the initial density, for a 40-year-old man subjected to medium loading
intensity.

According to Figure 6, a decrease of 20% in the initial density of the trabecular bone affects
the bone formation and resorption. It is noticed that, for the different regions of the bone,
and even for the most stressed ones (the femur head and the lower part of the neck), the
density does not exceed 0.9 g/cm3. However, an increase in the initial density results in a larger
densification area, going from the upper part of the femur head to the lower part of the neck.
The density evolution for an element in this large area is shown in Figure 7 (a) (Green curve).
Figure 7| Evolution of the apparent density for different solicitation zones for an element in
the trabecular bone for different values of the initial density. (a): absorbed zone, (b)
balanced zone, (c) formed zone.

As noticed in Figure 7, the curves of the evolution of the 3D model are closer to reality than
the curves in Figure 5, since the evolution of the apparent density follows the evolution of the
diagram of 𝑑𝜌⁄𝑑𝑡 illustrated in Figure 1.

Young’s modulus influence on bone remodeling

Figure 8 shows the evolution of the Young’s modulus of the mineral as a function of the bone
density, illustrating the effect of the Young’s modulus of the mineral on the evolution of the
apparent density. The simulated femur is stressed for over 20 years and corresponds to a 40-
year-old man.

Figure 8| Density distribution of the trabecular bone during the remodeling period in terms
of the Young’s modulus of the mineral, for a 40-year-old man subjected to medium loading
intensity.

Figure 9 shows the evolution of the density distribution of the trabecular bone as a function
of its Young’s modulus, and reveals that the variation of the Young’s modulus of the trabecular
bone lead to a variation in its apparent density.

Figure 9| Density distribution of the trabecular bone during the remodeling period in terms
of the Young’s modulus of the trabecular tissue, for a 40-year-old man subjected to medium
loading intensity.
Discussion

As a salient property of bone, density plays an important role in determining the bone
mechanical properties. As illustrated in Figure 4, the initial density affects the distribution of
the apparent density during the remodeling process, and the highest initial density results in
a high apparent density. At high relative densities, more material is accumulated in the cell
walls, and its structure is transformed into more plate closed network (Gupta and Dan 2004).
Figure 6 shows that an increase in the initial density results in an important densification area.
This is due to the mineral content in the bone matrix, for which the variability increases with
increasing remodeling rates that produce more newly forming matrix (Ames et al. 2010;
Mercuri et al. 2016; Roschger et al. 2008; Ruffoni et al. 2007; Yao et al. 2007).

Actually, bone is composed of two phases: an organic phase mainly formed by collagen type
I, and a mineral phase mainly formed by mineral crystals of carbonate substituted
hydroxyapatite (Abdulghani et al. 2009). Further, the osteoblasts embedded in collagen
become osteocytes after mineralization. The number of osteoblasts affects the rate of
collagen synthesis. However, the exact effect of this parameter is difficult to identify because
of the coupling with the mineralization process (Liotier et al. 2013). On the other hand, the
organic and the mineral phases have extremely different mechanical properties. The mineral
phase provide strength and stiffness (Boskey 2003). However, at high levels of mineralization,
the bone becomes brittle, which reduces the energy required for fracture (Jaschouz et al.
2003). In turn, the organic phase provide toughness and ductility, and acts like a scaffold for
the mineralization process (Currey 1999). Since bone is continuously replaced by newly
formed bone due to the cellular activities during the remodeling process, the mechanical
properties of the trabecular bone vary as a function of the collagen content and its
mineralization, giving the high heterogeneity of the mineralization density in local areas of the
bone matrix (Abdulghani et al. 2009; Fratzl et al. 2004), and the discontinuities in the bone
matrix playing a crucial role in the crack initiation and propagation.

It has been theoretically and experimentally established that the Young’s modulus of the
trabecular bone is tightly dependent on its apparent density (Gupta and Dan 2004). Figure 8
shows that apparent density increases with increasing in the mineral Young’s modulus, and as
illustrated in Figure 9, the formation process is greater in bone with a high stiffness than that
with a low stiffness. This makes sense, since the compressive Young’s modulus in both
trabecular and cortical bone is related to the volume fraction of bone and to the mineralization
degree of the tissue. Thus, the stiffness and strength of the trabecular bone are typically
correlated with Young’s modulus (Hernandez 2016).

Indeed, it has been reported that an increase in the density is associated with a decrease in
the Young’s modulus (Gupta and Dan 2004). Upon loading, the collagen is subjected to tensile
and shear loading, causing, at some threshold level, a dissociation of the crystallites from the
collagen matrix. This results in a loss of structural integrity, which means a loss in stiffness
(Winwood et al. 2006). It has been reported that hydroxyapatite crystals are rigid and
extremely fragile. They have an elastic isotropic behavior (Siegmund et al. 2008; Vashishth
2007). Instrumented indentation studies have been carried out to study the mechanical
properties of the single-hydroxyapatite crystals (Zamiri and De 2011). These studies have
shown that, at the microscopic scale, hydroxyapatite crystals are highly fragile. The presence
of these crystals further changes the onset of plastic deformation, characterized by a sudden
drop in the stress-strain response (Buehler 2007). Since the collagen has a lower Young’s
modulus than bone, the apposition of collagenic tissue causes a decrease in the effective
Young’s modulus. Then, the mineralization, governing the formation of hydroxyapatite
crystals, gradually increases the effective stiffness of the bone (Liotier et al. 2013). This has
been confirmed by experimental results revealing that Young’s modulus continuously
increases under mineralization, reaching a factor of 3 for a high mineral content (Gupta et al.
2004).

The Young’s modulus shows how stiff the bone material is (Abdulghani et al. 2009; Maïsetti et
al. 2012), and the dominant stiffness is that related to the orientation direction of the collagen
(Blanchard et al. 2013). According to previous research, the Young’s modulus declines under
cyclic loading (Allen and Neptune 2012; Carter and Hayes 1977; Pattin et al.1996; Schaffler et
al. 1990; Zioupos and Currey 1994; Zioupos et al. 1996). Other studies reported that the
accumulation of microcracks contributes to a reduction in Young’s modulus (Burr et al. 1985;
Mori and Burr 1993; Schaffler et al. 1989; Zioupos and Currey 1994), but the link between
these two independent observations has not been quantified. This means that the
manifestation of damage, which is a deterioration of the structural integrity of the bone,
affects the mechanical behavior of the tissue, since it affects the bone response to the applied
strains, the distribution of the stresses, the final outcome of the fracture, and so forth
(Winwood et al. 2006). This leads to an impairment in the mechanical properties of bone.
However, extensive microdamage was not detected until bone had lost 15% of its Young’s
modulus (Burr et al. 1998). Nevertheless, small amounts of microscopic damage in the
trabecular bone was associated with a reduction of about 50 to 60% in strength, and with the
use of 90% of the fatigue life of the trabecular bone (Hernandez et al. 2014; Lambers et al.
2013).

In summary, an increase in bone density strongly contributes to bone strength. In addition,

the mineral and the collagen contents and architecture are determinant factors of the
mechanical properties of the trabecular bone. The focus in the current work is on the effect
of the mineral density and the Young’s modulus, in terms of the apparent density, on the bone
remodeling process. Nevertheless, the current work has some limitations. The investigation is
based on the assumption of the isotropic homogeneous material. This induces an idealization
of the bone behavior under cyclic loadings, since the distribution of density is non-uniform.
These results can be improved by using orthotropic heterogeneous femur models based on
medical imaging of specific known patients. Besides, the simulations is performed based on
constant displacements, but the results can be improved by using constant forces, traducing
a specific state of a patient, such as weight and physical activities. This will be the subject of
further studies. Indeed, we previously showed that different displacement values, reflecting
different activity levels, is able to accelerate or to slow the formation process in many regions
of the bone, and that applying these displacements on proximal femurs of different ages
results in different damage rates, which reflects the influence of the initial bone conditions on
the obtained results. The importance of experimental validation of the obtained numerical
results should be noted. However, the current simulation deals with human bone remodeling
throughout life, which is not possible to validate with experiments on in vivo nor in vitro
human bones. On the other hand, bone remodeling models regarding short periods of time
can be validated with experiments performed on animals, such as mice, but the current work
provides a numerical model of bone remodeling during several years, which makes this kind
of validation hard to perform, in addition to the currently unavailable means. Still, the model
provides an accurate approach for the mechanical behavior of the bone subjected to fatigue
damage, and clearly reveals the decrease of Young’s modulus with the manifestation of
damage resulting from walking. It also indicates that, whenever the apposition and the
mineralization processes are disturbed, the overall bone density and the structural
architecture are affected.

Conflict of Interest

The authors declare that they have no conflict of interest.

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