Exercise training, Bone and Aging. Evidence from different impact loading exercise interventions on age-related bone loss. Elisa Amélia Alves Fernandes Marques The present dissertation was written in Dissertação apresentada com vista à order to achieve the PhD degree included in obtenção do grau de Doutor no âmbito do the doctoral course in Physical Activity and Curso de Doutoramento em Atividade Health designed by the Research Centre in Física e Saúde, organizado pelo Centro Physical Activity Health and Leisure de Actividade Física, Saúde e Lazer (CIAFEL), Faculty of Sports - University of (CIAFEL) da Faculdade de Desporto da Porto, according to the Decree-Law Universidade do Porto, nos termos do No.74/2006 from March 24th. Decreto-lei 74/2006 de 24 de Março. Supervisors: Joana Carvalho, PhD Jorge Mota, PhD Porto, 2011 Marques, E. A. (2011). Exercise training, Bone and Aging. Evidence from different impact loading exercise interventions on age-related bone loss. Porto: E. A. Marques. Dissertação de Doutoramento em Atividade Física e Saúde apresentada à Faculdade de Desporto da Universidade do Porto. KEY-WORDS: AGE, PHYSICAL ACTIVITY, BONE DENSITY, FRACTURE RISK, BIOMARKERS, META-ANALYSIS. Old age is like everything else. To make a success of it, you’ve got to start young. Fred Astaire Funding The candidate work was supported by a doctoral grant from Portuguese Foundation for Science and Technology (FCT) SFRH/BD/36319/2007, and the doctoral thesis was included in a financed research project PTDC/DES/102094/2008 FCOMP-01-0124- FEDER-009587 from FCT. Acknowledgments I’m grateful to my supervisor Professor Joana Carvalho for her guidance during the course of this work, and for the support in all moments (far beyond the academic level). Thanks for the friendship and happiness that describes our bond, which I define as exceptional. I own to you not only my academic path but above all what defines me now, different from whom I would be if you have not invited me for the challenging (present and future) research field in physical activity and health. I would like to extend my gratitude to Professor Jorge Mota for his guidance, constant attention and care. Thanks for making everything always possible, more accessible and straightforward. I’m grateful for the trusting vote that you gave me, and I hope never disappointing you. I’m grateful to Professor Pedro Moreira from the Faculty of Nutrition and Food Sciences UP for his help and suggestions provided, looking for the nutritional contribution, but especially for his constant readiness and kindness. To Doctor Tiago Guimarães from Department of Clinical Pathology - Hospital de S. João, and Department of Biochemistry – Faculty of Medicine UP for the generous support and suggestions. To Doctor Rosa Pereira, Valéria Caparbo and Liliam Takayama from Bone metabolism laboratoty - Department of Rheumatology - University of São Paulo, Brasil for their hospitality and support during the traineeship period. To Wojtek and Andiara for being so supportive on both the personal and scientific level. To Professors Paula Santos and José Carlos Ribeiro for having accepted me at your office with friendship and consideration. To Dr. Diana Tuna, Nádia, Joana, Margarida and Dr. Conceição for the exceptional support during the laboratory assays. To my colleagues Daniel, João, Flávia, and Gustavo for the support, assistance and teamwork. To Andreia, with whom I share everything, for her sincerely friendship and care. To Alberto and Luisa Miranda for being always available for our “scientific meetings” of honest exchange of opinions. To my sample of study for the commitment and kindly support and care. To all who collaborate in the collecting process and data management of this study. To Leandro Machado and André Seabra for always having their office door open. To my friends Filipa Sousa, António Ascensão and José Magalhães for their cheering friendship and support. VII Contents Acknowledgments VI List of figures XI List of tables XIII Abstract XV Resumo XVII List of abreviations XIX General introduction ..................................................................... 23 1. Theoretical background .................................................................................. 31 2. Experimental work ............................................................................................ 59 Paper I Marques EA, Moreira P, Wanderley F, Pizarro A, Leão-Rosas JP, Mota J, Carvalho J. Appendicular fat mass is positively associated with femoral neck bone mineral density in older women. Menopause. 2011 Accepted Jun 22. .................................. 63 Paper II Marques EA, Mota J, Machado L, Sousa F, Coelho M, Moreira P, Carvalho J. Multicomponent training program with weight-bearing exercises elicits favorable bone density, muscle strength, and balance adaptations in older women. Calcif Tissue Int. 2011 Feb;88(2):117-29. Epub 2010 Nov 27. .......................................... 77 Paper III Marques EA, Wanderley F, Machado L, Sousa F, Viana JL, Moreira-Gonçalves D, Moreira P, Mota J, Carvalho J. Effects of resistance and aerobic exercise on physical function, bone mineral density, OPG and RANKL in older women. Exp Gerontol. 2011 Jul;46(7):524-32. Epub 2011 Feb 23. .............................................................. 93 Paper IV IX Marques EA, Mota J, Tuna D, Guimarães T, Carvalho J. Response of bone mineral density, inflammatory cytokines, and biochemical bone markers to a 32-week combined loading exercise programme in older men and women. Submitted. ....... 101 Paper V Marques EA, Mota J, Carvalho J. Exercise effects on bone mineral density in older adults: A meta-analysis of randomized controlled trials. Age (Dordr). 2011. Epub 2011 Set 16. ............................................................................................................ 121 3. Overall Discussion ......................................................................................... 147 4. Conclusions ....................................................................................................... 161 5. References ......................................................................................................... 165 X List of Figures Theoretical background Figure 1 – Schematic model of bone remodeling sequence (sequential action of osteoclasts and osteoblasts to remove old bone and replace it with new bone). ......... 33 Figure 2 – Schematic model of the disordered mechanisms of calcium homeostasis linked to age-related bone loss. .................................................................................... 45 Figure 3 – (A) DXA of normal lumbar spine L1-L4.(B) DXA of right hip; although BMD is provided in a number of different sites (femoral neck, oblong box; Ward’s area, small box; trochanter; and total hip), for clinical diagnosis of osteoporosis, femoral neck and total hip are used. ......................................................................................................... 54 Figure 4 – Schematic model of the experimental work design (type of studie, final sample, mean age, outcome variables, measurement technique, statistical analyses).62 Paper I Figure 1 – Regions of trunk, legs, android fat, and gynoid fat assessed by DXA ........ 67 Figure 2 – Regression relationships between femoral neck bone mineral density (g/cm2) and indices of soft tissue mass (A: fat mass, B: lean mass) in 100 older women. ......................................................................................................................... 69 Paper II Figure 1 – Ground reaction forces (GRFs) recorded during heel-drops performed with shoes by a 72-kg woman. N/BW Newtons/body weight ............................................... 79 Figure 2 – Flow of participants through the study ........................................................ 81 Paper III Figure 1 – Flow of participants through the study ........................................................ 95 Figure 2 – Percentage of changes from baseline in serum OPG, RANKL an OPG/RANKL ratio, and bone mineral density of the proximal femur in response to exercise or placebo (control) over 8 months. Values are mean±SEM. RE: resistance exercise; AE: aerobic exercise; COM: control group. ................................................... 98 XI Paper V Figure 1 – Flow chart depicting the trial flow for selection of randomized controlled trials (RCTs) to be included ........................................................................................ 128 Figure 2 – Risk of bias summary ................................................................................ 136 Figure 3 – Forest plot for lumbar spine BMD. Diamonds represent overall weighted mean difference (WMD g/cm2) calculated by random-effect model with 95% CI.* Absolute change values; RVT, rotational vibration training; VVT, vertical vibration training; d-wk, days-week; H, high; L, low; Vib, vibration; RE, resistance exercise; TC, Tai Chi ........................................................................................................................ 137 Figure 4 – Forest plot for femoral neck BMD. Diamonds represent overall weighted mean difference (WMD g/cm2) calculated by random-effect model with 95% CI. * Absolute change values; RE, resistance exercise; AE, aerobic exercise; RVT, rotational vibration training; VVT, vertical vibration training; H, high; L, low ............................... 138 Figure 5 – Funnel plot test exploring publication bias (random-effects