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A model of bone remodeling during osteoporosis treatment to quickly compare
different (intermittent or alternating) treatment protocols.
Van der Linden JC1*, Verhaar JAN2, Weinans H1.
1 Erasmus Medical Center Rotterdam, department of orthopaedics, EE1614, PO Box 1738, 3000
DR Rotterdam, The Netherlands. 2 Erasmus Medical Center Rotterdam, department of
orthopaedics, HS 105, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
was 42 µm, which is in the biologically relevant
range5. In step 2, a check for disconnected
trabeculae was performed. Resorption cavities
Anti-resorptive treatment is widely used in
that disconnected trabeculae were not refilled. In step 3 all cavities that did not disconnect
osteoporotic patients. During osteoporosis treatment, the number of active remodeling sites,
trabeculae were refilled. One or more surface
the depth of resorption cavities and the amount of
elements in these cavities were not refilled in order to simulate the formation deficit. The
bone tissue made by osteoblasts are changed, resulting in an increase of bone mass and a
formation deficit in this simulation was 3% of a
resorption cavity, which is in the range of measured biological values6. A two-dimensional
Recently, it was shown that a combination of alendronate (a bisphosphonate) and ptH does not
representation of this simulation performed in three dimensions is shown in Fig 1.
have a synergistic effect1,2. The combination
therapy results in a bone mass only slightly higher than the bone mass resulting from bisphosphonates alone, probably because ptH can increase bone formation by active osteoblasts, while alendronate decreases bone
resorption and formation, resulting in a very small
Figure 1:2D representation of the remodeling
These three steps were repeated to simulate the
(1) whether this hypothesis can explain the
continuing process of physiological remodeling. In
each simulation cycle, new resorption cavities
were created and old cavities were refilled. Each
(2) whether a different treatment protocol, e.g.
simulation cycle corresponded to one month in
alternating bisphosphonate and ptH treatment,
real life. In the model the total time from the start
of resorption to refill was assumed to be three
months. The remodeling space was 4% of the
bone. This resulted in a turnover of 16% per year,
dimensional simulation model of remodeling in
which corresponds to values found in histological
trabecular bone4 to mimic changes in bone
studies of human bone. During the simulation,
remodeling during osteoporosis treatment, with
loose fragments could be generated, if a trabecula
was disconnected by resorption cavities at different locations. The loose fragments of bone,
Materials and methods
not connected to the main structure anymore,
The specimen used in this study was obtained
During bisphosphonate (bpp) or ptH treatment the
from an autopsy L4-vertebra of a 37 year old male
donor. The specimen was micro-CT scanned. The
according to changes reported in literature. During
dataset was segmented to obtain a 3D model of
bpp treatment, the number of resorption cavities
4*4*4 mm trabecular bone, with voxels of
was decreased by 50%, the amount of bone
14*14*14 µm. The volume fraction was 12.9%,
tissue made by osteoblasts was increased with
resulting in a computer model of 2.9 million brick
5%, the resorption depth was decreased with
33%. During simulated ptH treatment, the amount
of bone tissue made by active osteoblasts was
increased by 10%. We simulated 5 years of ptH or
The remodeling process was simulated in three
bpp treatment, started at the start of menopause
steps. In step 1 hemi-spherical resorption cavities
or 5 years later and combination therapy: bpp and
were created, randomly distributed over the
ptH simultaneous or after each other. A simulation
surface of the trabeculae. The resorption depth
of 30 years of bone remodeling took 30 minutes.
Results and discussion
According to the simulations, an early start of treatment results in a higher bone mass than a late start of treatment (Fig 1), ptH treatment results in a higher bone mass than bpp treatment.
Figure 3: Change in bone volume caused by ptH
treatment, in combination with bisphosphonate
(bpp) treatment started at several time points.
Figure 1: Change in bone volume (BV/TV(%))
over time, caused by menopause, 5 year of ptH or
bisphosphonate (bpp) treatment, started at the
start of menopause(t=0), or 5 years later.
Figure 4: Change in bone volume caused by
bisphosphonate (bpp) treatment, in combination
with ptH treatment started at several time points.
According to the model, combination therapy of
Figure 2: Change in bone volume caused by 5
ptH and bpp simultaneously yields only slightly
year of bisphosphonate (bpp) treatment, ptH
more bone than bpp treatment alone, which is in
treatment or a combination of both.
Combination treatment (bpp and ptH) resulted in a
When bisphosphonate (bpp) and ptH treatment
higher bone mass than bpp treatment alone. Five
are combined, it is best to start with the ptH
years after the start of the treatment the bone
treatment and start bpp treatment directly at the
mass achieved by ptH treatment alone was
slightly higher than the bone mass resulting from
With the described model we can test different
the combination treatment (Fig 2). This difference
combinations of bpp and ptH treatment. This
depends on the amount of extra bone mass made
might be a useful tool to optimize treatment
during ptH treatment and the decrease in
protocols for maximal bone gain, before in vivo
osteblast activity during bpp treatment. More
information about the changes in remodeling during combination treatment is needed, e.g. from bone histology.
Treatment with both ptH and bpp gives better
J.C. van der Linden was supported by the Technology
results if these treatments are given after each
Foundation STW (RPG 6294). The National Computing
other; ptH followed by bpp gives a higher bone
Facilities foundation provided computing time. We
thank prof Ruegsegger for providing CT-scan data from the EU project “Assessment of bone quality in
treatment (Fig 3 and 4). The bisphosphonate is
incorporated in the bone tissue during bpp treatment, resorption activity is decreased by the
drug in the tissue. This reduces bone turnover, and thereby decreases the bone gain during
1. Finkelstein et al, N Engl J Med, 2003. 349
(13): p. 1216-26.
2. Black et al., N Engl J Med, 2003. 349
(13): p. 1207-15.
3. Khosla, N Engl J Med, 2003. 349
(13): p. 1277-9.
Considering increases in bone volume, the best
4. van der Linden et al., Calc Tiss Int, 2003. 73
(6): p. 537-44.
treatment seems to be ptH treatment, followed by
5. Eriksen et al., Metab Bone Dis Relat Res 5
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