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Denosumab decreases cortical porosity in postmenopausal women with low BMD
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Abstracts / Bone 48 (2011) S173–S186
[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
Abstracts / Bone 48 (2011) S173–S186
[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