abstracts avances iii symposium internacional o en … · osteopenia en infancia y adolescencia....

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III Symposium Internacional

enAO

vancessteoporosis

Barcelona,10 -11 febrero 2012

Dra. Núria GuañabensDirectora Científica

ABSTRACTS

III Symposium Internacional

enAO

vancessteoporosis

Barcelona,10 -11 febrero 2012

Dra. Núria GuañabensDirectora Científica

ABSTRACTS

Secretaría Técnica

Aula Médica CongresosPº Pintor Rosales, 26 - 28008 Madrid

Tel: 91 357 66 09 Fax: 91 357 65 [email protected]

www.grupoaulamedica.com

Índice

CURRICULUM

Coordinadora científicaDra. Núria Guañabens .................................................................... 9

Intervienen

Dr. Richard Eastell .......................................................................... 10Dr. Luis Miguel del Río Barquero ....................................................... 11Dra. Elizabeth Shane ....................................................................... 13Dr. Carlos Gómez Alonso ................................................................ 14Dr. Graham Russell ......................................................................... 15Dr. Manuel Muñoz Torres ................................................................ 16Dr. Ernesto Canalis ......................................................................... 17Dra. Pilar Peris .............................................................................. 19Dr. Sundeep Khosla ........................................................................ 20Dr. Lluis Pérez Edo ......................................................................... 21Dr. Christian Roux .......................................................................... 22

ABSTRACTS

◦ Bone Turnover Markers in 2012 (Richard Eastell) ................................. 25◦ Premenopausal osteoporosis. How should it be managed? (Elizabeth Shane) 27◦ Differential Characteristics and Long term Skeletal Effects of Bisphosphonates (Graham Russell) ......................................................................... 30◦ Effects of Glucocorticoids on Bone Tissue (Ernesto Canalis) ..................... 32◦ Drugs for osteoporosis on the waiting list (Sundeep Khosla) ..................... 33◦ Criteria for selecting the optimal treatment (Christian Roux) ...................... 34

CURRICULUM

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Coordinadora científica

Núria Guañabens es Jefe del Servicio de Reumatología del Hospital Clínic de Barcelona y responsable del Equipo de Investigación de Patología Metabólica Ósea del Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). Es profesora agregada de la Facultad de Medicina de la Universidad de Barcelona. Ha sido Presidenta y Tesorera de la Sociedad Española de Investigación Ósea y del Metabolismo Mineral, además de vocal de la Sociedades Catalana y Española de Reumatología.

Licenciada y Doctora en Medicina por la Universidad de Barcelona, durante su carrera profesional ha dedicado un especial interés a las enfermedades metabólicas óseas y junto con su equipo de colaboradores ha tenido una producción científica de más de cien publicaciones, incluyendo artículos originales, editoriales y revisiones, así como un número elevado de capítulos de libro.

Dra. Núria Guañabens

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cuadrode ponentes y discusores

Professor Eastell is Professor of Bone Metabolism at the University of Sheffield and Director of the NIHR Biomedical Research Unit for Musculoskeletal Diseases at the Sheffield Teaching Hospitals Trust. He qualified in medicine from Edinburgh in 1977.

He trained in endocrinology at the Mayo Clinic under Dr B L Riggs for 5 years. He leads a research group on the pathogenesis, diagnosis and treatment of osteoporosis; of particular note is the contribution to the clinical utility of biochemical markers of bone turnover and the development of treatments for osteoporosis. The publications of the Sheffield group put them in the top 4 internationally in osteoporosis (ISI Thompson). His work has been recognised by the award of the Corrigan Medal (Royal College of Physicians of Ireland, 1998), Kohn Foundation Award (National Osteoporosis Society, 2004) and Society for Endocrinology Medal (2004).

Dr. Richard Eastell

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- Doctor en Medicina y Cirugía. Universidad de Barcelona. Jefe de Dpto. Director Médico CETIR. Centre Médic.- L. del Rio “Osteoporosis postmenopausica” . Guia Dexeus de la Salud de la Mujer. Editorial Planeta. 1997.- L. del Rio. Osteopenia en Infancia y adolescencia. Tratado de Reumatología, PP 2293-2311. Aran Ediciones, Madrid

1998- M. Luengo, C. Picado, L. del Rio, N. Guañabens, J.M. Montserrat, J. Setoain. Treatment of Steroid-Inauced Osteopenia

with calcitonin in corticosteroid-Dependent Asthma. AM. Rev. Respir Dis. 1990; 142:104-107.- M. Monreal, A. Olive, E. Lopez, L. del Rio. Heparins, Coumarin and bone density. Lancet Vol 338: Sept 14

1991:706- M. Luengo, C.Picado, L del Rio, N. Guañabens, J.M.Montserrat, J. Setoain.Vertebral fractures in steroid dependent

asthma and involutional osteoporosis:a comparative study. Thorax 1991;46:803-806- M. Luengo, C.Picado, L del Rio, N. Guañabens, J.M.Montserrat, J. Setoain. Treatment of Steroid-Induced Osteopenia

with Calcitonin in Corticosteroid- Dependent asthma: A One Year Follow-up Study. Am. Rev. Respir. Dis 142:104-107- L. del Rio, M. Romera, J. Pavía, J. Setoain, C. Serra, P. Gaces, C. Lafuente, F.M. Domènech. Bone Mineral Density in

Two Different Socioeconomic Population Groups. Bone and Mineral, 18 (1992): 159-168- M. Minoves, J.R. Garcia, S. Mañe, L. del Rio, R. Herranz and J. Setoain. Infected knee prothesis visualization of the

fistulous tract by Tc99m HMPAO leukocyte scintigraphy. Clinical Nuclear Medicine. Vol 7,nº 7 July 1992: 593-595- N. Guañabens, A. Pares, L. del Rio, M.Roca, R.Gomez, J.Muñoz and J. Rodes. Sodium Fluoride. Prevents Bone Loss in

Primary Biliary Cirrhosis. Journal of Hepatology, 1992; 15: 345-349- L. del Rio, M. Manubens, E. Figuerola. Precision of Lumbar Spine BMD in PA and Lateral Projections. Journal of Bone and

Mineral Research. Vol 7, Supplement 1. August 1992: S186- L. del Rio, Carrascosa A, Pons F, Gussinye M, Yeste D and Domenech F. Bone Mineral Density of the Lumbar Spine in

Caucasian Mediterranean Spanish Children and Adolescents. Changes Related to Age, Sex and Puberty. Journal of Pediatric Research . Vol 35, nº 3, 1994 362-365

- L. del Rio, Pons F, Huguet M, Setoain FJ, Setoain J. Anteroposterior versus lateral bone mineral density of spine assessed by dual xray absorptiometry. European Journal of Nuclear Medicine 22: 407-412, 1995

- F. Pons, L del Rio, F.J Setoain, D. Fuster, J. Setoain. Are lumbar spine measurements if bone mass enough assessing osteoporosis risk at the menopause? European Journal of Nuclear Medicine (PTu473) 23/9: 1150. 1996.

- L. del Rio, F. Pons, F.J Setoain, S. Vidal. Spine and femur bone densitometry: Is it necessary to explore both region in menopausia? Calcif Tissue Int, 58: 289, 1996

- L. del Rio, F.J Setoain. Bone mass peak: influence of physical activity during chilhhod and adolescence. Calcif Tissue Int, 58: 289, 1996

- M. Luengo, Del Rio L, Pons F, Picado C. Bone mineral density in asthmatic patients trated with inhaled corticosteroids: a case-control study. Eur Respir J 1997; 10: 2110-2113

- L. Del Rio, P. Bassa, P. Reyner, M. Manubens. Menarche onset as a risk factor for development of perimenopausal osteoporosis. Bone, 1998; 23: S309.

- L. del Rio. Densitometría ósea por doble foton. Aplicaciones clínicas. REV. ESP. MED. NUCLEAR, 7, SUP III (Pág. 54-60). 1988.

- R. Herranz, F. Pons, L. del Rio. Exploraciones Isotópicas del Sistema musculo-esquelético. MEDICINA 25: 211.238. 1988

- F. Pons, L. del Rio. La determinación de la masa ósea mediante fotodenstiometría. MEDICINA INTEGRAL 14: 87-94, 1989.

- L. del Rio. Densitometría ósea. REV. ESP. MEDI. NUCLEAR, 8, Supl. III (53-64). 1989.- F. Pons y L. del Rio. Aplicación de los estudios densitométricos en pediatría REV. ESP. MEDI. NUCLEAR, 10, Supl. II

(65-67). 1991

Dr. Luis Miguel del Río Barquero

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- L. del Rio, F. Pons. Densitometría en Infancia y adolescencia. Formación Médica Continuada. JANO Vol XLV 1051: 17-23 Septiembre de 1993, pag 41-46

- F. Pons y L. del Rio. Importancia de la densitometría ósea en la evaluación del paciente. Formación Médica Continuada. Tema Monografico Osteoporosis. Jano 30 Septiembre-6 de Octubre Vol XLVII, 1095:57-62, 1994

- L. del Rio. F. Pons. Nuevas aplicaciones de la densitometría ósea. Todo Hospital 120, Octubre de 1995, 27-33 - Gomez Castilla JC, Roca Burniol J, Ruiz Calavia JA, del Rio L Análisis densitométrico del efecto de la instrumentación pedicular en la fusión lumbar: Modelo ovino. Mapfre Medicina Vol 8: 2533, 1997

- Blanca Herrera, Nuria Guañabens, Pilar Peris, Ana Monegal, Irene Halperin, Francesca Pons, Luis del Rio y Jose Muñoz Gomez. Osteoporosis y hemocromatosis: descripción de cuatro casos. Rev Esp Reumatol 1996, 24: 11-15.

- L. del Rio. Mediciones óseas con ultrasonidos. Revista Española de Enfermedades Metabolicas Óseas, Mayo-Junio 1997 Vol 6, 3;107-112.

- P. Reyner, P. Bassa, L del Rio. Valoración de un nuevo densitometro periférico por DXA.Revista Española de Enfermedades Metabolicas Óseas, Mayo-Junio 1999 Vol8, 3;99-104

- L- del Rio, D. Roig, Actividad física y calidad ósea, Archivos de Medicina del Deporte, 2001, XVIII; 83: 211- 221- M. Espallargues, L. Sampietro-Colom, M.D. Estrada, M. Sola, L. del Rio, J. Setoian y A. Granados, Identifying Bone-

Mass Related Risk Factors for Fracture to Guide Bone Densitometry Measurements: A Systematic Review of the Literature. Osgteoporosis Int, 2001, 12:811-822.

- M. Espallargues, M.D. Estrada, M. Sola, L. Sampietro-Colom, L. del Rio, A. Granados Guía para la indicación de la densitometría ósea en la valoración del riesgo de fractura. REEMO (Revista Española de Enfermedades Metabolicas Óseas), 2001, 10; 6:197.

- Kanterewicz E., Yáñez A., Pérez-Pons A., Codony I., Del Río L. i Díez-Pérez A. .Association between colles’ fracture and low bone mass: age-based differences in postmenopausal women. Osteoporos Int (2002);13:824-828

- Del Río L., Kanterewicz E. i Yáñez A.Del Río L., Kanterewicz E. i Yáñez A. “Morphometric X-ray absorptiometry in Colles’ fracture patients”, J Bone Miner Res, 2002, 17: S357

- Del Río L., Bassa P., Balius R., Ruíz-Cotorro A. i Parra J. “Effect of physical activity, intensity and length on dimensions and mineral density of apendicular skeleton: study on a tennis players population”. J Bone MIner Res, 2002, 17: S334

- Kanterewicz E, Yáñez A, Perez Pons A, Codony I, Del Rio L i Diez Perez A. “Association between colles’ fracture and low bone mass: age-based differences in postmenopausal women”. Osteoporos Int, 2002;13:824-828

- Ibañez L., Ongt K., Zeghert F., Marcos M. V., Del Río L. i Dungert D. B. “Fat distribution in non-obese girls with and without precocious pubarche: central adiposity related to insulinaemia and androgenaemia from prepuberty to postmenarche”. Clinical Endocrinology (2003) 58:372-379

- Di Gregorio s, Del Rio L, Bassa P “Discrepancy in follop-up absorptiometry measurements of lumbar spine and proximal femur” J Bone MIner Res, 2003, 18:S162

- Alvarez R, Garcia R, Luis J, Lopez J, Gutierrez A, Gonzalez M, Del Rio L, Aguilera F, Vazquez R. Bone mineral density in children with osteogenesis imperfecta. Rev Esp Med Nucl. 2003 22(4): 224-8.

- Del Rio L. Bone densitometry and Nuclear Medecine Rev Esp Med Nucl. 2003 22(4): 215-6- IIbañez L., Ongt K., Zeghert F., Marcos M. V., Del Río L. i Dungert D. B. “Fat distribution in non-obese girls with and

without precocious pubarche: central adiposity related to insulinaemia and androgenaemia from prepuberty to postmenarche”. Clinical Endocrinology (2003) 58:372-379

- Del Río L. Densitometría ósea. En: Riancho Moral JA, González Macías J. Manual práctico de Osteoporosis y Enfermedades del Metabolismo Mineral. Madrid: JARPYO Editores S.A., 2004.

- Checa MA, Del Rio L, Rosales J, Nogues X, Vila J, Carreras R. Timing of follow-up densitometry in hormone replacement therapy users for optimal osteoporosis prevention. Osteoporos Int. 2005 16; 937-942

- Negredo E, Martinez-Lopez E, Paredes R, Rosales J, Perez-Alvarez N, Holgado S, Gel S, del Rio L, Tena X, ReyJoly C, Clotet B. Reversal of HIV-1-associated osteoporosis with once-weekly alendronate. AIDS. 2005 Feb 18;19(3):343-5.

- Valverde E, Casinos A, Alba-Fernandez C, Del Rio L. Lumbar ontogenetic allometry and dimorphism in humans. A case for comparison between interspecific and intraspecific scaling. Eur J Morphol. 2005 Oct-Dec;42(4-5):185-92.

- Kenneth G. Faulkner, W. K. Wacker, H. S. Barden, C. Simonelli, P. K. Burke, S. Ragi , L. Del Rio. Femur strength index predicts hip fracture independent of bone density and hip axis length.. Osteoporos Int. 2006 April;17(4):593-9

- Podzamczer D, Ferrer E, Sanchez P, Gatell JM, Crespo M, Fisac C, Lonca M, Sanz J, Niubo J, Veloso S, Llibre JM, Barrufet P, Ribas MA, Merino E, Ribera E, Martinez-Lacasa J, Alonso C, Aranda M, Pulido F, Berenguer J, Delegido A, Pedreira JD, Lerida A, Rubio R, del Rio L; ABCDE (Abacavir vs. d4T (stavudine) plus efavirenz) Study Team. Less lipoatrophy and better lipid profile with abacavir as compared to stavudine: 96-week results of a randomized study. J Acquir Immune Defic Syndr. 2007 Feb 1;44(2):139-47.

- Ibanez L, Lopez-Bermejo A, Del Rio L, Enriquez G, Valls C, de Zegher F. Combined Low-Dose Pioglitazone, Flutamide, and Metformin for Women with Androgen Excess. J Clin Endocrinol Metab. 2007 Feb 13 (ahead to print).

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Elizabeth Shane, M.D. is Professor of Medicine, Vice Chair of Medicine for Clinical and Epidemiological Research at Columbia University, College of Physicians & Surgeons in New York City. She received her M.D. from the University of Toronto and completed her medical residency and training in Endocrinology and Metabolism at the College of Physicians and Surgeons and the Presbyterian Hospital in New York. Her research interests include transplantation osteoporosis, premenopausal osteoporosis, bone disease associated with HIV/AIDS, renal bone disease and bone loss due to medications and gastrointestinal diseases. Dr. Shane was Associate Editor of the Journal of Clinical Endocrinology and Metabolism (2000-2004), Associate Editor of the First through Sixth Editions of the Primer of the Metabolic Bone Diseases and Disorders of Mineral Metabolism, and serves on the Editorial Boards of Bone and the Journal of Bone and Mineral Research. Dr. Shane is past President of the American Association for Bone and Mineral Research (ASBMR), and served on the Board of Directors of FASEB from 2007-2011. She chaired or co-chaired three ASBMR Task Forces, on Ethics in Publishing in 2005, Osteonecrosis of the Jaw in 2006-7 and Atypical Femur Fractures in 2009-10.

Dra. Elizabeth Shane


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Nacido en Burgos, en 1960, licenciado en Medicina por la Universidad de Valladolid en 1983. Realizó la especialización en Medicina Interna (MIR) en el Hospital General de Asturias durante los años 1984-1989. En 1992 obtiene el grado de doctor en Medicina por la Universidad de Oviedo con la tesis “Utilidad clínica y experimental de a densitometría DEXA en el estudio de la osteoporosis”, siendo premio extraordinario de doctorado. Desde 1990 es Facultativo Especialista de Área de Medicina Interna del Hospital Universitario Central de Asturias y médico adjunto del Servicio de Metabolismo Óseo y Mineral, siendo desde su fundación investigador asociado del Instituto Reina Sofía de Investigación. Profesor asociado de Medicina Interna, en la Universidad de Oviedo desde 2006.

Ha participado en diversos estudios epidemiológicos (relacionados con fractura vertebral, fractura de cadera, masa ósea, vitamina D, calidad de vida, ultrasonidos cuantitativos), en líneas de investigación básica (toxicidad del aluminio, regulación de PTH, polimorfismos VDR), así como en ensayos clínicos multinacionales en fase III (raloxifeno, alendronato, risedronato, ranelato de estroncio, teriparatide).

Ha publicado cerca de un centenar de artículos científicos y capítulos de libros, fundamentalmente relacionados con el Metabolismo Óseo. Miembro de la Sociedad Española de Investigación Ósea y Metabolismo Mineral (SEIOMM), Sociedad Española de Medicina Interna (SEMI), de la Asociación Española para el Estudio de La Menopausia (AEEM), de la International Bone and Mineral Society (IBMS) y de la American Society for Bone and Mineral Research (ASBMR).

Dr. Carlos Gómez Alonso

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Professor of Musculoskeletal PharmacologyNuffield Department of Orthopaedics, Rheumatology and Musculoskeletal SciencesThe Oxford University Institute of Musculoskeletal SciencesThe Botnar Research CentreNuffield Orthopaedic CentreHeadingtonOxford, OX3 7LDUnited Kingdom

Graham Russell (R G G Russell) graduated in Biochemistry from Cambridge University and subsequently gained his PhD from Leeds, and medical degrees from Oxford. Following appointments at Bern University and then Harvard, he became Professor and Head of the Department of Human Metabolism and Clinical Biochemistry at Sheffield University in 1977. His research interests are in skeletal biology and disease, and he is author of more than 500 publications. In particular, his early work with Herbert Fleisch in Switzerland led to the discovery of the biological effects of bisphosphonates, and to their eventual successful clinical use in the treatment of bone disorders, including Paget’s disease, cancer metastases in bone, and osteoporosis. His group later discovered how bisphosphonates act within cells as inhibitors of the mevalonate pathway.

From 1998-2001 he was President of the International Bone and Mineral Society (IBMS). He has received the W F Neuman award of the American Society of Bone and Mineral Metabolism, the Gaillard award of the IBMS, and in 2008 he was elected a Fellow of the Royal Society of London (FRS).

From 2001-7 he was the Norman Collisson Professor of Musculoskeletal Sciences at Oxford University, and the first Director of the Botnar Research Centre. He is continuing his research as Professor of Musculoskeletal Pharmacology in Oxford and in the Mellanby Centre at Sheffield University.

Dr. Graham Russell

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Endocrinólogo y Coordinador de la Unidad de Metabolismo Óseo del Hospital Universitario San Cecilio de Granada. Profesor Asociado del Departamento de Medicina de la Universidad de Granada. Ex-vicepresidente de la Sociedad Española de Investigación Ósea y Metabolismo Mineral (SEIOMM). Coordinador del Grupo de Metabolismo Óseo de la Sociedad Española de Endocrinología y Nutrición (SEEN). Miembro de la Red Temática de Investigación Cooperativa en Envejecimiento y Fragilidad (RETICEF) del Instituto Carlos III. Pertenece a la IBMS, ECTS, ASBMR y a la sociedad Española de Endocrinología. Ha publicado más de 140 artículos en revistas científicas y presentado más de 350 comunicaciones a congresos. Es investigador principal de diversos proyectos en el campo de la osteoporosis y el metabolismo óseo.

Dr. Manuel Muñoz Torres

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Ernesto Canalis, MD

Director, Department of Research

Saint Francis Hospital and Medical Center

Hartford, Connecticut

Professor of Medicine

University of Connecticut School of Medicine

Farmington, Connecticut

Biographical Sketch

Ernesto Canalis, MD completed his internship in internal medicine at the University of Connecticut Health Center in Farmington, Connecticut and his residency at Henry Ford Hospital in Detroit, Michigan, and the University of Connecticut Health Center in Farmington. He received a fellowship in endocrinology from Tufts–New England Medical Center, Boston, Massachusetts.

Dr. Canalis is Director of Research at Saint Francis Hospital and Medical Center in Hartford. He is also a Professor of Medicine at the University of Connecticut School of Medicine. He has served as an editor of The Journal of Clinical Endocrinology and Metabolism and Bone. In addition, he served as a member of the editorial boards of Endocrinology, Calcified Tissue International, and The Journal of Clinical Investigation. He has served as an officer and as a member of numerous societies including the Association of American Physicians, the American Society for Clinical Investigation, the Endocrine Society, the American Society for Bone and Mineral Research (ASBMR), and the International Bone and Mineral Society. He is former president of ASBMR.

Dr. Ernesto Canalis

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Dr Canalis’ research has been continuously funded by the National Institutes of Health since 1981. His interests center around skeletal growth factors and their antagonists, hormonal action in bone, mechanisms of glucocorticoid action in bone, and anabolic agents in bone. He has published over 300 articles. He is the recipient of the 1990 Kappa Delta Award of the American Academy of Orthopedic Surgeons, a MERIT award from the National Institute of Arthritis, Musculoskeletal and Skin Diseases, the 1996 Gerald Aurbach Award of the Endocrine Society, the 1998 Marshall R Urist Award of the Orthopedic Research Society and the 2004 Louis Avioli Award of the ASBMR.

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Especialista en Reumatología y Doctor en Medicina y Cirugía, Servicio de Reumatología. Miembro de la Unidad de Patología Metabólica Osea de dicho hospital y del IDIBAPS (Instituto de Investigaciones Biomédicas August Pi i Sunyer). Ha colaborado en 25 capítulos de libro, en 107 artículos en revistas nacionales e internacionales (incluyendo originales, notas clínicas, cartas, revisiones y editoriales) y en 215 comunicaciones a Congresos nacionales e internacionales.

Dra. Pilar Peris Bernal

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Dr. Sundeep Khosla is the Dr. Francis Chucker and Nathan Landow Research Professor of Medicine and Physiology, Mayo Foundation Distinguished Investigator, and Associate Director for Research at the College of Medicine, Mayo Clinic. Dr. Khosla received his A.B. degree from Harvard College and his M.D. from Harvard Medical School. He was subsequently a resident in Internal Medicine and a fellow in Endocrinology at the Massachusetts General Hospital. In 1988 he moved to Mayo Clinic, where his research interests include mechanisms of postmenopausal and age-related bone loss, sex steroid regulation of bone metabolism, and osteoblast/stem cell biology. Dr. Khosla has served as chair of the NIH SBDD Study Section and has been appointed to the Council of the National Institute on Aging from 2007-2010. He has received numerous awards and honors for his work, including the Frederic C. Bartter Award for Clinical Investigation from the American Society for Bone and Mineral Research, the Innovation Award from the National Osteoporosis Foundation, and election to the ASCI and AAP. He has been elected President of the American Society for Bone and Mineral Research for 2010-2011. He is also Associate Editor of the Journal of Bone and Mineral Research and has served or is serving as a member of the editorial boards for the Journal of Clinical Investigation, Journal of Bone and Mineral Research, Journal of Clinical Endocrinology and Metabolism, Bone, and Endocrine Reviews.

Dr. Sundeep Khosla

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El Dr. Pérez Edo es Jefe de la Sección de Metabolismo Óseo del Sevicio de Reumatología de los hospitales Universitarios del Mar i de la Esperanza de Barcelona (UAB). Miembro del grupo de la Unidad de Investigación URFOA ( Unitat de Recerca de la Fisiopatologia Ósea y Articular).

Licenciado en Medicina i cirugía por la Universidad de Barcelona el año 1974. Desde 1978 ejerce la especialidad de Reumatología. Profesor de la Universidad de Medicina Autónoma de Barcelona (UAB) los cursos 1990-1991 y 1991-1992. Profesor del Master de Reumatología de la Universidad Oberta de Catalunya (UOC) del Módulo de Osteoporosis, 2007-2008, y 2008-2009. Coordinador del Tercer Domumento de la Sociedad Española de Reumatología (SER) (2006) sobre la Osteoporosis Posmenopáusica. Miembro del panel de las Guías de Practica Clínica de Osteoporosis posmenopáusica, Inducida por Glucocorticoides y del Varón. (2006). Miembro de la SER, SEIOOM. IOF, ASBMR

Actualmente en la Unidad están abiertas líneas de investigación en la vertiente clínica, histomorfométrica de experimentación básica (cultivos celulares ) y de genética en poblaciones diana como: la osteoprorosis del varón, osteoporosis posmenopáusica y en las artropatías inflamatorias.

Dr. Lluis Pérez Edo

Christian Roux received his medical training at the University of Paris, and his PhD at the University of Compiègne. He is currently Head of Bone Unit, Rheumatology Department, Paris Descartes University. He has published works in the areas of primary and secondary osteoporosis, malignant bone diseases, and Paget’s disease. He is author and co-author of 190 original papers, and chapters of books. He is the past President of GRIO, the French Society of Osteoporosis. He is a member of the Editorial Board of Osteoporosis International.

Conflicts of interest: he received research grants, and/or speaker or consultant fees from: Alliance, Amgen, Lilly, MSD, Novartis, Roche, Servier.

Dr. Christian Roux

ABSTRACTS

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Abstracts

BONE TURNOVER MARKERS IN 2012

Richard Eastell

Introduction

Bone turnover markers reflect the processes of bone formation and bone resorption (see table). They can be measured by immunoassay in the serum or urine. It is important to know the sources of variability in order to use them well.

They may be used to identify patients at risk of rapid bone loss, fractures or secondary osteoporosis. They are particularly useful for use in monitoring osteoporosis treatment.

BONE RESORPTION MARKERS BONE FORMATION MARKERSCollagen Degradation ProductsHydroxyproline (OHPr)Pyridinium crosslinks: Pyridinoline (PYD), deoxypyridinoline (DPD)Telopeptides of type I collagen: C terminal (CTX, ICTP or CTX-MMP), Nterminal (NTX)Non-collagenous ProteinsBone SialoproteinOsteoclast EnzymesTartrate resistant acid phosphatase(TRAcP5b)Cathepsin K

Collagen Synthesis By-productsPropeptides of type I procollagen:C terminal (PICP)N terminal (PINP)

Matrix ProteinsOsteocalcin (OC)Osteoblast EnzymesTotal alkaline phosphatase (total ALP)Bone alkaline phosphatase (bone ALP)

Key learning points· Know what bone turnover markers are available.· Know what affects their variability.· Know about the association of high bone turnover and rapid bone loss and increased fracture risk

in the older woman.· Know how to identify the target for therapy for osteoporosis treatments.

Controversies in the field· Which marker is optimal?· Do markers predict the risk of fracture?· Can markers replace bone density testing for monitoring the effect of osteoporosis therapy.

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Future developmentsThis will include the use of bone markers to study the effect and mechanism of new treatments for

osteoporosis, particularly ones that are anabolic to bone.

Key references1 Vasikaran S, Eastell R, Bruyere O, Foldes AJ, Garnero P, Griesmacher A, Mcclung M, Morris HA, Silverman S, Trenti T, Wahl

DA, Cooper C, Kanis JA: Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int 2011;22:391-420.

2 Eastell R, Hannon RA: Biomarkers of bone health and osteoporosis risk. Proc Nutr Soc 2008;67:157-162.3 Naylor KE, Eastell R. Bone turnover markers: use in osteoporosis. Nature Reviews Rheumatology 2012 (in press).

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PREMENOPAUSAL OSTEOPOROSIS. HOW SHOULD IT BE MANAGED?

Elizabeth Shane

DIAGNOSIS AND ETIOLOGY OF OSTEOPOROSIS IN PREMENOPAUSAL WOMEN

In postmenopausal women, osteoporosis is defined as a BMD of the spine, hip, or forearm more than 2.5 SD below the young adult mean (T-score ≤-2.5), with or without the presence of a low trauma fracture; osteopenia refers to T scores between - 1.0 and -2.5. In premenopausal women, T scores should not be used to categorize BMD and terms like “osteopenia” or “osteoporosis” should be avoided. Instead, Z scores, which compare a young woman’s BMD to the mean of an age-, gender-, and ethnicity-matched reference population, should be used. Based on the definition of a Zscore, 2.5% of the population will have a Z-score ≤ 2.0. A Z score that is ≤-2.0 can be designated “low bone density” or “below expected for age”. However, low BMD measurements alone should not be used to diagnose “osteoporosis” because the clinical significance of isolated low BMD in young women is unknown. The term “osteoporosis” should be reserved for women with a history of low trauma fractures or when secondary causes of osteoporosis (e.g., glucocorticoid therapy, hypogonadism, hyperparathyroidism) accompanies a low Z score.

Premenopausal women with small skeletons may appear to have low BMD, because DXA scanners cannot distinguish between small bones and less dense bones. Premenopausal woman may have low BMD because of low body weight. They may have low peak bone mass because of genetic predisposition, life style choice (alcohol, tobacco, low calcium intake, lack of exercise) or an underlying illness or exposure to medication that interfere with acquisition of peak bone mass during adolescence. Such secondary causes of osteoporosis may also cause excessive bone loss after adolescence. Lactation is associated with losses of 3-10% at the spine and hip over the first 3-6 months with recovery after weaning over the next 12-18 months. When BMD is measured soon after pregnancy or lactation, it may be difficult to separate physiologic from pathophysiologic changes.

Routine BMD screening of premenopausal or perimenopausal women is not recommended unless there is a history of fragility fracture(s), or conditions or medications associated with low bone mass or bone loss (estrogen deficiency, glucocorticoids, etc). Premenopausal women with a low trauma fracture or Z score ≤-2.0 should have a thorough history, physical examination and laboratory evaluation to identify potential secondary causes of bone loss, such as renal or liver disease, hyperthyroidism, hyperparathyroidism, Cushing’s syndrome, early menopause, celiac disease and other forms of malabsorption, idiopathic hypercalciuria, or connective tissue disorders.

IDIOPATHIC OSTEOPOROSIS IN PREMENOPAUSAL WOMEN

Premenopausal women with no identifiable etiology after extensive evaluation for secondary causes are said to have idiopathic osteoporosis (IOP). Idiopathic osteoporosis primarily affects Caucasians, men and women equally. Presentation may occur during pregnancy or lactation. The mean age at diagnosis is in the mid-thirties. 2

Abstracts

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Fractures are usually multiple, occurring over a 5 to 10 year period. Abnormalities of osteoblast function and decreased IGF-1 have been found in some studies, but not others. In a recent bone biopsy study of women with IOP, both those with fractures and those with Z scores ≤ 2.0 but no fractures had evidence of low volumetric BMD of the hip and spine (by central QCT), distal radius and tibia (by high resolution peripheral QCT or HR-pQCT) and iliac crest bone biopsies (by microCT). In addition, both groups had comparable microarchitectural disruption and reduced estimated strength (by finite element analysis or FEA). In addition, both groups of affected women had increased marrow fat (independent of bone volume fraction), reduced bone mineralization density distribution (BMDD by quantitative backscattered electron imaging) and abnormal bone matrix (by Fourier transform infrared spectroscopy). Bone turnover was heterogeneous, but those in the lowest tertile of bone turnover had the most marked deficits in volumetric BMD, microarchitecture and strength.

MANAGEMENT

There are no official guidelines for management of premenopausal low bone mass or osteoporosis. Lifestyle modifications should be encouraged for all women with low bone mass since peak bone mass may improve well into the fourth decade. The following should be encouraged: adequate calcium intake (1000 – 1200 mg elemental calcium daily); adequate vitamin D intake (400-800 IU vitamin D3 daily) or sufficient to maintain serum 25-OHD levels above 20 ng/ml; regular physical activity, particularly weight-bearing exercise; cessation of smoking; avoid excessive dieting and maintain normal body weight; avoid excess alcohol, caffeine and phosphorus containing drinks. A recent study of 16 premenopausal women with IOP treated only with increased dietary calcium and physical activity revealed significant increases in lumbar spine and femoral neck BMD after 2 or 3 years and no new fractures.

When a secondary cause of osteoporosis is detected in premenopausal women, treatment should be targeted to that disease or abnormality. Examples of specific approaches that have been shown to lead to increases in BMD include: institution of a gluten-free diet in celiac disease; parathyroidectomy in patients with primary hyperparathyroidism; discontinuation of medroxyprogesterone acetate; oral contraceptives for women with oligo- or amenorrhea, on gonadotropin-releasing hormone (GnRH) therapy with perimenopausal bone loss.

Pharmacologic therapy should be avoided unless the patient is losing bone or fracturing. Selective estrogen receptor modulators (SERMs) such as raloxifene should not be used in menstruating women as they block estrogen action on bone, leading to further bone loss. Bisphosphonates carry a Category C rating for safety in pregnancy as they cross the placenta and accumulate in fetal bones in an experimental rat model. While they are probably safe, their long half-life in bone makes their use in reproductive age women a concern. In premenopausal women without fractures or known secondary causes for fractures, bisphosphonates are generally not indicated. Teriparatide has been shown to prevent bone loss in premenopausal women on GnRH agonists for endometriosis, to increase BMD in premenopausal women with GIOP, and with IOP. Teriparatide has the advantage of not being retained in the skeleton but its effects may dissipate after cessation.

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Aggressive therapy with anti-osteoporosis agents may be necessary for women with glucocorticoid-induced osteoporosis. However, the 2010 American College of Rheumatology guidelines do not recommend pharmacologic therapy for prevention and treatment of glucocorticoid-induced osteoporosis patients under age 50, unless they have a history of spine or hip fracture and have taken at least 7.5 mg of prednisone or equivalent daily for 90 days. Premenopausal women receiving chemotherapy for breast cancer represent another group at risk for rapid bone loss, primarily related to induction of premature menopause. Prospective studies demonstrate bone loss at 1 year of 4–8% in the spine and 2–4% at the hip in premenopausal women who become menopausal after receiving adjuvant chemotherapy. Intravenous bisphosphonates prevent bone loss in premenopausal women with chemotherapy-induced amenorrhea. Premenopausal women with osteogenesis imperfecta (OI) can be treated with either oral alendronate or intravenous pamidronate.

SUGGESTED REFERENCES1. Peris P, Guanabens N, Martinez de Osaba MJ, Monegal A, Alvarez L, Pons F, Ros I, Cerda D, Munoz-Gomez J 2002 Clinical

characteristics and etiologic factors of premenopausal osteoporosis in a group of Spanish women. Semin Arthritis Rheum 32(1):64-70

2. Peris P, Monegal A, Martinez MA, Moll C, Pons F, Guanabens N 2007 Bone mineral density evolution in young premenopausal women with idiopathic osteoporosis. Clin Rheumatol 26(6):958-61.

3. Cohen A, Fleischer J, Freeby MJ, McMahon DJ, Irani D, Shane E. Clinical characteristics and medication use among premenopausal women with osteoporosis and low BMD: the experience of an osteoporosis referral center. J Womens Health (Larchmt), Jan-Feb; 18(1):79-84, 2009 PMID 19132880

4. Cohen A, Liu XS, Stein EM, McMahon DJ, Rogers HF, LeMaster J, Recker RR, Lappe JM, Guo XE, Shane E. Bone Microarchitecture and stiffness in premenopausal women with idiopathic osteoporosis. J Clin Endocrinol Metab. Nov; 94(11):4351-4360, 2009. PMID: 19837923

5. Cohen A, Recker RR, Lappe J, Dempster DW, Cremers S, McMahon DJ, Stein EM, Fleischer J, Rosen CJ, Rogers HF, Staron RB, LeMaster J, Shane E. Premenopausal women with idiopathic low trauma fractures and/or low bone mineral density. Osteoporos Int. 2011 Mar 2. [Epub ahead of print]

6. Cohen A, Dempster DW, ReckerRR, Zhou H, Wirth AJ, van Lenthe, GH, Kohler T, Müller R, SteinEM, RosenCJ, Nickolas TL, Rogers HF, Staron RB, LeMaster J, ShaneE. Abnormal bone microarchitecture and evidence of osteoblast dysfunction in premenopausal women with idiopathic osteoporosis. J Clin Endocrinol Metab. 2011 Oct;96(10):3095-105. Epub 2011 Aug 10

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Abstracts

DIFFERENTIAL CHARACTERISTICS AND LONG TERM SKELETAL EFFECTS OF BISPHOSPHONATES

Graham Russell

The biological effects of the bisphosphonates (BPs), originally called diphosphonates, were first reported in 1969. Their early use was for bone scintigraphy, and the treatment of Paget’s disease. Starting in the 1970s this was extended to hypercalcaemia of malignancy, and then to the prevention of skeletal-related events in patients with myeloma or bone metastases. Since the 1990s, bisphosphonates (BPs) have become well established as the leading drugs for the treatment of osteoporosis. In general they have proved to be not only highly effective but also very safe.

The pharmacological effects of BPs as inhibitors of bone resorption appear to depend upon two key properties; their affinity for bone mineral, and their inhibitory effects on osteoclasts, Several recent studies show that binding affinities for bone mineral (hydroxyapatite) differ among the clinically used BPs. This is predicted to influence their differential distribution within bone, their biological potency, and their duration of action.

Within bone bisphosphonates are internalised by osteoclasts and interfere with specific biochemical processes. The antiresorptive effects on osteoclasts of the nitrogen-containing BPs (including alendronate, risedronate, ibandronate, minodronate and zoledronate) appear to result principally from their inhibition of farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway, which generates isoprenoid lipids utilized for the post-translational modification of small GTP-binding proteins that are essential for osteoclast function. There is also evidence that BPs affect the differentiation of osteoclasts in addition to their effects on mature cells. The heterocyclic BPs (risedronate and zoledronate) are characterized by particularly strong and sustained inhibition as a result of induced conformational changes in FPPS.

The accumulation of the upstream metabolite, isopentenyl pyrophosphate (IPP), as a result of inhibition of FPPS may be responsible for immunomodulatory effects on gamma delta (γδ) T cells, and can also lead to production of another ATP metabolite called ApppI, which has intracellular actions. Effects on other cellular targets, such as osteocytes, may also be important and act through other pathways eg connexin channels.

Over the years many hundreds of BPs have been made, and more than a dozen have been studied in man. In terms of similarities and differences among individual BPs, it is clear that BPs share several common properties as a drug class. However, as with other classes of drugs, there are obvious chemical, biochemical, and pharmacological differences among the various BPs. Each BP has a unique profile that may help to explain observed clinical differences among the BPs in terms of speed of onset and anti-fracture efficacy, and the degree and duration of reduction of bone turnover.

In the case of osteoporosis some of the currently topical issues include who to treat and for how long; which BP to use, how to manage poor compliance and targeting therapy to those who will benefit most; and what happens when BPs are given in combination with other

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drugs. There is also a lot of attention devoted to issues of side effects and adverse events. These include well-recognized problems of gastrointestinal side effects, and acute phase responses with parenteral BPs. More contentious issues in relation to osteoporosis include osteonecrosis of the jaw (ONJ) and atypical femoral (subtrochanteric) fractures, where the nature of any association with BPs remains unclear.

Recent studies suggest that BPs may be associated with other clinical benefits outside the field of bone diseases, eg on mortality, and reduction of colon cancer, suggesting that we have more to learn about the pharmacology and clinical effects of this interesting group of drugs.

Fleisch, H., Russell, R.G.G. and Francis, M.D. (1969). Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science, 165, 1262-1264.

Burr D, Russell R G. Guest editors of Special issue of Bone to mark the 40th anniversary of bisphosphonates. (Authors of the foreword on bisphosphonates in this issue.) Bone. 2011 Jul;49(1):1.

Pazianas M, Abrahamsen B, Eiken P, Eastell R, Russell RG, Reduced colon cancer incidence and mortality in postmenopausal women treated with an oral bisphosphonate—Danish National Register Based Cohort Study Osteoporos Int DOI 10.1007/s00198-012-1902-4

Russell RG. Bisphosphonates: The first 40 years. Bone. 2011 Jul;49(1):2-19. Epub 2011 May 1.

Russell RG, Watts NB, Ebetino FH, Rogers MJ. (2008). Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporosis International. 19:733–759

Varela I, Pereira S, Ugalde AP, et al. Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat Med. 2008; 14: 767-72.

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Abstracts

EFFECTS OF GLUCOCORTICOIDS ON BONE TISSUE

Ernesto Canalis

Glucocorticoids have profound effects on bone metabolism. Glucocorticoids increase bone resorption and have long-term suppressive effects on bone formation (1,2). The major cellular targets of glucocorticoids are cells of the osteoblastic lineage, and glucocorticoids cause a loss of osteoblasts leading to a state of decreased bone remodeling. Glucocorticoids impair the replication of osteoblast precursors and prevent their differentiation toward mature osteoblasts. In addition, glucocorticoids cause osteoblast and osteocyte apoptosis, and these actions, in conjunction with an impairment in cell differentiation, cause a depletion of cells of the osteoblastic lineage (3). In addition, there is a shift in the differentiation of mesenchymal precursor cells toward cells of the adipocytic lineage since corticosteroids induce adipogenic CCAAT/enhancer binding proteins and peroxisome proliferator activated receptor ı2 (4). Central to the inhibitory effects of glucocorticoids on osteoblastic cell fate is the inhibition of Wnt signaling, and this mechanism involves the induction of the extracellular Wnt antagonist Dickkopf1 and the activation of glycogen synthase 3β, an enzyme that phosphorylates β catenin and favors its degradation by ubiquitination in the proteasome (5,6). Wnt signaling also suppresses osteoclastogenesis and bone resorption, and the inhibition of Wnt signaling by glucocorticoids can explain in part the increased bone resorption observed following corticosteroid exposure. Glucocorticoids inhibit the differentiated function of mature osteoblasts, since they decrease the transcription of type I collagen and of insulin like growth factor I in these cells, contributing to the decrease in bone formation. The inhibitory effects of glucocorticoids on the genesis and function of bone forming cells lead to a decrease in bone remodeling and to bone loss. The consequences are an increased risk in fractures, which occur in 30-50% of patients receiving chronic glucocorticoid therapy. There is an early rapid decline in bone mineral density (BMD) after glucocorticoid exposure, possibly explained by an increase in bone resorption and this is followed by a slower progressive decline in BMD, when bone remodeling is suppressed (7). It is important to note that fractures occur at higher BMD values in the context of glucocorticoid induced osteoporosis (GIO) than in that of postmenopausal osteoporosis. Bisphosphonates are effective in the prevention and treatment of GIO, and the anabolic agent teriparatide is effective in the treatment of established GIO (8).

References1. Canalis, E. Clinical review 83: Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis.

J.Clin.Endocrinol.Metab 81:3441-3447, 19962. Canalis, E. Mechanisms of glucocorticoid-induced osteoporosis. Curr.Opin.Rheumatol. 15:454-457, 20033. Weinstein, R. S., O’Brien, C. A., Almeida, M., Zhao, H., Roberson, P. K., Jilka, R. L., and Manolagas, S. C. Osteoprotegerin

prevents glucocorticoid induced osteocyte apoptosis. Endocrinology 152:3323-3331, 20114. Pereira, R. C., Delany, A. M., and Canalis, E. Effects of cortisol and bone morphogenetic protein-2 on stromal cell differentiation:

correlation with CCAATenhancer binding protein expression. Bone 30:685-691, 20025. Smith, E. and Frenkel, B. Glucocorticoids inhibit the transcriptional activity of LEF/TCF in differentiating osteoblasts in a glycogen

synthase kinase-3betadependent and -independent manner. J.Biol.Chem. 280:2388-2394, 20056. Westendorf, J. J., Kahler, R. A., and Schroeder, T. M. Wnt signaling in osteoblasts and bone diseases. Gene 341:19-39, 20047. Canalis, E., Mazziotti, G., Giustina, A., and Bilezikian, J. P. Glucorticoid- Induced Osteoporosis: Pathophysiology and

Therapy. Osteoporos.Int. 18:1319-1328, 20078. Carpinteri, R., Porcelli, T., Mejia, C., Patelli, I., Bilezikian, J. P., Canalis, E., Angeli, A., Giustina, A., and Mazziotti, G.

Glucocorticoid-induced osteoporosis and parathyroid hormone. J Endocrinol.Invest 33:16-21, 2010

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Abstracts

DRUGS FOR OSTEOPOROSIS ON THE WAITING LIST

Sundeep Khosla

Currently approved drugs for the prevention or treatment of osteoporosis in the US include estrogen, a selective estrogen receptor modulator (raloxifene), four bisphosphonates (alendronate, risedronate, ibandronate, and zoledronic acid), the RANKL inhibitor denosumab, and teriparatide. There are, however, a number of both anti-resorptive and anabolic drugs in development.

On the anti-resorptive side, the closest drug in terms of coming to market is the cathepsin K inhibitor, odanacatib (ODN), which is entering phase III trials. In a phase II study, ODN increased BMD at multiple sites relative to placebo and reduced markers of bone resorption (1). Interestingly, bone formation markers initially decreased, but by 24 months returned to baseline values. In subsequent studies in monkeys, ODN was found to preserve bone mass at multiple sites, lead to an increase in relatively normal appearing osteoclasts on bone surfaces, and decrease bone resorption markers (2, 3). Histologically measured bone

formation rates decreased in trabecular bone but increased on the periosteal surface. These complex effects of ODN (and other cathepsin K inhibitors) on bone formation are likely explained by bone compartment-specific alterations in osteoclast-osteoblast coupling.

On the anabolic side, the phase III study with the sclerostin antibody, AMG 785, is in the planning stage. In human studies, sclerostin levels increase with age (4), are suppressed by estrogen (5) and PTH treatment (6). In preclinical studies, AMG 785 increases bone mass in animals and by a remarkable 5% at the lumbar spine in humans just over the course of 3 months (7).

As these new drugs become available, clinicians treating patients with osteoporosis will have increasing options. Relevant questions will include which drug to use and when, combination therapies, the sequence of specific drugs, and the duration of therapy with different drugs.

REFERENCES

1. Bone HG, McClung MR, Roux C, Recker RR, Eisman JA, Verbruggen N, Hustad CM, DaSilva C, Santora AC, Ince BA 2010 Odanacatib, a cathespin-K inhibitor for osteoporosis: a two-year study in postmenopausal women with low bone density. J Bone Miner Res 25:937- 947

2. Masarachia PJ, Pennypacker BL, Pickarski M, Scott KR, Wesolowski GA, Smith SY, Samadfam R, Goetzmann JE, Scott BB, Kimmel DB, Duong LT 2011 Odanacatib reduces bone turnover and increases bone mass in the lumbar spine of skeletally mature ovariectomized rhesus monkeys. J Bone Miner Res (In press)

3. Cusick T, Chen CM, Pennypacker BL, Pickarski M, Kimmel DB, Scott BB, Duong LT 2011 Odanacatib treatment increases hip bone mass and cortical thickness by preserving endocortical bone formation and stimulating periosteal bone formation in the ovariectomized adult rhesus monkey. J Bone Miner Res (In press)

4. Modder UI, Hoey KA, Amin S, McCready LK, Achenbach SJ, Riggs BL, Melton LJI, Khosla S 2011 Relation of age, gender, and bone mass to circulating sclerostin levels in women and men. J Bone Miner Res 26:373- 379

5. Modder UIL, Clowes JA, Hoey K, Peterson JM, McCready L, Oursler MJ, Riggs BL, Khosla S 2011 Regulation of circulating sclerostin levels by sex steroids in women and men. J Bone Miner Res 26:27-34

6. Drake MT, Srinivasan B, Modder UI, Peterson JM, McCready LK, Riggs BL, Dwyer D, Stolina M, Kostenuik P, Khosla S 2010 Effects of parathyroid hormone treatment on ciculating sclerostin levels in postmenopausal women. J Clin Endocrinol Metab 95:5056-5062

7. Padhi D, Jang G, Stouch B, Fang L, Posvar E 2011 Single-dose, placebocontrolled, randomized study of AMG

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Abstracts

CRITERIA FOR SELECTING THE OPTIMAL TREATMENT

Christian Roux

A wide variety of drugs is now available for the treatment of osteoporosis and efforts have been made for the recognition of patients who should receive the highest priority for treatment. The demonstration of their anti fracture efficacy is unequivocal, with a positive risk/benefit balance. However comparisons between the different available drugs are not available on the fracture end-point, and only surrogate markers, i.e. BMD and biochemical parameters, have been used, which is not relevant for the therapeutic decision. Thus the choice of the appropriate treatment for a given patient is based on 3 cornerstones.

1- Regulatory rules for indication and reimbursement. Local recommendations must be followed, although huge discrepancies, related to non-scientific reasons, exist.

2- Comparability of the patient with the patients included in the study. Some data strongly suggest that patients characteristics are determinants of treatment efficacy: The level of evidence related to the non vertebral or hip anti fracture effect is different among the treatments, and drugs without a proven efficacy on hip fractures are not prescribed in elderly patients with a low hip T score. Only one bisphosphonate has been assessed in a population of patients with a prevalent hip fracture, and is thus the first-line treatment in such patients. Only anti RANK L antibody can be used in osteoporosis with clearance below 30ml/mn. Anti fracture effect may be different in elderly and early post menopausal women. Baseline T scores and number of prevalent fractures can drive a different effect on the decrease in risk of sustaining a new fracture. Moreover baseline bone remodelling can influence the BMD change, over 1 or 3 years; whether this in turn can be translated in anti fracture effect remains to be proven.

3- Patient’s opinion: on early post menopausal women, treatment of climacteric symptoms, or prevention of breast cancer may be considered as the optimal goal by some patients. In some individuals, the predicted adherence to treatment is low, and/or the patient has gastro intestinal disturbances, leading to the prescription of treatment with a non-oral route administration.

Selecting an optimal second-line treatment cannot be evidence-based, as data are lacking for conducting appropriate strategies. Practical considerations are thus the rationale for switch proposals.

Clinical decision making in osteoporosis is complex. Beyond the nationspecific guidelines, a case finding strategy is useful to select an optimal treatment for an individual.

Producto de investigación de Les Laboratoires ServierComercializado por Rovi bajo licencia de Laboratoires Servier

Osseor® 1. NOMBRE DEL MEDICAMENTO: OSSEOR 2 g granulado para suspensión oral. 2. COMPOSICIÓN CUALITATIVA Y CUANTITATIVA: Cada sobre contiene 2 g de ranelato de estroncio.

Excipiente: cada sobre también contiene 20 mg de aspartamo (E951). Para consultar la lista completa de excipientes, ver sección 6. 1. 3. FORMA FARMACÉUTICA: Granulado para suspensión oral. Gránulos de color amarillo. 4. DATOS CLÍNICOS: 4. 1. Indicaciones terapéuticas: Tratamiento de la osteoporosis en mujeres posmenopáusicas a fi n de reducir el riesgo de fracturas vertebrales y de cadera (ver sección 5). 4. 2. Posología y forma de administración: Posología: La dosis recomendada consiste en un sobre de 2 g, una vez al día, por vía oral. Dada la naturaleza de la enfermedad tratada, el ranelato de estroncio está destinado al uso a largo plazo. La absorción del ranelato de estroncio disminuye con los alimentos, la leche y los productos lácteos, de modo que OSSEOR debe administrarse entre las comidas. Como OSSEOR se absorbe lentamente, debe tomarlo preferiblemente al acostarse, si es posible, dos horas después de cenar como mínimo (ver sección 4. 5). Las pacientes tratadas con ranelato de estroncio deben recibir suplementos de vitamina D y calcio, si la ingestión alimentaria resulta insufi ciente. Pacientes de edad avanzada: Se han constatado la efi cacia y la seguridad del ranelato de estroncio para mujeres posmenopáusicas con osteoporosis de una amplia franja de edad (en los estudios se ha incluido incluso a mujeres de 100 años). No es necesario el ajuste de dosis en función de la edad. Insufi ciencia renal: El ranelato de estroncio no se recomienda para las pacientes con insufi ciencia renal grave (aclaramiento de creatinina menor de 30 ml/min) (ver secciones 4. 4). Las pacientes con insufi ciencia renal leve o moderada (aclaramiento de creatinina de 30-70 ml/min) no precisan ningún ajuste de dosis. Insufi ciencia hepática: Como el ranelato de estroncio no se metaboliza, las pacientes con insufi ciencia hepática no precisan ningún ajuste de dosis. Población pediátrica: No se ha establecido todavía la seguridad y efi cacia de OSSEOR en niños menores de 18 años. No hay datos disponibles. Forma de administración: Para uso oral. Los gránulos contenidos en los sobres deben tomarse en forma de suspensión en un vaso conteniendo un mínimo de 30 ml de agua (aproximadamente un tercio de un vaso estándar). Aunque los estudios sobre su uso han demostrado la estabilidad del ranelato de estroncio en suspensión durante las 24 horas siguientes a su preparación, la suspensión debe beberse de inmediato una vez preparada. 4. 3. Contraindicaciones: Hipersensibilidad al principio activo o a alguno de los excipientes. 4. 4. Advertencias y precauciones especiales de empleo: Uso en pacientes con Insufi ciencia renal: Al no disponer de datos sobre la seguridad ósea entre pacientes con insufi ciencia renal grave tratadas con ranelato de estroncio, se desaconseja el uso de OSSEOR si el aclaramiento de creatinina es inferior a 30 ml/min. De conformidad con la buena práctica clínica, se aconseja una evaluación periódica de la función renal de las pacientes con insufi ciencia renal crónica. La continuación del tratamiento con OSSEOR por parte de las pacientes con insufi ciencia renal grave se sopesará de manera individual. Tromboembolia venosa: En los estudios de fase III, controlados con placebo, el tratamiento con ranelato de estroncio se asoció con una mayor incidencia anual de tromboembolia venosa (TEV), incluida la embolia pulmonar (ver sección 4. 8). Se ignora la causa de este hallazgo. OSSEOR debe utilizarse con precaución en pacientes con un riesgo elevado de TEV, incluyendo las pacientes con antecedentes de TEV. Cuando se trate a pacientes de riesgo, de TEV o en las que esté apareciendo ese riesgo, se prestará atención a los posibles signos y síntomas de la tromboembolia venosa y se adoptarán las medidas preventivas pertinentes. Reacciones cutáneas: Se han notifi cado casos de síndromes de hipersensibilidad graves, incluyendo, en particular, erupción cutánea con eosinofi lia y síntomas sistémicos (DRESS), algunas veces mortales, con el uso de OSSEOR (ver sección 4. 8). El síndrome DRESS se caracteriza por erupción cutánea, fi ebre, eosinofi lia y afectación orgánica (ej. : adenopatía, hepatitis, nefropatía intersticial, enfermedad pulmonar intersticial). El tiempo de aparición fue normalmente alrededor de 3-6 semanas tras el inicio del tratamiento y el desenlace, en la mayoría de los casos, fue favorable tras la interrupción del tratamiento con OSSEOR y tras el inicio del tratamiento con corticosteroides. La recuperación podría ser lenta y se han notifi cado recaídas del síndrome en algunos casos tras suspender el tratamiento con corticosteroides. Se debe informar a las pacientes de que, en caso de aparición de erupción cutánea, interrumpan inmediatamente y de forma permanente el tratamiento con OSSEOR y acudan al médico. Las pacientes que han interrumpido su tratamiento por reacciones de hipersensibilidad u otras reacciones alérgicas graves no deben reiniciar el tratamiento con OSSEOR. Interacción con pruebas analíticas: El estroncio interfi ere los métodos colorimétricos para la determinación de las concentraciones sanguíneas y urinarias de calcio. Por eso, en la práctica clínica, para medir con exactitud las concentraciones sanguíneas y urinarias de calcio se requieren métodos de espectrometría de emisión atómica con plasma de acoplamiento inductivo o bien de espectrometría de absorción atómica. Excipientes: OSSEOR contiene una fuente de fenilalanina que puede ser perjudicial para las personas con fenilcetonuria. 4. 5. Interacción con otros medicamentos y otras formas de interacción: Los alimentos, la leche y los productos lácteos y los medicamentos que contienen calcio pueden reducir la biodisponibilidad del ranelato de estroncio en un 60-70%. Por eso, hay que separar la administración de OSSEOR y de dichos productos, como mínimo, dos horas. Como los cationes divalentes pueden formar complejos en el tracto gastrointestinal con la tetraciclina y las quinolonas administradas por vía oral y, en consecuencia, podrían reducir su absorción, se desaconseja la administración simultánea del ranelato de estroncio con estos medicamentos. Como medida de precaución, el tratamiento con OSSEOR debe suspenderse mientras se administren la tetraciclina o las quinolonas por vía oral. En un estudio de interacción clínica in vivo se comprobó que la administración de los hidróxidos de aluminio y magnesio, bien dos horas antes o junto con el ranelato de estroncio, reducía ligeramente la absorción del ranelato de estroncio (descenso de AUC del 20-25%), mientras que la absorción apenas se modifi caba cuando el antiácido se administraba dos horas después del ranelato de estroncio. Por consiguiente, es preferible tomar los antiácidos, como mínimo, dos horas después de OSSEOR. No obstante, si esta pauta posológica no es factible, dada la recomendación de administrar OSSEOR al acostarse, se puede aceptar la ingestión concomitante. No se ha encontrado ninguna interacción con los suplementos de vitamina D por vía oral. En los ensayos clínicos no se apreció ningún indicio de interacción clínica o de aumento relevante de los valores sanguíneos de estroncio con los fármacos que es de esperar que se prescriban habitualmente junto con OSSEOR a la población destinataria. Estos medicamentos comprendían: antiinfl amatorios no esteroideos (incluido el ácido acetilsalicílico), anilidas (como el paracetamol), antagonistas H2 inhibidores de la bomba de protones, diuréticos, digoxina y glucósidos digitálicos, nitratos orgánicos y otros vasodilatadores para las enfermedades cardíacas, antagonistas del calcio, betabloqueantes, IECA, antagonistas de la angiotensina II, agonistas selectivos de los receptores adrenérgicos beta–2, anticoagulantes orales, antiagregantes plaquetarios, estatinas, fi bratos y benzodiazepinas. 4. 6. Fertilidad, embarazo y lactancia: Embarazo: OSSEOR sólo debe administrarse a mujeres posmenopáusicas. No existen datos sobre la utilización de ranelato de estroncio en mujeres embarazadas. En los estudios con animales, las dosis altas mostraron efectos óseos reversibles en la descendencia de las ratas y conejas tratadas durante la gestación. Si se administrara OSSEOR involuntariamente durante el embarazo, se suspenderá el tratamiento. Lactancia: Datos físico-químicos indican que el ranelato de estroncio se excreta en la leche humana. OSSEOR no debe administrarse durante la lactancia. Fertilidad: no se observaron efectos sobre la fertilidad de machos y hembras en estudios en animales. 4. 7. Efectos sobre la capacidad para conducir y utilizar máquinas: La infl uencia de OSSEOR sobre la capacidad para conducir y utilizar máquinas es nula o insignifi cante. 4. 8. Reacciones adversas: OSSEOR se ha investigado en ensayos clínicos donde intervinieron casi 8. 000 participantes. La seguridad a largo plazo se ha evaluado en estudios de fase III entre mujeres posmenopáusicas con osteoporosis que recibieron tratamiento con 2 g/día de ranelato de estroncio (n=3. 352) o placebo (n=3. 317) a lo largo de 60 meses, como máximo. La media de edad en el momento de la inclusión era de 75 años y el 23% de las pacientes reclutadas tenía entre 80 y 100 años. No hubo ninguna diferencia en la naturaleza de las reacciones adversas entre los diferentes grupos tratados, con independencia de que las pacientes tuvieran una edad inferior o superior a 80 años en el momento de la inclusión. Las tasas de incidencia generales de las reacciones adversas causadas por el ranelato de estroncio no difi rieron de las del placebo y las reacciones adversas tuvieron, por lo común, un carácter leve y pasajero. Las reacciones adversas más frecuentes consistieron en náuseas y diarrea que, por regla general, aparecieron al comienzo del tratamiento sin que luego se apreciaran grandes diferencias entre los grupos. La retirada del tratamiento obedeció, sobre todo, a las náuseas (1,3% en el grupo del placebo y 2,2% en el del ranelato de estroncio). En los estudios de fase III, la incidencia anual de tromboembolia venosa (TEV) observada a lo largo de 5 años se aproximó a 0,7%; el riesgo relativo para las pacientes tratadas con ranelato de estroncio resultó de 1,4 en comparación con el del placebo (95% CI = [1,0; 2,0]) (ver sección 4. 4). Las siguientes reacciones adversas han sido notifi cadas durante los ensayos clínicos y/o durante la utilización post-comercialización con ranelato de estroncio. Las reacciones adversas, defi nidas como los acontecimientos adversos, al menos, posiblemente atribuibles al ranelato de estroncio, que sucedieron en los estudios de fase III se enumeran a continuación empleando la convención siguiente (frecuencia frente al placebo): muy frecuentes (>1/10); frecuentes (>1/100, <1/10); poco frecuentes (>1/1. 000, <1/100); raras (>1/10. 000, <1/1. 000); muy raras (<1/10. 000); frecuencia no conocida (no puede estimarse a partir de los datos disponibles). Trastornos psiquiátricos. Frecuencia no conocidaa: estado de confusión, insomnio. Trastornos del sistema nervioso. Frecuentes: cefalea (3,3% frente a 2,7%), trastornos de la consciencia (2,6% frente a 2,1%), pérdida de memoria (2,5% frente a 2,0%). Poco frecuentes: crisis convulsivas (0,4% frente a 0,1%). Trastornos vasculares. Frecuentes: tromboembolia venosa (2,7% frente a 1,9%). Trastornos respiratorios, torácicos y mediastínicos. Frecuencia no conocidaa: hiperreactividad bronquial. Trastornos gastrointestinales. Frecuentes: náuseas (7,1% frente a 4,6%), diarrea (7,0% frente a 5,0%), heces blandas (1,0% frente a 0,2%). Frecuencia no conocidaa: vómitos, dolor abdominal, irritación de la mucosa oral (estomatitis y/o úlceras bucales), refl ujo gastroesofágico, dispepsia, estreñimiento y fl atulencia. Trastornos hepatobiliares. Frecuencia no conocidaa: aumento de las transaminasas séricas (asociado con reacciones de hipersensibilidad cutánea) y hepatitis. Trastornos de la piel y del tejido subcutáneo. Frecuentes: dermatitis (2,3% frente a 2,0%), eccema (1,8% frente a 1,4%). Frecuencia no conocidaa: reacciones de hipersensibilidad cutánea (erupción cutánea, prurito, urticaria, angioedema), síndromes de hipersensibilidad graves incluyendo síndrome de Stevens-Johnson, necrólisis epidérmica tóxica y (DRESS) (ver sección 4. 4), Alopecia. Trastornos musculoesqueléticos y del tejido conjuntivo. Frecuencia no conocidaa: artromialgias (calambres musculares, mialgias, dolores óseos, artralgias y dolores en las extremidades). Trastornos generales y alteraciones en el lugar de administración. Frecuencia no conocidaa: edema periférico, fi ebre (asociada con reacciones de hipersensibilidad cutánea). Trastornos de la sangre y del sistema linfático. Frecuencia no conocidaa :insufi ciencia de la médula ósea, eosinofi lia (asociada con reacciones de hipersensibilidad cutánea) y linfadenopatía (asociada con reacciones de hipersensibilidad cutánea). Exploraciones complementarias. Frecuentes: aumento de la creatina-fosfocinasa sanguínea (CPK)b (1,4% frente a 0,6%). aExperiencia post-comercialización. bFracción musculoesquelética >3 veces el límite superior de la normalidad. En la mayoría de los casos, estos valores revirtieron espontáneamente a la normalidad sin modifi car el tratamiento. 4. 9. Sobredosis: En un estudio clínico donde se investigó la administración repetida de 4 g de ranelato de estroncio al día durante 25 días, las mujeres posmenopáusicas sanas toleraron bien la medicación. La administración aislada de dosis de hasta 11 g a varones voluntarios jóvenes y sanos no causó ningún síntoma especial. Tras los episodios de sobredosifi cación durante los ensayos clínicos (hasta 4g/día durante un máximo de 147 días) no se observó ninguna complicación clínica. La administración de leche o antiácidos podría reducir la absorción del principio activo. En el caso de una sobredosifi cación considerable, cabe plantear la inducción del vómito para eliminar el principio activo no absorbido. 5. PROPIEDADES FARMACOLÓGICAS: 5. 1. Propiedades farmacodinámicas: Grupo farmacoterapéutico: Medicamentos para tratar las enfermedades óseas – Otros fármacos que modifi can la estructura y la mineralización ósea, código ATC: M05BX03. Mecanismo de acción: En condiciones in vitro, el ranelato de estroncio: aumenta la formación de hueso en los cultivos de tejido óseo así como la replicación de los precursores de osteoblastos y la síntesis de colágeno en los cultivos de células óseas; reduce la resorción ósea al disminuir la diferenciación de los osteoclastos y la actividad de resorción. De esta manera, el balance del recambio óseo se inclina a favor de la formación de hueso. 6. DATOS FARMACÉUTICOS: 6. 1. Lista de excipientes: Aspartamo (E951), Maltodextrina, Manitol (E421) 6. 2. Incompatibilidades: No procede. 6. 3. Periodo de validez: 3 años. Una vez reconstituida en agua, la suspensión es estable durante 24 horas. Sin embargo, se recomienda beber la suspensión inmediatamente después de su preparación (ver sección 4. 2). 6. 4. Precauciones especiales de conservación: Este medicamento no requiere condiciones especiales de conservación. 6. 5. Naturaleza y contenido del envase: Sobres de papel/polietileno/aluminio/polietileno. Presentación: Cajas con 7, 14, 28, 56, 84 ó 100 sobres. Puede que solamente estén comercializados algunos tamaños de envases. 6. 6. Precauciones especiales de eliminación: Ninguna especial 7. TITULAR DE LA AUTORIZACIÓN DE COMERCIALIZACIÓN: LES LABORATOIRES SERVIER, 50,rueCannot, 92284 Suresnes cedex, Francia. 8. REGIMEN DE PRESCRIPCIÓN Y DISPENSACIÓN por el SNS: Con receta médica. Financiado por la Seguridad Social. Aportación normal. 9. PRESENTACIÓN Y P. V. P. IVA: OSSEOR 2 g, caja con 28 sobres, 49,39 €. 10. FECHA DE LA PRIMERA AUTORIZACIÓN O RENOVACIÓN DE LA AUTORIZACIÓN: 21 de Septiembre de 2009. 11. FECHA DE REVISIÓN: Septiembre de 2011. 12. REPRESENTANTE LOCAL: Laboratorios Farmacéuticos ROVI, S. A. Para mayor información consultar la fi cha técnica completa.

Bibliografía: 1. Marie PJ. Strontium ranelate: a dual mode of action rebalancing bone turnover in favour of bone formation. Curr Opin Rheumatol. 2006 Jun;18 Suppl 1:S11-5. 2. Kanis JA, Burlet N, Cooper C et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2008; 19(4): 399-428. 3. Roux C, Reginster JY, Fechtenbaum J et al. Vertebral fracture risk reduction with strontium ranelate in women with postmenopausal osteoporosis is independent of baseline risk factors. J Bone Miner Res. 2006; 21(4): 536-42. 4. Roux C, Fechtenbaum J, Koltas et al. Strontium ranelate reduces the risk of vertebral fracture in young postmenopausal women with severe osteoporosis. Ann Rheum Dis. 2008; 67: 1736-8. 5. Seeman E, Vellas B, Benhamou CL et al. Strontium ranelate reduces the risk of fracture in elderly women with osteoporosis in the fi rst year of treatment. J Bone Min Res. 2006; 21 (7): 1113-20. 6. Seeman E. Strontium ranelate: vertebral and non-vertebral fracture risk reduction. Curr Opin Rheumatol 2006; 18 Suppl 1:S17-20. 7. Meunier PJ, Roux C, Seeman E et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004; 350: 459-68. 8. Marquis P, Roux C, de la Loge C et al. Strontium ranelate prevents quality of life impairment in post-monopausal women withestablished vertebral osteoporosis. Osteoporos Int. 2008; 19 :503-10. 9. Guía de buena práctica clínica en geriatría. Osteoporosis. Mesa, P. Guañabens, N. Sociedad Española de Geriatría y Gerontología, y Sociedad Española de Reumatología. [en línea] [fecha de acceso 30 de junio de 2009]. Disponible en: http://www.segg.es/page/guias/de/practica/clinica/para/profesionales. 10. Maclaughlin EJ, Sleeper RB, McNatty D et al. Management of age-related osteoporosis and prevention of associated fractures. Ther Clin Risk Manag. 2006; 2(3): 281-95. 11. Sunyecz JA. The use of calcium and vitamin D in the management of osteoporosis. Ther Clin Risk Manag. 2008; 4(4): 827-36.

OSSEOR-anuncio(21x28)-def.indd 2OSSEOR-anuncio(21x28)-def.indd 2 31/01/12 11:3831/01/12 11:38

OS

S-0

1-12

/001

• Osseor® reequilibra el remodelado óseo a favor de la formación1.

• Osseor® es eficaz en todo tipo de fracturas vertebrales y de cadera en pacientes con osteoporosis posmenopáusica2, en un amplio rango de edad3, 4-6.

• Osseor® presenta un valor muy bajo de NNT* para prevenir una fractura vertebral osteoporótica7.

• Osseor® mejora la calidad de vida y disminuye el número de pacientes con dolor de espalda en un 30%8, lo que podría ayudar al cumplimiento terapéutico.

• La terapia integral de la osteoporosis posmenopáusica es diaria 9-11.

*NNT: número necesario de pacientes a tratar.

Construires nuestra vocación

OSSEOR-anuncio(21x28)-def.indd 1 31/01/12 11:42

abstracts avances iii symposium internacional o en … · osteopenia en infancia y adolescencia....

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