- Email: [email protected]
The effect of a disturbed mineralization process on the bone mineralization density distribution (BMDD)
Abstracts / Bone 48 (2011) S173–S186 ing to sites of primary mineralization and CaHigh, the fraction of high mineralized bone. CaHigh was only determined for metaphyseal bone. The BMDD curves exhibited a shift towards higher matrix mineralization in both diabetic and control samples from metaphyseal to epiphyseal and to cortical bone reflecting the differences in local average tissue age due to the different remodeling situations. However, the comparison of BMDDs from diabetic with control rats did not reveal any significant differences, except in the metaphyseal site, where CaWith (+25%, p = 0.041) and CaHigh (+ 53.5%, p = 0.013) were increased in ZDF rats. The results show that the mineralization pattern is in general not affected by the diabetic phenotype. The differences in CaWidth and CaHigh observed are due to an increased fraction of residual cartilage in the bone trabeculae, suggesting alterations in endochondral bone formation in the ZDF rats. Our findings indicate that mineralization density distribution is normal in this type 2 diabetes rat model and therefore other pathophysiological factors might be responsible for the observed impaired bone phenotype. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared. doi:10.1016/j.bone.2011.03.419
PP260-M Association between bone stiffness and age. A micro-finite element analysis in women from the OFELY cohort N. Vilayphiou a,⁎, S. Boutroy a, E. Sornay-Rendu a, F. Munoz a, B. Van Rietbergen b, P. Delmas a, R. Chapurlat a a INSERM U831 and Université de Lyon, Lyon, France b Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands Abstract: Areal bone mineral density (aBMD) decreases with age in women, but our knowledge of bone biomechanical properties is limited, so we have studied the decline of bone strength with age, as assessed with micro-finite element analysis (μFEA) using high resolution peripheral QCT (HR-pQCT). So far, our cross-sectional analysis has involved 483 out of 841 women from the OFELY cohort who had an HR-pQCT radius scan at the 14th year of follow-up. There were 203 pre(preM) and 280 postmenopausal (postM) women, aged 40 ± 9 and 71 ± 9 years old respectively. In postM women, 101 women sustained fragility fractures during the follow-up. Distal radius HR-pQCT scans were used to measure volumetric BMD (vBMD) and microarchitecture parameters, after segmentation of cortical (Ct) bone with advanced algorithm (Burghardt, Nishiyama et al. Bone 2010). Estimated failure load was assessed by μFEA as the main outcome of radius bone strength, and the load to strength ratio Φ was derived to estimate the risk for wrist fracture. Total hip aBMD was recorded by DXA at the same visit. In preM women, most parameters did not vary with age. In postM women, Ct porosity and trabecular (Tb) heterogeneity increased importantly with age, respectively from 0.7 to 3.4% and from 210 to 580 μm in total (both p<0.001). Total, Ct and Tb vBMD decreased with age, as well as Ct thickness and Tb number (r=−0.39 to −0.54, p<0.001). The deterioration of microarchitecture with age resulted in a decrease of the μFE-failure load of −9 to −14% by decade, with an overall loss of a third of bone strength throughout the postmenopausal period compared to preM women. A total increase of Φ by 48% was observed, so that after the age of 70 more than half (70%) of the elderly women had a risk factor Φ>1. Considering Φ as a general factor of risk (not only wrist fracture), we compared the ROC curves of Φ and total hip aBMD, with respect to prevalent fractures. The area under the curves was slightly higher for Φ than total hip aBMD (AUC=0.80 and 0.77, respectively). However, sensitivity and specificity for fracture of the mechanical criterion Φ>1 were 73 and 74% respectively, whereas that of the T-score<−2.5 were 15 and 98% respectively. μFEA are still ongoing to complete this cross sectional dataset of the OFELY cohort, but those preliminary data show a consistent decline of bone strength with age at the radius. We suggest that the calculated load to strength ratio might be a relevant indicator of fracture risk. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: N. Vilayphiou Grant/Research Support from ECTS/Servier Fellowship 2009, S. Boutroy: None Declared, E. Sornay-Rendu: None Declared, F. MUNOZ: None Declared, B. Van Rietbergen Consulting fees from Scanco Medical AG, P. Delmas: None Declared, R. Chapurlat: None Declared. doi:10.1016/j.bone.2011.03.420
PP261-T The interplay between calcium homeostasis and bone mineralization — A computational approach P. Kollmannsberger a,⁎, C. Lukas a, P. Roschger b, P. Fratzl a, R. Weinkamer a a Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany b Ludwig Boltzmann Institute of Osteology, 4th Department, Hanusch Hospital & UHK-Meidling, Vienna, Austria
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Abstract: The mineral flux into and out of bone due to remodeling and mineralizaton plays an important role in calcium homeostasis and is tightly controlled by hormones. Endocrine diseases result in disturbed plasma hormone and mineral levels and cause long-term changes in bone mineralization. These changes can be diagnosed by deviations of the heterogeneity of the mineral content within bone, as quantified by the bone mineralization density distribution (BMDD) from the healthy reference [1]. Despite the large amount of available data, an intuitive understanding of how plasma hormone levels affect bone mineralization is lacking due to the complexity of the bone-endocrine regulatory system. Computer simulations are therefore a valuable tool to quantify the role of different influencing factors and to interpret physiological data. Our investigations are based on measurements of the BMDD using quantitative backscattered electron imaging (qBEI), and plasma mineral and hormone data of the same patients. We present a theoretical model that quantitatively links mineral and hormone kinetics to the long-term evolution of the BMDD. The model integrates current knowledge about the interactions of calcium, parathyroid hormone (PTH), calcitriol and bone cells, and incorporates it into an established theoretical description of the BMDD as a function of bone remodeling and mineralization [2]. As an example of particular interest, we apply our model to experimental data from patients with mild primary hyperparathyroidism (PHPT) [3]. We show how the reported broadening of the BMDD peak and its shift to lower calcium content can be predicted quantitatively based on plasma mineral and hormone data. The results demonstrate that bone is itself part of a feedback loop that contributes to long-term calcium homeostasis. Our study highlights how computer simulations can help to characterize the role of different influencing factors and to study generic control principles underlying the bone-endocrine regulatory system. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared. References [1] Roschger P, et al. Bone mineralization density distribution in health and disease. Bone 2008;42(3):456–66. [2] Ruffoni D, et al. The bone mineralization density distribution as a fingerprint of the mineralization process. Bone 2007;40(5):1308–19. [3] Roschger P, et al. New observations on bone quality in mild primary hyperparathyroidism as determined by quantitative backscattered electron imaging. J Bone Miner Res 2007;22 (5):717–23. doi:10.1016/j.bone.2011.03.421
PP262-S The effect of a disturbed mineralization process on the bone mineralization density distribution (BMDD) C. Lukas a, P. Kollmannsberger a, D. Ruffoni b, P. Roschger c, P. Fratzl a, R. Weinkamer a,⁎ a Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany b Institute for Biomechanics, ETH Zurich, Zurich, Switzerland c Ludwig Boltzmann Institute of Osteology, 4th Department, Hanusch Hospital & UHK-Meidling, Vienna, Austria Abstract: Trabecular bone consists of a patchwork of bone packets with different mineral contents. This heterogeneity of bone can be measured, for instance, in the electron microscope using quantitative backscattered electron imaging (qBEI) and quantified in a frequency distribution called the bone mineralization density distribution (BMDD). The BMDD has proven to be a sensitive diagnostic tool for bone diseases [1]. Mathematical modeling allows connecting pathological changes in the BMDD with disturbances in bone remodeling and mineralization. The model was successfully applied to situations of changes in bone turnover occurring at the onset of menopause and following antiresorptive therapy [2]. One limitation of the comparison between theoretical prediction and BMDD measurements is due to the fact that the experimental data are affected by the stochastic nature of the backscattering of electrons and the finite acquisition time. We have now devised an approach using regularization tools to deconvolve and correct measured BMDDs. As a result, the reference BMDD for healthy human adults could be defined with improved precision. Moreover, the mathematical model was applied to situations where the mineralization process is disturbed. The inadequate mineralization in osteomalacia and the increased bone turnover at menopause both lead to a shift of the BMDD histogram towards lower mineral contents, in comparison to reference. With the use of mathematical modeling, it became possible to differentiate the time evolution of the BMDD, for both disease scenarios. The influence of Sr-treatment was also considered in the mathematical model, taking into account the difference in electron backscattering between Sr and Ca. When about 5% of the Ca atoms are replaced by Sr in the newly formed bone only [3], the model predicts a strong transient narrowing of the BMDD. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared. References [1] Roschger P, et al. Bone mineralization density distribution in health and disease. Bone 2008;42(3):456–66.
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[2] Ruffoni D, et al. Effect of Temporal Changes in Bone Turnover on the Bone Mineralization Density Distribution: A Computer Simulation Study. Journal of Bone and Mineral Research 2008;23(12):1905–14. [3] Roschger P, et al. Bone Material Quality in Transiliac Bone Biopsies of Postmenopausal Osteoporotic Women After 3 Years of Strontium Ranelate Treatment. Journal of Bone and Mineral Research 2010;25(4):891–900. doi:10.1016/j.bone.2011.03.422
PP264-T (For more information visit the Amgen/GlaxoSmithKline Scientific Booth) Denosumab decreases cortical porosity in postmenopausal women with low BMD S.K. Boyd a, K.K. Nishiyama a, R.M. Zebaze b, D.A. Hanley a, J.R. Zanchetta c, T. Thomas d, S. Boutroy e, C. Bogado c, M. Austin f, C. Libanati f,⁎, E. Seeman g a University of Calgary, Calgary, Canada b University of Melbourne, Melbourne, Australia c Instituto de Investigaciones Metabolicas, Buenos Aires, Argentina d INSERM U890, University Hospital of St-Etienne, St-Etienne, France e INSERM U831 and Universite de Lyon, Lyon, France f Amgen Inc., Thousand Oaks, USA g Austin and Repatriation Medical Centre, University of Melbourne, Melbourne, Australia Abstract: Recent evidence highlights the importance of the cortical compartment in postmenopausal bone loss and its relevance to bone strength during aging.1,2 We have reported that denosumab increased BMD at the total, cortical and trabecular compartments of the distal radius, as assessed by HRpQCT, and increased polar moment of inertia, a surrogate of strength, as estimated by QCT.3 We now report the changes in cortical porosity that occurred over the same 1-year study. Postmenopausal women (N = 247) with a mean (SD) age of 60.6 (5.4) years and mean BMD T-Scores at the spine, total hip, and radius of −2.44, −1.30 and −1.85, respectively, were enrolled and randomly assigned in a double-blind, double-dummy fashion to denosumab 60 mg Q6M (N = 83), alendronate 70 mg QW (N = 82), or placebo (N = 82). Porosity was evaluated in the compact appearing cortex of the distal radius at baseline and month 12 from HRpQCT scans using an enhanced method that identifies the cortex with automatic threshold segmentation.4 Pores above ~82 μm are identifiable; porosity was expressed as percent of the total cortical volume. The accuracy5 and reproducibility6 of this method have been previously reported. Baseline cortical porosity was 2.6%. Over 12 months, cortical porosity increased in placebo subjects, remained unchanged in alendronate-treated subjects, and tended to decrease in denosumab-treated subjects (Fig. 1). Denosumab significantly reduced cortical porosity by 8.18% (P = 0.01) compared to placebo. Denosumab prevented the progression of porosity seen with placebo, an effect that is likely to improve bone strength, reduce fracture risk and contribute to a better understanding of the mechanism of action of denosumab. Limitations of the current study include (i) thresholding: porosity may be underestimated in the setting of a low-density cortex; (ii) the inability of the instrument to assess porosity below ~82 μm; (iii) lack of specificity to assess the effect of therapies on porosity produced by trabecularization of the inner cortex (where most of the porosity occurs1). Ongoing work exploring non-threshold methods and assessing porosity over the entire cortex including the trabecularized cortex may identify additional differences between therapies. 1 Zebaze, Lancet 2010; 2Holzer, JBMR 2009, 3Seeman, JBMR 2010; 4Buie, Bone 2007, 5 Nishiyama, JBMR 2010 6Burghardt, Bone 2010.
This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: S. Boyd Grant/Research Support from Amgen, Servier, Consulting fees from Merck, K. Nishiyama: None Declared, R. Zebaze Grant/Research Support from Amgen, Speaker Fees from Servier, D. Hanley Grant/Research Support from Amgen, Warner-Chilcott, Eli Lilly, NPS Pharmaceuticals, Servier, Merck, Novartis, Advisory Board Membership of Amgen, Eli Lilly, Novartis, Warner-Chilcott, Speaker Fees from Amgen, Eli Lilly, Novartis, Warner-Chilcott, Merck, J. Zanchetta Grant/Research Support from Amgen, Eli Lilly, Merck, Pfizer, Advisory Board Membership of Amgen, Eli Lilly, GSK, Merck, Pfizer, Servier, Consulting fees from Amgen, Eli Lilly, GSK, Merck, Pfizer, Servier, T. Thomas Grant/Research Support from Amgen, Chugai, Eli Lilly, Merck, Pfizer, Roche, Servier, Warner-Chilcott , Advisory Board Membership of Amgen, Merck, Novartis, Consulting fees from Daiichi-Sankyo, BMS, Eli Lilly, Speaker Fees from Amgen, Daiichi-Sankyo, GSK, Eli Lilly, Merck, Novartis, Roche, Servier, Warner-Chilcott, S. Boutroy: None Declared, C. Bogado Advisory Board Membership of GSK, M. Austin Shareholder of Amgen, Employee of Amgen, C. Libanati Shareholder of Amgen, Employee of Amgen, E. Seeman Speakers Bureau with Amgen, Servier, Sanofi Aventis, MSD, Novartis, Advisory Board Membership of Amgen, Servier, Sanofi Aventis, MSD, Novartis, Consulting fees from Amgen, Servier, Sanofi Aventis, MSD, Novartis, Speaker Fees from Amgen, Servier, Sanofi Aventis, MSD, Novartis. doi:10.1016/j.bone.2011.03.423
PP265-S Parathyroid hormone modulates AP1-mediated mechanosensitivity of mesenchymal stem cells (MSC) S.M. Müller-Deubert⁎, L. Seefried Universität Würzburg, Würzburg, Germany Abstract: Parathyroid hormone modulates AP1-mediated Mechanosensitivity of Mesenchymal Stem Cells (MSC) S. Müller-Deubert, L. Seefried, M. Kober, Moustapha Kassem, R. Ebert, F. Jakob Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany Department of Endokrinology, University Hospital of Odense, Odense, Denmark Mechanical forces are essential for cell differentiation and the functional adaptation of many tissues. “Mechanoreceptors” activate various signal transduction pathways and modulate gene expression in various mammalian systems. Promoters comprising Activator Protein (AP) 1 response elements have been shown to respond to mechanical strain. In addition to cell adhesion molecules, membrane associated receptors and calcium channels in the cell membrane play a role in converting physical forces into chemical signals. The latter can be modulated by calcium channel blockers like verapamil. Intermittent parathyroid hormone (PTH) treatment is clinically applied as an anabolic regimen for osteoporosis, while chronically high levels of PTH cause osteoporosis. We developed a reporter system where an AP1 DNA binding site was cloned in front of the luciferase-gene. Stable human telomerase immortalized MSC clones (hMSC-TERT) expressing this reporter system were generated. Using a recently published bioreactor system the reporter system was modulated by stimulation with PTH. Treatment with PTH of the hMSC-TERT clones for one hour before strain application leads to an enhanced strain-responsive induction of AP1 transactivation. In contrast, long time exposure to PTH even reduces AP1 activity after application of cyclic strain. In cells pretreated with Verapamil and PTH for the short time, AP1-activation by mechanical strain was completely abolished. In summary we can demonstrate that intermittent but not chronic PTH treatment enhances AP1-mediated mechanotransduction in human MSC. This system will allow for rapid dissection of the molecular pathways regulating strain-responsive gene regulation in hMSC and its modulation by PTH including the crosstalk with other signaling pathways that modulate mechanosensitivity. Literature: Seefried L, Mueller-Deubert S, Schwarz T, Lind T, Mentrup B, Kober M, Docheva D, Liedert A, Kassem M, Ignatius A, Schieker M, Claes L, Wilke W, Jakob F, Ebert R. A small scale cell culture system to analyze mechanobiology using reporter gene constructs and polyurethane dishes. e Cells and Materials 2010. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared.
doi:10.1016/j.bone.2011.03.424
PP266-M Structural characteristics of trabecular bone fracture Preliminary results S. Tassani⁎, F. Demenegas, G. Matsopoulos Institute of Communication and Computer System, National Technical University of Athens, Athens, Greece Fig. 1. Mean (95% Cl) percent changes in cortical porosity at the radius as assessed by HRpQCT at 12 months.
Abstract: Bone fracture due to tissue pathologies are a major health issue. Correct prediction of bone fracture risk in bone disease is a mandatory issue for the prevention of
PP260-M Association between bone stiffness and age. A micro-finite element analysis in women from the OFELY cohort N. Vilayphiou a,⁎, S. Boutroy a, E. Sornay-Rendu a, F. Munoz a, B. Van Rietbergen b, P. Delmas a, R. Chapurlat a a INSERM U831 and Université de Lyon, Lyon, France b Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands Abstract: Areal bone mineral density (aBMD) decreases with age in women, but our knowledge of bone biomechanical properties is limited, so we have studied the decline of bone strength with age, as assessed with micro-finite element analysis (μFEA) using high resolution peripheral QCT (HR-pQCT). So far, our cross-sectional analysis has involved 483 out of 841 women from the OFELY cohort who had an HR-pQCT radius scan at the 14th year of follow-up. There were 203 pre(preM) and 280 postmenopausal (postM) women, aged 40 ± 9 and 71 ± 9 years old respectively. In postM women, 101 women sustained fragility fractures during the follow-up. Distal radius HR-pQCT scans were used to measure volumetric BMD (vBMD) and microarchitecture parameters, after segmentation of cortical (Ct) bone with advanced algorithm (Burghardt, Nishiyama et al. Bone 2010). Estimated failure load was assessed by μFEA as the main outcome of radius bone strength, and the load to strength ratio Φ was derived to estimate the risk for wrist fracture. Total hip aBMD was recorded by DXA at the same visit. In preM women, most parameters did not vary with age. In postM women, Ct porosity and trabecular (Tb) heterogeneity increased importantly with age, respectively from 0.7 to 3.4% and from 210 to 580 μm in total (both p<0.001). Total, Ct and Tb vBMD decreased with age, as well as Ct thickness and Tb number (r=−0.39 to −0.54, p<0.001). The deterioration of microarchitecture with age resulted in a decrease of the μFE-failure load of −9 to −14% by decade, with an overall loss of a third of bone strength throughout the postmenopausal period compared to preM women. A total increase of Φ by 48% was observed, so that after the age of 70 more than half (70%) of the elderly women had a risk factor Φ>1. Considering Φ as a general factor of risk (not only wrist fracture), we compared the ROC curves of Φ and total hip aBMD, with respect to prevalent fractures. The area under the curves was slightly higher for Φ than total hip aBMD (AUC=0.80 and 0.77, respectively). However, sensitivity and specificity for fracture of the mechanical criterion Φ>1 were 73 and 74% respectively, whereas that of the T-score<−2.5 were 15 and 98% respectively. μFEA are still ongoing to complete this cross sectional dataset of the OFELY cohort, but those preliminary data show a consistent decline of bone strength with age at the radius. We suggest that the calculated load to strength ratio might be a relevant indicator of fracture risk. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: N. Vilayphiou Grant/Research Support from ECTS/Servier Fellowship 2009, S. Boutroy: None Declared, E. Sornay-Rendu: None Declared, F. MUNOZ: None Declared, B. Van Rietbergen Consulting fees from Scanco Medical AG, P. Delmas: None Declared, R. Chapurlat: None Declared. doi:10.1016/j.bone.2011.03.420
PP261-T The interplay between calcium homeostasis and bone mineralization — A computational approach P. Kollmannsberger a,⁎, C. Lukas a, P. Roschger b, P. Fratzl a, R. Weinkamer a a Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany b Ludwig Boltzmann Institute of Osteology, 4th Department, Hanusch Hospital & UHK-Meidling, Vienna, Austria
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Abstract: The mineral flux into and out of bone due to remodeling and mineralizaton plays an important role in calcium homeostasis and is tightly controlled by hormones. Endocrine diseases result in disturbed plasma hormone and mineral levels and cause long-term changes in bone mineralization. These changes can be diagnosed by deviations of the heterogeneity of the mineral content within bone, as quantified by the bone mineralization density distribution (BMDD) from the healthy reference [1]. Despite the large amount of available data, an intuitive understanding of how plasma hormone levels affect bone mineralization is lacking due to the complexity of the bone-endocrine regulatory system. Computer simulations are therefore a valuable tool to quantify the role of different influencing factors and to interpret physiological data. Our investigations are based on measurements of the BMDD using quantitative backscattered electron imaging (qBEI), and plasma mineral and hormone data of the same patients. We present a theoretical model that quantitatively links mineral and hormone kinetics to the long-term evolution of the BMDD. The model integrates current knowledge about the interactions of calcium, parathyroid hormone (PTH), calcitriol and bone cells, and incorporates it into an established theoretical description of the BMDD as a function of bone remodeling and mineralization [2]. As an example of particular interest, we apply our model to experimental data from patients with mild primary hyperparathyroidism (PHPT) [3]. We show how the reported broadening of the BMDD peak and its shift to lower calcium content can be predicted quantitatively based on plasma mineral and hormone data. The results demonstrate that bone is itself part of a feedback loop that contributes to long-term calcium homeostasis. Our study highlights how computer simulations can help to characterize the role of different influencing factors and to study generic control principles underlying the bone-endocrine regulatory system. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared. References [1] Roschger P, et al. Bone mineralization density distribution in health and disease. Bone 2008;42(3):456–66. [2] Ruffoni D, et al. The bone mineralization density distribution as a fingerprint of the mineralization process. Bone 2007;40(5):1308–19. [3] Roschger P, et al. New observations on bone quality in mild primary hyperparathyroidism as determined by quantitative backscattered electron imaging. J Bone Miner Res 2007;22 (5):717–23. doi:10.1016/j.bone.2011.03.421
PP262-S The effect of a disturbed mineralization process on the bone mineralization density distribution (BMDD) C. Lukas a, P. Kollmannsberger a, D. Ruffoni b, P. Roschger c, P. Fratzl a, R. Weinkamer a,⁎ a Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany b Institute for Biomechanics, ETH Zurich, Zurich, Switzerland c Ludwig Boltzmann Institute of Osteology, 4th Department, Hanusch Hospital & UHK-Meidling, Vienna, Austria Abstract: Trabecular bone consists of a patchwork of bone packets with different mineral contents. This heterogeneity of bone can be measured, for instance, in the electron microscope using quantitative backscattered electron imaging (qBEI) and quantified in a frequency distribution called the bone mineralization density distribution (BMDD). The BMDD has proven to be a sensitive diagnostic tool for bone diseases [1]. Mathematical modeling allows connecting pathological changes in the BMDD with disturbances in bone remodeling and mineralization. The model was successfully applied to situations of changes in bone turnover occurring at the onset of menopause and following antiresorptive therapy [2]. One limitation of the comparison between theoretical prediction and BMDD measurements is due to the fact that the experimental data are affected by the stochastic nature of the backscattering of electrons and the finite acquisition time. We have now devised an approach using regularization tools to deconvolve and correct measured BMDDs. As a result, the reference BMDD for healthy human adults could be defined with improved precision. Moreover, the mathematical model was applied to situations where the mineralization process is disturbed. The inadequate mineralization in osteomalacia and the increased bone turnover at menopause both lead to a shift of the BMDD histogram towards lower mineral contents, in comparison to reference. With the use of mathematical modeling, it became possible to differentiate the time evolution of the BMDD, for both disease scenarios. The influence of Sr-treatment was also considered in the mathematical model, taking into account the difference in electron backscattering between Sr and Ca. When about 5% of the Ca atoms are replaced by Sr in the newly formed bone only [3], the model predicts a strong transient narrowing of the BMDD. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared. References [1] Roschger P, et al. Bone mineralization density distribution in health and disease. Bone 2008;42(3):456–66.
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[2] Ruffoni D, et al. Effect of Temporal Changes in Bone Turnover on the Bone Mineralization Density Distribution: A Computer Simulation Study. Journal of Bone and Mineral Research 2008;23(12):1905–14. [3] Roschger P, et al. Bone Material Quality in Transiliac Bone Biopsies of Postmenopausal Osteoporotic Women After 3 Years of Strontium Ranelate Treatment. Journal of Bone and Mineral Research 2010;25(4):891–900. doi:10.1016/j.bone.2011.03.422
PP264-T (For more information visit the Amgen/GlaxoSmithKline Scientific Booth) Denosumab decreases cortical porosity in postmenopausal women with low BMD S.K. Boyd a, K.K. Nishiyama a, R.M. Zebaze b, D.A. Hanley a, J.R. Zanchetta c, T. Thomas d, S. Boutroy e, C. Bogado c, M. Austin f, C. Libanati f,⁎, E. Seeman g a University of Calgary, Calgary, Canada b University of Melbourne, Melbourne, Australia c Instituto de Investigaciones Metabolicas, Buenos Aires, Argentina d INSERM U890, University Hospital of St-Etienne, St-Etienne, France e INSERM U831 and Universite de Lyon, Lyon, France f Amgen Inc., Thousand Oaks, USA g Austin and Repatriation Medical Centre, University of Melbourne, Melbourne, Australia Abstract: Recent evidence highlights the importance of the cortical compartment in postmenopausal bone loss and its relevance to bone strength during aging.1,2 We have reported that denosumab increased BMD at the total, cortical and trabecular compartments of the distal radius, as assessed by HRpQCT, and increased polar moment of inertia, a surrogate of strength, as estimated by QCT.3 We now report the changes in cortical porosity that occurred over the same 1-year study. Postmenopausal women (N = 247) with a mean (SD) age of 60.6 (5.4) years and mean BMD T-Scores at the spine, total hip, and radius of −2.44, −1.30 and −1.85, respectively, were enrolled and randomly assigned in a double-blind, double-dummy fashion to denosumab 60 mg Q6M (N = 83), alendronate 70 mg QW (N = 82), or placebo (N = 82). Porosity was evaluated in the compact appearing cortex of the distal radius at baseline and month 12 from HRpQCT scans using an enhanced method that identifies the cortex with automatic threshold segmentation.4 Pores above ~82 μm are identifiable; porosity was expressed as percent of the total cortical volume. The accuracy5 and reproducibility6 of this method have been previously reported. Baseline cortical porosity was 2.6%. Over 12 months, cortical porosity increased in placebo subjects, remained unchanged in alendronate-treated subjects, and tended to decrease in denosumab-treated subjects (Fig. 1). Denosumab significantly reduced cortical porosity by 8.18% (P = 0.01) compared to placebo. Denosumab prevented the progression of porosity seen with placebo, an effect that is likely to improve bone strength, reduce fracture risk and contribute to a better understanding of the mechanism of action of denosumab. Limitations of the current study include (i) thresholding: porosity may be underestimated in the setting of a low-density cortex; (ii) the inability of the instrument to assess porosity below ~82 μm; (iii) lack of specificity to assess the effect of therapies on porosity produced by trabecularization of the inner cortex (where most of the porosity occurs1). Ongoing work exploring non-threshold methods and assessing porosity over the entire cortex including the trabecularized cortex may identify additional differences between therapies. 1 Zebaze, Lancet 2010; 2Holzer, JBMR 2009, 3Seeman, JBMR 2010; 4Buie, Bone 2007, 5 Nishiyama, JBMR 2010 6Burghardt, Bone 2010.
This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: S. Boyd Grant/Research Support from Amgen, Servier, Consulting fees from Merck, K. Nishiyama: None Declared, R. Zebaze Grant/Research Support from Amgen, Speaker Fees from Servier, D. Hanley Grant/Research Support from Amgen, Warner-Chilcott, Eli Lilly, NPS Pharmaceuticals, Servier, Merck, Novartis, Advisory Board Membership of Amgen, Eli Lilly, Novartis, Warner-Chilcott, Speaker Fees from Amgen, Eli Lilly, Novartis, Warner-Chilcott, Merck, J. Zanchetta Grant/Research Support from Amgen, Eli Lilly, Merck, Pfizer, Advisory Board Membership of Amgen, Eli Lilly, GSK, Merck, Pfizer, Servier, Consulting fees from Amgen, Eli Lilly, GSK, Merck, Pfizer, Servier, T. Thomas Grant/Research Support from Amgen, Chugai, Eli Lilly, Merck, Pfizer, Roche, Servier, Warner-Chilcott , Advisory Board Membership of Amgen, Merck, Novartis, Consulting fees from Daiichi-Sankyo, BMS, Eli Lilly, Speaker Fees from Amgen, Daiichi-Sankyo, GSK, Eli Lilly, Merck, Novartis, Roche, Servier, Warner-Chilcott, S. Boutroy: None Declared, C. Bogado Advisory Board Membership of GSK, M. Austin Shareholder of Amgen, Employee of Amgen, C. Libanati Shareholder of Amgen, Employee of Amgen, E. Seeman Speakers Bureau with Amgen, Servier, Sanofi Aventis, MSD, Novartis, Advisory Board Membership of Amgen, Servier, Sanofi Aventis, MSD, Novartis, Consulting fees from Amgen, Servier, Sanofi Aventis, MSD, Novartis, Speaker Fees from Amgen, Servier, Sanofi Aventis, MSD, Novartis. doi:10.1016/j.bone.2011.03.423
PP265-S Parathyroid hormone modulates AP1-mediated mechanosensitivity of mesenchymal stem cells (MSC) S.M. Müller-Deubert⁎, L. Seefried Universität Würzburg, Würzburg, Germany Abstract: Parathyroid hormone modulates AP1-mediated Mechanosensitivity of Mesenchymal Stem Cells (MSC) S. Müller-Deubert, L. Seefried, M. Kober, Moustapha Kassem, R. Ebert, F. Jakob Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Würzburg, Germany Department of Endokrinology, University Hospital of Odense, Odense, Denmark Mechanical forces are essential for cell differentiation and the functional adaptation of many tissues. “Mechanoreceptors” activate various signal transduction pathways and modulate gene expression in various mammalian systems. Promoters comprising Activator Protein (AP) 1 response elements have been shown to respond to mechanical strain. In addition to cell adhesion molecules, membrane associated receptors and calcium channels in the cell membrane play a role in converting physical forces into chemical signals. The latter can be modulated by calcium channel blockers like verapamil. Intermittent parathyroid hormone (PTH) treatment is clinically applied as an anabolic regimen for osteoporosis, while chronically high levels of PTH cause osteoporosis. We developed a reporter system where an AP1 DNA binding site was cloned in front of the luciferase-gene. Stable human telomerase immortalized MSC clones (hMSC-TERT) expressing this reporter system were generated. Using a recently published bioreactor system the reporter system was modulated by stimulation with PTH. Treatment with PTH of the hMSC-TERT clones for one hour before strain application leads to an enhanced strain-responsive induction of AP1 transactivation. In contrast, long time exposure to PTH even reduces AP1 activity after application of cyclic strain. In cells pretreated with Verapamil and PTH for the short time, AP1-activation by mechanical strain was completely abolished. In summary we can demonstrate that intermittent but not chronic PTH treatment enhances AP1-mediated mechanotransduction in human MSC. This system will allow for rapid dissection of the molecular pathways regulating strain-responsive gene regulation in hMSC and its modulation by PTH including the crosstalk with other signaling pathways that modulate mechanosensitivity. Literature: Seefried L, Mueller-Deubert S, Schwarz T, Lind T, Mentrup B, Kober M, Docheva D, Liedert A, Kassem M, Ignatius A, Schieker M, Claes L, Wilke W, Jakob F, Ebert R. A small scale cell culture system to analyze mechanobiology using reporter gene constructs and polyurethane dishes. e Cells and Materials 2010. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared.
doi:10.1016/j.bone.2011.03.424
PP266-M Structural characteristics of trabecular bone fracture Preliminary results S. Tassani⁎, F. Demenegas, G. Matsopoulos Institute of Communication and Computer System, National Technical University of Athens, Athens, Greece Fig. 1. Mean (95% Cl) percent changes in cortical porosity at the radius as assessed by HRpQCT at 12 months.
Abstract: Bone fracture due to tissue pathologies are a major health issue. Correct prediction of bone fracture risk in bone disease is a mandatory issue for the prevention of