Supplementum 1+2/2010 - Společnost pro pojivové tkáně

Supplementum 1+2/2010 - Společnost pro pojivové tkáně Supplementum 1+2/2010 - Společnost pro pojivové tkáně

12.07.2015 Views

The stimulus for remodeling can comefrom internal factors (e.g., hormones, cytokines-growthfactors) and external factors(e.g., physical activity and mechanical loading).It is widely accepted that physicalactivity benefits the musculoskeletal systembut the mechanisms affecting bonemass and density that are set off by physicalactivity in general and mechanical loadingin particular are still poorly understood.It appears that mechanical strain inhibitsRANKL production and up-regulates OPGproduction in vitro. Hence, lack of mechanicalstrain during immobilisation (disuse)may favour an enhanced RANKL-to-OPG ratio leading to increase bone loss.Nowadays, it is believed that the staticloading is not osteogenic. Instead, thedynamic loading plays the essential role ofstimulating the bone remodelling process,which is supported by many experimentaland clinical studies. Increasing age,declining levels of sex hormones, or calciumdeficiencies produce an imbalancebetween resorption and formation resultingin bone loss. Physical activity throughits mechanical effects on bone can mitigatethis bone loss. Optimal mechanical stimulidiffer between growing and mature bone,and mature bone is influenced by ageingor other systemic factors such as nutritionand hormones.MethodsWith the development of computer-aidedstrategies and based on theknowledge of bone geometry, applied forces,and elastic properties of the tissue, itmay be possible to calculate the mechanicalstress transfer inside the bone (FiniteElements analysis or FE analysis). The changeof stresses is followed by a change ininternal bone density distribution. Thisallows formulate mathematical models thatcan be used to study functional adaptationquantitatively and furthermore, to createthe bone density distribution patterns.Such mathematical models have been builtin the past. Since they calculate just mechanicaltransmission inside the bone and notconsidering cell-biologic factors of bonephysiology, they just partially correspondto the reality seen in living organisms.Basically, there are essentially two groupsof models for bone remodelling. One assumesthat the mechanical loading is thedominant effect, almost to the exclusion ofother factors, and treatment of biochemicaleffects are included in parameter with littlephysical interpretation. The results or predictionsof these models yield the correctdensity distribution patterns in physiologicalcases. However, they have a limitedability to simulate disease. The secondgroup, the biochemical models, considercontrol mechanisms of bone adaptation ingreat detail, but with limited possibilitiesfor including mechanical effects that areknown to be essential.We realize that biochemical reactionsare initiated and influenced primarily bygenetic effects and then by external biomechanicaleffects (stress changes). Ourthermodynamic model enables to combinebiological and biomechanical factors. Sucha model may also reflect changes in remodellingbehaviour resulting from pathologicalchanges to the bone metabolism or fromhip joint replacement. However, it is a modeland thus it is a great simplification of thecomplex process of bone remodelling. Inthis talk, a more detailed description of biochemicalcontrol mechanisms will be addedto the mentioned model which in turn leads220 15. Kubátův den

to possibility to study several concrete bonerelated diseases using this model.RANKL-RANK-OPG pathway mediatesmany of the above mention biochemicalfactors. Moreover, RANKL levels alsoreflect microcrack density. Hence, it isessential to incorporate this pathway intoour model. The connection will be enabledthrough the amount RANKL-RANK bondsthat are one of the components of thedeveloped model, noted as RR. Kineticsof RANKL-RANK-OPG pathway was addedwhich enables us to add other biochemicalfactors that are actually translated throughthis pathway as NO, estradiol.ResultsWe may now simulate the response ofbone remodelling to changing environment,both mechanical and biochemical.Similarly, as was described in our previouswork, density distribution patterns may beobtained using FEM. The results from theprevious section will be used.Example – menopause: During menopause,a decline in estradiol levels occur. Insome women, the decrease is very dramatic(a drop bellow 5 pg/ml is observed, whereasa standard serum level is 40–60 \pg/ml)while in some not (serum level remainsabove 20 pg/ml). Further it was observedthat, together with estradiol, there is a declinein nitric oxide levels. An example ofa woman who is physically active (correctmechanical stimuli on regular daily basis,i.e. approximately 20000 steps per day) butin a consequence of menopause has decreasedserum levels of estradiol will be shown.The presented model predicts a decreaseof 8% in bone tissue density, which doesnot seem to be osteoporosis yet. This maybe because menopause is accompanied bymore effects than these two mentioned(as the mentioned decrease in NO) andalso most probably because they are lessphysically active (may be caused by pain).If we combine the 8% decrease caused bymenopause alone with another 9% decline(not yet published results) caused byimproper loading, we get a significant dropby almost 20% in the overall bone densityof the femur, which can be considered asosteoporotic state. One possible treatmentof bone loss connected with menopauseis treated with hormone therapy (HRT).Simulation of such a treatment that increasedestradiol serum levels to 20 pg/mlwill be shown. Again, the importance ofmechanical stimulation shown when increasedphysical activity (running 30 minutesevery other day) increases bone densityin similar fashion as HRT treatment. Andbest results are reached when both effectsare combined and even the original bonetissue density can be restored.References1. Beaupré, G. S., Orr, T. E. and Carter,D. R. (1990). An approach for time-dependentbone modeling and remodeling-application:a preliminary remodeling simulation, Journal ofOrthopaedic Research 8: 662–670.2. Carter, D. R. (1987). Mechanical loadinghistory and skeletal biology, Journal ofBiomechanics 20: 1095–1109.3. Doblaré, M. and García, J. M. (2002).Anisotropic bone remodelling model based ona continuum damage-repair theory, Journal ofBiomechanics 35(1): 1–17.4. Huiskes, R., Weinans, H., Grootenboer,H., Dalstra, M., Fudala, B. andSlooff, T. (1987). Adaptive bone-remodelingtheory applied to prosthetic-design analysis.,ambul_centrum@volny.cz221

to possibility to study several concrete bonerelated diseases using this model.RANKL-RANK-OPG pathway mediatesmany of the above mention biochemicalfactors. Moreover, RANKL levels alsoreflect microcrack density. Hence, it isessential to incorporate this pathway intoour model. The connection will be enabledthrough the amount RANKL-RANK bondsthat are one of the components of thedeveloped model, noted as RR. Kineticsof RANKL-RANK-OPG pathway was addedwhich enables us to add other biochemicalfactors that are actually translated throughthis pathway as NO, estradiol.ResultsWe may now simulate the response ofbone remodelling to changing environment,both mechanical and biochemical.Similarly, as was described in our previouswork, density distribution patterns may beobtained using FEM. The results from theprevious section will be used.Example – menopause: During menopause,a decline in estradiol levels occur. Insome women, the decrease is very dramatic(a drop bellow 5 pg/ml is observed, whereasa standard serum level is 40–60 \pg/ml)while in some not (serum level remainsabove 20 pg/ml). Further it was observedthat, together with estradiol, there is a declinein nitric oxide levels. An example ofa woman who is physically active (correctmechanical stimuli on regular daily basis,i.e. ap<strong>pro</strong>ximately 20000 steps per day) butin a consequence of menopause has decreasedserum levels of estradiol will be shown.The presented model predicts a decreaseof 8% in bone tissue density, which doesnot seem to be osteoporosis yet. This maybe because menopause is accompanied bymore effects than these two mentioned(as the mentioned decrease in NO) andalso most <strong>pro</strong>bably because they are lessphysically active (may be caused by pain).If we combine the 8% decrease caused bymenopause alone with another 9% decline(not yet published results) caused byim<strong>pro</strong>per loading, we get a significant dropby almost 20% in the overall bone densityof the femur, which can be considered asosteoporotic state. One possible treatmentof bone loss connected with menopauseis treated with hormone therapy (HRT).Simulation of such a treatment that increasedestradiol serum levels to 20 pg/mlwill be shown. Again, the importance ofmechanical stimulation shown when increasedphysical activity (running 30 minutesevery other day) increases bone densityin similar fashion as HRT treatment. Andbest results are reached when both effectsare combined and even the original bonetissue density can be restored.References1. Beaupré, G. S., Orr, T. E. and Carter,D. R. (1990). An ap<strong>pro</strong>ach for time-dependentbone modeling and remodeling-application:a preliminary remodeling simulation, Journal ofOrthopaedic Research 8: 662–670.2. Carter, D. R. (1987). Mechanical loadinghistory and skeletal biology, Journal ofBiomechanics 20: 1095–1109.3. Doblaré, M. and García, J. M. (2002).Anisotropic bone remodelling model based ona continuum damage-repair theory, Journal ofBiomechanics 35(1): 1–17.4. Huiskes, R., Weinans, H., Grootenboer,H., Dalstra, M., Fudala, B. andSlooff, T. (1987). Adaptive bone-remodelingtheory applied to <strong>pro</strong>sthetic-design analysis.,ambul_centrum@volny.cz221

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