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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 Introduction
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. Conclusion
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. Acknowledgements
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 References
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(5): p.235-42.


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