Accepted Manuscript

Title: Bone structural changes in osteoarthritis as a result of mechanoregulated bone

adaptation: a modeling approach

Authors: Lieke G.E. Cox, B. van Rietbergen, C.C. van Donkelaar, K. Ito

PII: S1063-4584(11)00055-0
DOI: 10.1016/j.joca.2011.02.007
Reference: YJOCA 2404

To appear in: Osteoarthritis and Cartilage

Received Date: 4 October 2010

Revised Date: 2 February 2011
Accepted Date: 2 February 2011

Please cite this article as: Cox LG, van Rietbergen B, van Donkelaar CC, Ito K. Bone structural changes
in osteoarthritis as a result of mechanoregulated bone adaptation: a modeling approach, Osteoarthritis
and Cartilage (2011), doi: 10.1016/j.joca.2011.02.007

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Title Page & Abstract
ACCEPTED MANUSCRIPT

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Bone structural changes in osteoarthritis as a result

of mechanoregulated bone adaptation: a modeling

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approach

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Lieke G.E. Cox†, B. van Rietbergen†, C.C. van Donkelaar†, K. Ito†

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†Department of Biomedical Engineering, Eindhoven University
of Technology, Eindhoven, The Netherlands
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January 11, 2011

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Abstract

Objective There are strong indications that subchondral bone may play

an important role in osteoarthritis (OA), making it an interesting target for

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medical therapies. The subchondral bone structure changes markedly during

OA, and it has long been assumed that this occurs secondary to cartilage

degeneration. However, for various conditions that are associated with OA,
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it is known that they may also induce bone structural changes in the ab-
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sence of cartilage degeneration. We therefore aimed to investigate if OA bone

structural changes can result from mechanoregulated bone adaptation, inde-

pendent of cartilage degeneration. Method With a bone adaptation model,

we simulated various conditions associated with OA -without altering the

articular cartilage- and we evaluated if mechanoregulated bone remodeling

by itself could lead to OA-like bone structural changes. Results For each of

the conditions, the predicted changes in bone structural parameters (bone

fraction, trabecular thickness, trabecular number, and trabecular separation)

were similar to those observed in OA. Conclusion This indicates that bone

adaptation in OA can be mechanoregulated with structural changes occurring

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independent of cartilage degeneration.

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1 1 Introduction

2 Osteoarthritis (OA) is a common cause of long-term disability1 . It is characterized

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3 by degeneration of cartilage and modification of the structural and material prop-
4 erties of subchondral bone2 . Patients suffer from chronic joint pain, restriction of
5 motion, crepitus with motion, and joint effusions. For many years, pharmaceutical

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6 therapies have been focussed on cartilage. The bone changes were thought to occur
7 secondary to cartilage degeneration, and not to play a major role in the disease pro-

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8 cess. However, it has been shown in animal studies that subchondral bone changes
9 occur at early stages of OA3, 4 , and that alterations to subchondral bone can lead
to cartilage degeneration5, 6 . Furthermore, there is an increased incidence of OA

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11 in patients with certain bone disorders7, 8, 9 , and it has been shown that bone cells
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derived from OA patients can directly influence cartilage metabolism10, 11, 12 .
For these reasons, currently the bone is considered as a therapeutic target as well,
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14 and in various OA patient and animal studies, the subchondral bone structure has

15 been investigated. OA is associated with marked increases in subchondral bone

fraction and trabecular thickness, accompanied by decreases in trabecular number
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17 and separation13, 14, 15, 16, 17 . The cause of these bone structural changes remains
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18 unresolved and a better understanding might help in developing bone targeting

19 therapies18 .
A wide variety of conditions is associated with OA. Obesity19, 20, 21 , strenuous
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21 exercise22 , and physically demanding professions20, 23, 24 are all known risk fac-
22 tors for OA, which is largely attributed to the high joint loads associated with these
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23 conditions22, 25, 26 . Other conditions that alter joint loads and are strongly asso-
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24 ciated with OA are (partial) meniscectomy27, 28 , anterior cruciate ligament (ACL)

25 injury29 , and joint malalignment30 . In addition, OA is associated with the bone dis-
26 ease osteopetrosis7, 8, 31 , which is characterized by a decrease in osteoclast number
27 and activity31 . Finally, bone matrix mineralization and stiffness have been found to

28 be decreased in OA bone32, 33, 34, 35 , and although it is unclear whether this should
29 be regarded as a cause or an effect of OA, it has been suggested that bone sclerosis
30 in OA occurs to counteract the decrease in matrix stiffness36 .
31 The conditions associated with OA do not only alter joint mechanics and bone cel-
32 lular activities in distinct ways; in addition they differ in the time course in which

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33 these changes occur. For example, osteopetrosis is already present at birth, while
34 obesity may lead to a gradual increase in load, and ACL injury may alter joint me-
35 chanics abruptly. Considering the wide variety of conditions associated with OA,

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36 it is clear that OA can develop via multiple pathways. It is also known for most of

37 these conditions that they themselves can induce bone structural changes even in

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38 the absence of OA, via mechanoregulated bone adaptation. This may explain why
39 bone structural changes can occur early in the OA disease process, independent of

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40 cartilage degeneration. However, it is unclear if these structural changes caused
41 by mechanoregulated bone adaptation are similar to the changes observed in OA,
42 or that in addition a different, pathological mechanism is involved. We therefore

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43 aimed to investigate if mechanoregulated bone adaptation can lead to OA-like bone
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structural changes for various conditions associated with OA, independent of carti-
lage degeneration. In addition, we questioned whether countering bone adaptation
46 as a therapeutic target is likely to reduce the progression of OA.
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47 For this purpose, we used an established computational model of mechanoregu-
48 lated bone adaptation to simulate conditions associated with OA, that influence
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49 joint mechanics or bone remodeling in different ways. We changed boundary condi-

tions and model parameters, but not the remodeling algorithm itself, such that the
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51 simulations reflected the mentioned conditions. Subsequently, we evaluated if the

52 simulated bone structural changes that were obtained as a result of mechanoreg-
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53 ulated bone remodeling in these conditions were similar to OA experimental data

54 from literature. In the simulations, no changes to the articular cartilage were con-
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55 sidered, as we aimed to investigate if OA-like bone structural changes could develop

56 independent of cartilage degeneration.
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57 2 Methods

58 2.1 Computational model

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59 The computational model is based on the theory of Huiskes et al 37 , that describes
60 the metabolic processes in bone as a result of bone tissue loading sensed by osteo-

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61 cytes. It was previously shown that this theory can be used to simulate basal bone
62 remodeling, and the adaptation of trabecular bone to alternative loading conditions
and changes in bone cellular activities38, 39 .

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64 In the model, osteocytes are randomly distributed throughout the bone tissue, and
65 each osteocyte produces a stimulus P in response to the local strain energy density

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66 (SED) rate. At each location x on the bone surface, the total osteocyte stimulus
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P (x, t) is calculated by summation of the stimuli by the surrounding osteocytes:

P (x, t) = f (x, xk )µU (xk , t). (1)

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k=1

68 Here, U (xk , t) is the SED rate at the location of osteocyte k, n is the total number of
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69 osteocytes within the influence distance of x, µ is the osteocyte mechanosensitivity,

70 and f (x, xk ) is a signal decay function:
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−d(x,xk )
f (x, xk ) = e D , (2)
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71 depending on the distance between osteocyte k and location x on the bone surface
72 d(x, xk ), and decay parameter D. If the total osteocyte stimulus P (x, t) exceeds
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73 formation threshold kthr , bone is formed according to:

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dVf (x, t)
= τ (P (x, t) − kthr ) if P (x, t) > kthr . (3)
dt

dVf,b (x,t)
74 Here, dt is the change in bone volume at location x due to bone formation,
75 and τ is a time constant related to the rate of bone formation. Resorption is assumed
76 to be triggered by randomly occurring microcracks. This means that the chance of

77 resorption is equal at all locations x on the bone surface. Furthermore, it is assumed

78 that at each location x where resorption occurs, the same amount of bone Vcl is
79 resorbed within one increment, making the change of volume due to resorption at

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80 this location:

R R
dVr (x, t)  −Vcl if r(x, t) ≤ t x Fres dx dt

= (4)
dt r(x, t) >
R R
0 if t x Fres dx dt

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
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81 Here, r(x, t) is a random number between 0 and 1, and Fres is the resorption

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82 frequency, indicating the frequency with which new resorption pits are formed on
83 the bone surface. The total change of bone volume becomes:

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dV (x, t) dVf (x, t) dVr (x, t)
= + (5)
dt dt dt

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84 2.2 Finite element analysis

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To calculate the local SED values, finite element analysis was used. We evaluated
our hypothesis in a 2D domain that represents part of the articular cartilage and
87 bone below the articular cartilage. We used a square mesh of 200 x 200 elements,
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88 with an element size of 50 x 50 µm. The model consisted of 194 rows of bone tissue
89 and 6 rows of articular cartilage. In the bone tissue, osteocytes were randomly
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90 distributed. The mesh was loaded statically with 2 MPa compression in the vertical
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91 direction (perpendicular to the cartilage), and 1.2 MPa in the horizontal direction,
92 which for a linear elastic material represents the maximum SED rate of a dynamic
93 load of 1 MPa and 0.6 MPa at 1 Hz respectively40 . The initial mesh and boundary
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94 conditions are shown in figure 1, as well as the different loads applied for the different
95 simulations.
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96 The volume change is calculated per integration point. If an integration point

97 volume is completely filled with bone, the relative density is 1. If an integration
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98 point does not contain any bone tissue, the relative density is 0. At the trabecular
99 surface, integration point volumes can be partially filled with bone, leading to a
100 relative density of bone volume per integration point volume between 0 and 1. At
101 these locations, the elastic modulus was calculated using Currey’s power law41 :

E(n, k) = Eb ρ(n, k)γ . (6)

102 Here, Eb is the elastic modulus of the bone matrix, ρ(n, k) is the bone volume
103 density at integration point location n at time increment k, and γ is a material

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104 constant. The model parameter values are in table 1. Since we used 2D analyses,
105 parameters are related to area instead of volume. The derivation of the model
106 parameter values was described in a previous paper39 .

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Table 1: Model parameters.

Symbol Variable Value Unit Ref

n Osteocyte density 1600 mm−2 42
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D Osteocyte signal decay parameter 0.1 mm
Vcl Resorption space 1.5x10−3 mm2 h−1 44, 45
γ Material constant 3.0 - 41
µ Osteocyte mechanosensitivity 0.5 nmol mm J−1 h−1
kthr Formation threshold 2.0x10−4 nmol mm−2 h−1
τ Time constant 9.1x10−4 mm5 nmol−1

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Fres Resorption frequency 12.8 mm−2 h−1
Eb Elastic modulus bone 5x103 MPa 46, 47, 48
νb Poisson ratio bone 0.3 - 49, 50
Ec Elastic modulus articular cartilage 6 MPa 51, 52
νc Poisson ratio articular cartilage 0.49 - 52

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2.3 Simulations of conditions associated with OA
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108 High joint load

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109 Obesity, strenuous exercise, and physically demanding professions uniformly
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110 increase joint loads, while partial meniscectomy, ACL injury, and malalignment
111 increase joint loads in a spatially non-uniform matter. ACL injury and varus
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112 alignment increase medial loading30, 53, 54 , and valgus alignment increases lateral
loading30, 54 , while for partial meniscectomy the redistribution of load depends on
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114 the location of the meniscectomy.

115 We simulated bone remodeling in response to both a spatially uniform and a
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116 spatially non-uniform increase in load (table 2, figure 1). For the uniform high load
117 we chose a 40% increase compared to normal26 . For the non-uniform increase in
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118 load we applied a ramp load on top of the cartilage, ranging from the normal load
119 to a 40% increase53, 55, 56 .
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121 Decreased bone matrix stiffness

122 To simulate bone remodeling in response to a decrease in mechanical bone matrix

123 properties, we decreased bone matrix stiffness by 40%, based on nanoindentation

124 measurements from an OA patient study33 .
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126 Bone disease

127 Osteopetrosis is mainly characterized by a decrease in osteoclast number and

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128 activity31 , and we simulated osteopetrosis by decreasing the corresponding model

129 parameters (table 2). Because the amount of decrease in osteoclast number and
130 activity varies for different forms and severities of the disease, no exact parame-

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131 ter changes could be derived from the literature. Therefore, we made an arbitrary

132 choice to decrease the resorption frequency by 60% and the resorption cavity size

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133 by 30%.

Table 2: Overview of the simulated conditions.

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Condition Model parameter change
1. obesity, strenuous exercise uniform 40% increase in load
2. malalignment, ACL injury, 0-40% increase in load perpendicular to
partial meniscectomy the joint surface (ramp load)
3. decreased mineralization 40% decrease in bone matrix stiffness Eb

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4. osteopetrosis 60% decrease in resorption frequency F res and
30% decrease in resorption cavity size Vcl

134 2.4 Simulation protocols

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135 First, we performed a simulation with the normal parameter set, until equilibrium
136 was obtained. Subsequently, we used this ‘normal’ structure as starting point for
137 the simulation of condition 1, condition 2, and condition 3 (table 2), assuming that
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138 these conditions develop at a certain time during adulthood. For condition 4, we
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139 did not use the normal structure as starting point, since osteopetrosis is already

140 present at birth. Instead we started from the uniform structure that was also the
141 starting point for the ‘normal’ simulation.
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142 2.5 Bone structure parameters

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143 To evaluate the effect of the different simulated conditions, we determined structure
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144 parameters from the simulated bone architectures. Bone density was determined
145 by dividing the area of bone by the total area, and trabecular number by counting
146 the trabecular intersections along each horizontal pixel row. Trabecular thickness

147 was defined for each trabecular surface pixel as the smallest distance to another
148 trabecular surface pixel, bordering a different marrow cavity. Trabecular separation
149 was defined for each marrow cavity as the largest distance between two bone surface
150 pixels bordering the marrow cavity.

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151 3 Results

152 From the simulated structures (figure 2), bone structural parameters were deter-

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153 mined. These parameters are in table 3, together with literature values determined
154 from human cancellous bone at different sites. Trabecular dimensions for the nor-
155 mal simulation are similar to experimentally determined values (table 3), although

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156 the simulated bone fraction is slightly high, while trabecular number is slightly
157 low compared to literature values. The explanation for these deviations is that in

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158 our simulations all trabeculae are interconnected in the 2D plane in contrast with
159 normal bone structures, thereby leading to a higher bone fraction for the same

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160 trabecular number and thickness.
Table 3: Bone structure parameters baseline simulation

Bone fraction (BF)

Trabecular thickness (Tb.Th)
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0.56
270µm
Literature 57, 58, 59, 60
0.15-0.41
119-330 µm
Trabecular number (Tb.N) 1.18 mm−1 1.30-1.90 mm−1
Trabecular separation (Tb.Sp) 646 µm 300-740 µm
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161 Experimentally determined changes in bone structure parameters as a result of OA

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162 vary considerably, depending on for example the severity of the disease, making
quantitative comparison to our simulations inexpedient. However, to obtain an
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164 idea of the in vivo range of change in structural parameters, we included OA data
165 from clinical and animal studies from the literature in table 4.
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Table 4: Changes in bone structural parameters for the simulated conditions compared to the
simulated normal structure.

Condition BF Tb.Th Tb.N Tb.Sp

1. Obesity, strenuous exercise +32% +29% -25% -20%
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2. ACL injury, partial meniscectomy, malalignment +11% +11% -2% -7%

3. Reduced mineralization +23% +22% -14% -17%
4. Osteopetrosis +63% +7% -22% -68%
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Literature data on OA 13, 14, 15, 17, 61 +(18-80)% +(13-87)% -(9-15)% -(18-26)%

166 From figure 2 and table 4, it can be seen that each simulated condition led to an
167 increase in bone fraction and trabecular thickness, and a decrease in trabecular
168 number and separation, in concurrence with experimental data from OA patients
169 and animal studies.
170 The simulation representing joint malalignment and ACL injury resulted in the

171 smallest changes in bone structural parameters. The explanation for this is that
172 bone changes in this simulation were local, while the determined structure parame-

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173 ter values are an average for the whole mesh. The changes mostly occurred on the
174 right side of the structure, underneath the area of the most highly loaded cartilage.
175 Such localized sclerosis is in agreement with experimental data from OA patients

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176 with bone malalignment62 . The increase in bone fraction is the most marked in the

177 simulation of osteopetrosis, which agrees with the association of osteopetrosis with

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178 severe sclerosis.
179 We calculated the average SED value in the bone tissue during the period of bone

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180 remodeling for each condition and compared these to the average SED value for
181 the normal equilibrium simulation (figure 3). Obesity, strenuous exercise, malalign-
182 ment, ACL injury, partial meniscectomy and decreased mineralization all led to an

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183 increase in SED. This was either due to an increase in both stress and strain result-
184

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ing from an increase in load, or due to an increase in strain caused by a decrease
in matrix stiffness. During remodeling, bone fraction increased such that the SED
186 returned to the normal level or even decreased to slightly below the normal level.
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187 The SED values for osteopetrosis are not shown in figure 3, since we did not use the
188 normal structure as input for this simulation. The average SED value in the bone
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189 was much lower in the simulation of osteopetrosis, due to the higher bone fraction.

We also determined the apparent bone stiffness at the onset of the conditions and
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191 after remodeling (figure 4). The stiffness before and at the onset of the conditions is
192 not shown for osteopetrosis, since there was no clear onset point in this case, but at
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193 the end of this simulation the apparent bone stiffness was 172% higher than normal.
194 As expected, the apparent bone stiffness at the onset of the condition decreased by
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195 approximately 40% in case of the decreased matrix stiffness, while there was no
196 change in apparent bone stiffness at the onset of the conditions for the simulations
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197 in which the load was increased. Remodeling resulted in an increase in apparent
198 bone stiffness for all conditions. In case of the increased loads, the increase in bone
199 fraction that occurred during remodeling led to an apparent bone stiffness which
200 was higher than normal (74% increase for obesity/ exercise, and 17% increase for
201 ACL injury/ meniscectomy/ malalignment), while the increase in bone fraction in
202 case of decreased mineralization normalized the apparent bone stiffness (from 40%

203 lower than normal at the onset of the condition to 8% lower than normal after
204 remodeling).

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205 4 Discussion

206 The bone structural changes that we predicted using a mechanoregulated bone

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207 adaptation model, are in agreement with bone structural changes observed in OA.
208 This indicates that subchondral bone structural changes observed in OA can occur
209 independent of cartilage degeneration, and that they do not need to result from

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210 disturbed mechanoregulation or inflammatory processes that occur as a direct re-
211 sult of the disease. However, this does not mean that cartilage degeneration can

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212 not (indirectly) induce or promote bone structural changes in OA. Although in the
213 current study we focused on the adaptation of the subchondral bone, altered joint

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214 mechanics also affect the articular cartilage. Pathology begins if the repair capacity
215 of the osteochondral tissue has been exceeded, which usually is a process of many
216

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years. Once the degeneration has begun, the degenerative processes and mechanical
adaptation likely interact. Degeneration of cartilage is thought to increase the stress
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218 in the subchondral bone56 , and additionally, it may lead to joint malalignment63 ,

219 which would both induce a remodeling response according to our simulations. Fur-
thermore, the decrease in bone matrix stiffness observed in OA may be related to
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221 cartilage degeneration. In OA femoral heads, bone matrix stiffness was found to be
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222 most markedly decreased directly underneath the cartilage34 and in a study on OA
223 knees, the bone structural changes were also most marked directly underneath the
cartilage, and additionally seemed correlated to the degree of degeneration of the
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224

225 overlying cartilage15 .

226 Our simulations do not exclude the possibility that a different, pathological process
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227 influences bone formation and resorption in OA. However, they do show that it is
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228 likely that mechanoregulation is still present, ensuring that bone is formed at loca-
229 tions of high mechanical load, and resorbed at locations of low mechanical load. If
230 mechanoregulated bone remodeling is indeed the mechanism behind the bone struc-
231 tural changes in OA, what does this mean for the development of bone-targeting

232 therapies? Currently, pharmaceutical therapies are being developed that target os-
233 teoblasts and osteoclasts, and decrease the bone remodeling rate. Although the
234 bone turnover rate is indeed increased in OA, our study indicates that bone for-
235 mation and bone resorption are not necessarily disturbed. Furthermore, inhibiting
236 bone remodeling may negatively affect bone, since it may lead to higher local bone

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237 tissue loading as shown in figure 3.

238 In addition to the effect that bone-targeting therapies have on bone, they may have
239 an effect on cartilage. It has been suggested that cartilage degeneration in OA is

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240 related to the subchondral bone stiffness. Both an increase64, 65 and a decrease66, 67

241 in apparent bone stiffness have been suggested to lead to cartilage degeneration. If

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242 both hypotheses hold, the effect of inhibiting bone remodeling on cartilage may
243 depend on the underlying cause of the disease. Inhibiting bone remodeling in case

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244 high joint loads or osteopetrosis are the underlying cause of the disease may be
245 beneficial, since this may prevent an increase in bone stiffness (figure 4). However,
246 in case decreased mineralization is the underlying cause of the disease, inhibiting

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247 remodeling may have a negative effect on cartilage, since it may prevent ‘normal-
248

249
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ization’ of the apparent bone stiffness (figure 4). Of course, if inhibiting remodeling
would prevent the replacement of normal bone tissue by less mineralized bone ma-
250 trix, this may counteract the initial decrease in apparent bone stiffness observed in
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251 our simulations. Furthermore, it should be noted that other factors may play a role
252 as well, as it has been shown that bone cells isolated from OA bone may directly
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253 alter cartilage metabolism in vitro 10, 11, 12 .

In our model it is assumed that osteocytes can sense an SED equivalent loading
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255 measure and that they can stimulate osteoblast cells in their vicinity. Although
256 these are assumptions, we have demonstrated in earlier studies that this model
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257 can explain a large number of trabecular bone features40 , and that its results are
258 not strongly dependent on the choice of the exact load parameter sensed by the
osteocytes68 or even the assumed regulation mechanism69 . In the present study we
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260 used a 2D model, which limits the structures that can be represented. However,
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261 a thorough parameter study showed that for this 2D model, alterations in bone
262 structure parameters in response to a change in various model parameters are in
263 agreement with experimental data from literature39 .
264 In conclusion, mechanoregulated bone remodeling may explain how various con-
265 ditions associated with OA can directly induce OA-like bone structural changes,
266 independent of changes occurring in the cartilage. Also, it may explain why bone

267 structural changes can occur secondary to cartilage degeneration. Given the hy-
268 pothesis underlying our theoretical work, we propose that decreasing the rate of

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269 bone remodeling in OA may increase bone tissue loading. Furthermore, we pos-
270 tulate that whether decreasing the rate of bone remodeling has a beneficial effect
271 on cartilage degeneration depend considerably upon the underlying cause of the

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272 disease.

Author contributions

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273

274 All authors contributed to the conception and design of the study, analysis and

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275 interpretation of the data, and revision of the article. L.G.E. Cox performed the

276 simulations and drafted the article. All authors granted final approval.

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277 Acknowledgements

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This project is funded by the Royal Netherlands Academy of Arts and Sciences.

279 Conflict of interest statement

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280 None.

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Figure captions
Figure 1. The different loading conditions: a) normal, b) obesity, strenuous
exercise, c) malalignment, ACL injury, partial meniscectomy.

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Figure 2. Simulated bone structures for different conditions. a) normal, b)
obesity, strenuous exercise, c) ACL injury, partial meniscectomy, malalignment, d)
reduced mineralization, e) osteopetrosis.

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Figure 3. Average SED in the bone during remodeling after changing the model

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parameters to simulate conditions associated with OA.

Figure 4. Apparent bone stiffness prior to and after the onset of different condi-

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