RT Generic
T1 Efecto de la hormona del crecimiento y los estrógenos en el hueso osteoporótico: Análisis morfométrico en ratas Wistar. Estudio piloto.
A1 Rosa García, Alba de la
AB La osteoporosis es una enfermedad sistémica esquelética que afecta a más de 200 millones de personas en el mundo. Es la enfermedad ósea más frecuente y la mayoría de las personas que la padecen, no van a ser conscientes hasta que no se produce una fractura. Se sabe desde hace tiempo que el déficit de estrógenos está implicado en la etiopatogenia de la osteoporosis, sin embargo, el déficit de otras hormonas, como la hormona de crecimiento (GH) y el aumento del estrés oxidativo constituyen uno de los más recientes descubrimientos en cuanto a los factores etiopatogénicos. Los tratamientos actuales contra la osteoporosis no carecen de efectos secundarios importantes, como la osteonecrosis de los maxilares y las fracturas subtrocantéreas atípicas. Aunque su prevalencia es baja, se están buscando nuevas alternativas terapéuticas eficaces y seguras. Se sabe que la GH está implicada en el crecimiento longitudinal del hueso y que es capaz de estimular la proliferación y diferenciación de osteoblastos y osteoclastos, es decir, de estimular el proceso de remodelado. Por otro lado, los estrógenos están implicados en la etiopatogenia de la osteoporosis y se utilizan en la terapia hormonal sustitutiva para tratar los síntomas de la menopausia. Sin embargo, por lo que nosotros sabemos, nunca se han empleado GH y estrógenos conjuntamente como tratamiento contra la osteoporosis.   Por ello, el propósito de este estudio piloto fue evaluar el efecto que la GH y los estrógenos, pudieran tener en el hueso osteoporótico de un animal de experimentación, tanto de manera conjunta como por separado. Asimismo, se estudió el efecto de la ovx en diferentes áreas óseas en tibias de ratas viejas.  Material y método: Para realizar este estudio piloto se utilizaron 25 ratas Wistar hembras viejas divididas aleatoriamente en 5 grupos experimentales, cada uno de ellos con 5 animales. Un grupo de 5 ratas se mantuvo como grupo control, y a los cuatro restantes se les realizó una ovariectomía bilateral (ovx). De estos cuatro grupos, uno quedó sin tratamiento, actuando como grupo ovx control, otro fue tratado con GH sc (2 mg/kg/día), otro con estradiol sc (125 µg/semana) y otro con una combinación de ambas, es decir, GH (2 mg/kg/día) más estradiol (125 µg/semana), todos ellos tratados durante 10 semanas. Tras ese período de tiempo, los animales fueron sacrificados por decapitación. Las tibias de los animales fueron extraídas, se eliminaron los tejidos blandos y se fijaron en formaldehido al 10% tamponado a pH 7. Se cortaron en bloques de 2 cm, que se incluyeron en metacrilato (2-hidroxietil-metacrilato), para posteriormente ser cortadas y pulidas mediante el sistema de corte y pulido Exakt. Las muestras se tiñeron con tricrómico de Masson y hematoxilina-eosina y se observaron al microscopio óptico. Se realizó un estudio morfométrico mediante el sistema MIP-4, midiendo: Área Ósea, Área Cortical y Área Trabecular y porosidad cortical. Se realizó el análisis estadístico de las medias con el programa SPSS 22.0 mediante la prueba de ANOVA para buscar significación estadística, considerando significativo si p<0,05.  Resultados:  Se pudo observar que la ovx disminuía el área ósea, el área cortical y el área trabecular, mientras que aumentaba la porosidad cortical, aunque las diferencias no alcanzaron significatividad estadística.  La administración sistémica de GH en ratas ovx aumentaba significativamente el área ósea (5,47±0,13 vs 4,53±0,17) y el área cortical (5,34±0,16 vs 0,42±0,20), respecto al grupo ovx control, mientras que el área trabecular y la porosidad cortical aumentaron, pero de forma no significativa. Respecto a los estrógenos no indujeron diferencias significativas en ningún parámetro estudiado. La administración conjunta de GH+estrógenos en ratas ovx aumentó el área ósea (5,18±0,60 vs 4,53±0,17) de manera significativa respecto a las ratas ovx sin tratamiento (p=0,02). El resto de los parámetros estudiados no alcanzó significatividad estadística.  Conclusiones:  La deprivación estrogénica mediante la ovx bilateral no indujo diferencias significativas en el área ósea, área cortical, área trabecular o porosidad cortical. La administración sistémica de GH a dosis de 2 mg/kg/día en ratas ovx incrementó de forma significativa el área ósea y el área cortical medidas por morfometría, respecto al grupo ovx control. La administración de estrógenos no indujo diferencias significativas en las ratas ovx respecto al grupo ovx control. La administración conjunta de GH+estrógenos incrementó de forma significativa el área ósea en ratas ovx, respecto al grupo ovx control.
YR 2018
FD 2018
LK https://hdl.handle.net/20.500.14352/19997
UL https://hdl.handle.net/20.500.14352/19997
LA spa
NO 1.Alaam MM, Hussien NI (2016). “A comparative study between the effect of 17-β estradiol and angiotensin converting enzyme inhibitor on osteoporosis in ovariectomized rats”. Gen Physiol Biophys, 35(4):433-441. 2. Albright F, Bloomberg E, Smith PH (1940). “Postmenopausal osteoporosis”. Trans Assoc Am Physicians, 298–205. 3. Almeida M, Martin-Millan M, Plotkin LI, Stewart SA, Roberson PK, Kousteni S, O'Brien CA, Bellido T, Parfitt AM, Weinstein RS, Jilka RL, Manolagas SC (2007). “Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids”. J Biol Chem, 282:27285–27297. 4.Almeida M, Laurent MR, Dubois V, et al (2017). “Estrogens and Androgens in Skeletal Physiology and Pathophysiology”. Physiological Reviews, 97(1):135-187.  5.Andreassen TT1, Oxlund H (2000). “The influence of combined parathyroid hormone and growth hormone treatment on cortical bone in aged ovariectomized rats”. J Bone Miner Res, 15(11):2266-75. 6.Aryal R, Chen XP, Fang C, Hu YC (2014). “Bone morphogenetic protein-2 and vascular endothelial growth factor in bone tissue regeneration: new insight and perspectives”. Orthop Surg, 6(3):171-8. 7.Assesment of fracture risk and its application to screening for postmenopausal osteoporosis. WHO Study Group, Geneva, WHO. 1994. No.843.  8.Bayliss L, Mahoney DJ, Monk P (2012). “Normal bone physiology, remodelling and its hormonal regulation”. Surgery, 30(2): 47-53.  9. Banu MJ, Orhii PB, Wang L, Kalu DN (2001). “Separate and combined effects of growth hormone and parathyroid hormone on cortical bone osteopenia in ovariectomized aged rats”. Aging, 13(4):282-92. 10. Bak B, Andreassen TT (1991). “The effect of growth hormone on fracture healing in old rats”. Bone 12:151-154. 11. Baker J, Liu JP, Robertson EJ, Efstratiadis A (1993). “Role of insulin-like growth factors in embryonic and postnatal growth”. Cell, 75:73–82.  12. Baumann G, Stolar MW, Amburn K, Barsano CP, DeVries BC (1986). “A specific growth hormone-binding protein in human plasma: initial characterization”. J Clin Endocrinol Metab, 62:134–141.  13. Bellido T (2014). “Osteocyte-Driven Bone Remodeling”. Calcified Tissue International, 94(1):25-34.  14. Bhukhai K, Suksen K, Bhummaphan N, Janjorn K, Thongon N, Tantikanlayaporn D, Piyachaturawat P, Suksamrarn A, Chairoungdua A (2012). “A phytoestrogen diarylheptanoid mediates estrogen receptor/Akt/glycogen synthase kinase 3beta protein-dependent activation of the Wnt/beta-catenin signaling pathway”. J Biol Chem, 287(43):36168–36178. 15. Bikle DD, Wang Y (2012). “Insulin like growth factor-I: a critical mediator of the skeletal response to parathyroid hormone”. Curr Mol Pharmacol, 5:135–142. 16. Biver E, Hardouin P, Caverzasio J (2013). “The "bone morphogenic proteins" pathways in bone and joint diseases: translational perspectives from physiopathology to therapeutic targets”. Cytokine Growth Factor Rev, 24(1):69-81. 17. Blackwell KA, Raisz LG, Pilbeam CC (2010). “Prostaglandins in Bone: Bad Cop, Good Cop?” Trends in Endocrinology and Metabolism, 21(5):294-301. 18. Bonewald LF, Johnson ML (2008). “Osteocytes, mechanosensing and Wnt signaling. Bone”, 42: 606-615.  19. Bord S, Horner A, Beavan S, Compston J (2001). “Estrogen receptors alpha and beta are differentially expressed in developing human bone”. J Clin Endocrinol Metab, 86(5):2309–14. 20. Bord S, Ireland DC, Beavan SR, Compston JE (2003). “The effects of estrogen on osteoprotegerin, RANKL, and estrogen receptor expression in human osteoblasts”. Bone, 32,136–141. 21. Brixen K, Kassem M, Nielsen HK, Loft AG, Flyvbjerg A, Mosekilde L (1995). “Short-term treatment with growth hormone stimulates osteoblastic and osteoclastic activity in osteopenic postmenopausal women: a dose response study”. J Bone Miner Res, 10(12):1865-74.  22. Brooks AJ, Dai W, O’Mara ML, Abankwa D, Chhabra Y, Pelekanos RA, et al (2014). “Mechanism of activation of protein kinase JAK2 by the growth hormone receptor”. Science, 344:1249783. 23. Burr, DB (2016). “Bone Biomechanics and Bone Quality: Effects of Pharmaceutical Agents Used to Treat Osteoporosis”. Clinic Rev Bone Miner Metab, 14: 197. 24. Buza JA, Einhorn T (2016). “Bone healing in 2016”. Clinical Cases in Mineral and Bone Metabolism,13(2):101-105. 25. Canalis E, Economides AN, Gazzerro E (2003). “Bone morphogenetic proteins, their antagonists, and the skeleton”. Endocr Rev, 24:218–235 26. Canalis E (2005). “Mechanisms of glucocorticoid action in bone”. Curr Osteoporos Rep,3:98–102. 27. Capulli M, Paone R, Rucci N (2014). “Osteoblast and osteocyte: games without frontiers”. Arch Biochem Biophys, 1;561:3-12. 28. Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Woodring J, Pacifici R (2000). “Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-a”. J Clin Invest,106:1229–1327. 29. Centrella M, McCarthy TL, Canalis E (1990). “Receptors for insulin-like growth factors-I and -II in osteoblast-enriched cultures from fetal rat bone”. Endocrinology, 126:39–44 30. Chang J, Wang Z, Tang E, Fan Z, McCauley L, Franceschi R, Guan K, Krebsbach PH, Wang C-Y (2009). “Inhibition of osteoblastic bone formation by nuclear factorkappaB”. Nat Med, 15:682–689. 31. Charoenlarp P, Rajendran AK, Iseki S (2017). “Role of fibroblast growth factors in bone regeneration”. Inflammation and Regeneration, 37:10.  32. Chen X, Wang L, Zhao K, Wang H (2018). “Osteocytogenesis: Roles of Physicochemical Factors, Collagen Cleavage, and Exogenous Molecules”. Tissue Eng Part B Rev, 24(3):215-225.  33. Chim SM, Tickner J, Chow ST, Kuek V, Guo B, Zhang G, Rosen V, Erber W, Xu J (2013). “Angiogenic factors in bone local environment”. Cytokine Growth Factor Rev, 24(3):297-310. 34. Compston JE (2001). “Sex steroids and bone”. Physiol Rev, 81: 419-47.  35. Crane JL, Cao X (2014). “Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling”. The Journal of Clinical Investigation, 124(2):466-472.  36. Crusode de Souza M, Sasso-Cerri E, Cerri PS (2009). “Immunohistochemical detection of estrogen receptor beta in alveolar bone cells of estradiol-treated female rats: possible direct action of estrogen on osteoclast life span”. J Anat, 215(6):673– 81. 37. Drazin D, Choi E, Garcia A, Rustagi T (2017). “Bone morphogenic proteins are a good choice for select spinal surgeries and merit further research”. Journal of Spine Surgery, 3(1):119-121 38. Donath K, Breuner G (1982). “A method for the study of undecalcified bones and teeth with attached soft tissues. The Saege-Schiff technique”. J Oral Pathol, 11:318320. 39. Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL, Riggs BL (2003). “Role of RANK ligand in mediating increased bone resorption in early postmenopausal women”. J Clin Invest, 111:1221–1230. 40. Eimar H, Tamimi I, Murshed M, Tamimi F (2013). “Cholinergic regulation of bone”. J Musculoskelet Neuronal Interact, 13(2):124-32. 41. Falahati-Nini A, Riggs BL, Atkinson EJ, O'Fallon WM, Eastell R, Khosla S (2000). “Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men”. J Clin Invest, 106:1553–1560. 42. Fernández-Tresguerres Hernández-Gil Isabel (1999). Efecto de la hormona de crecimiento en la osteointegración. Tesis Doctoral. 1999. UCM, Madrid.  43. Fernández-Tresguerres-Hernández-Gil I, Alobera-Gracia MA, del-Canto-Pingarrón M, Blanco-Jerez L. Physiological bases of bone regeneration I (2006) a. “Histology and physiology of bone tissue”. Med Oral Patol Oral Cir Bucal, 1;11(1): E47-51.  44. Fernández-Tresguerres-Hernández-Gil I, Alobera-Gracia MA, del-Canto-Pingarrón M, Blanco-Jerez L. Physiological bases of bone regeneration II (2006) b. “The remodeling process”. Med Oral Patol Oral Cir Bucal, 1;11(2): E151-7. b 45. Fisker S (2006). “Physiology and pathophysiology of growth hormone-binding protein: methodological and clinical aspects”. Growth Horm IGF Res, 16:1–28.  46. Fonseca H, Moreira-Gonçalves D, Coriolano HJ, Duarte JA (2014). “Bone quality: the determinants of bone strength and fragility”. Sports Med, 44(1): 37-53.  47. Garnero P (2017). “The utility of biomarkers in osteoporosis management”. Mol Diagn Ther, 21(4):401-418.  48. Gedmintas L, Solomon DH, Kim SC (2013). “Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis”. J Bone Miner Res, 28 (8): 1729-37.  49. Gevers EF, Van der Eerden BC, Karperien M, Raap AK, Robinson IC, Wit JM (2002). “Localization and regulation of the growth hormone receptor and growth hormone binding protein in the rat growth plate”. J Bone Miner Res, 17: 1408–1419.  50. Giustina A, Mazziotti G, Canalis E (2008). “Growth Hormone, Insulin-Like Growth Factors, and the Skeleton”. Endocrine Reviews, 29(5):535-559.  51. Green H, Morikawa M, Nixon T (1985). “A dual effector theory of growth-hormone action”. Differentiation, 29:195–198.  52. Guo D, Bonewald LF (2009). “Advancing our understanding of osteocyte cell biology”. Therapeutic Advances in Musculoeskeletal Diseases, 1(2): 87-96.  53. Harkonen PL, Vaananen HK (2006). “Monocyte-macrophage system as a target for estrogen and selective estrogen receptor modulators”. Ann N Y Acad Sci, 1089:218– 27. 54. Hemmatian H, Bakker AD, Klein-Nulend J, Van Lenthe GH (2017). “Aging, Osteocytes, and Mechanotransduction”. Current Osteoporosis Reports, 15(5):401411.  55. Hollinger JO, Hart CE, Hirsch SN, Lynch S, Friedlaender GE (2008). “Recombinant human platelet-derived growth factor: biology and clinical applications”. The Journal of Bone and Joint Surgery, 90 (Suppl 1):48–54.  56. Hong L, Colpan A, Peptan IA (2006). “Modulations of 17-beta estradiol on osteogenic and adipogenic differentiations of human mesenchymal stem cells”. Tissue Eng, 12(10):2747–2753. 57. Huber DM, Bendixen AC, Pathrose P, Srivastava S, Dienger KM, Shevde NK, Pike JW (2001). “Androgens suppress osteoclast formation induced by RANKL and macrophage-colony stimulating factor”. Endocrinology,142:3800–3808. 58. Isaksson OG, Jansson JO, Gause IA (1982). “Growth hormone stimulates longitudinal bone growth directly”. Science, 216:1237–1239. 59. Jung SM, Kim KW, Yang C-W, Park S-H, Ju JH (2014). “Cytokine-Mediated Bone Destruction in Rheumatoid Arthritis”. Journal of Immunology Research, 2014:263625.  60. Kassem M, Blum W, Ristelli J, Mosekilde L, Eriksen EF (1993). “Growth hormone stimulates proliferation and differentiation of normal human osteoblast-like cells in vitro”. Calcif Tissue Int, 52:222–226.  61. Kawai M, Rosen CJ (2012). The Insulin-Like Growth Factor System in Bone: Basic and Clinical Implications. Endocrinology and Metabolism Clinics of North America, 41(2):323-33. 62. Kenkre JS, Bassett J (2018). “The bone remodelling cycle”. Ann Clin Biochem, 55(3):308-327. 63. Khosla S, Atkinson EJ, Dunstan CR, O'Fallon WM, Riggs BL (2001). “Estrogen and testosterone have opposite effects on circulating OPG levels following induction of hypogonadism and aromatase inhibition in normal elderly men: potential mechanism for differential effects of estrogen versus testosterone on bone resorption”. J Bone Miner Res, 16(Suppl 1):S146. 64. Khosla S, Melton LJI, Riggs BL (2011). “The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed?” J Bone Miner Res,  26:441–451.  65. Khosla S, Oursler MJ, Monroe DG (2012). “Estrogen and the Skeleton”. Trends in Endocrinology and Metabolism, 23(11):576-581.  66. Kobayashi K, Takahashi N, Jimi E, et al (2000). “Tumor Necrosis Factor α Stimulates Osteoclast Differentiation by a Mechanism Independent of the Odf/Rankl–Rank Interaction”. The Journal of Experimental Medicine, 191(2):275-286. 67. Komori T (2010). “Regulation of osteoblast differentiation by Runx2”. Adv Exp Med Biol, 658:43-9. 68. Komori T (2013). “Functions of the osteocyte network in the regulation of bone mass”. Cell and Tissue Research, 352(2):191-198. 69. Kousteni S, Bellido T, Plotkin LI, O'Brien CA, Bodenner DL, Han L, Han K, DiGregorio GB, Katzenellenbogen JA, Katzenellenbogen BS, Roberson PK, Weinstein RS, Jilka RL, Manolagas SC (2001). “Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity”. Cell, 104:719–730. 70. Kovats S (2015). “Estrogen receptors regulate innate immune cells and signaling pathways”. Cell Immunol, 294(2):63–9. 71. Krantz E, Trimpou P, Landin-Wilhelmsen K (2015). “Effect of Growth Hormone Treatment on Fractures and Quality of Life in Postmenopausal Osteoporosis: A 10Year Follow-Up Study”. J Clin Endocrinol Metab, 100(9):3251-3259.  72. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA (1996). “Cloning of a novel receptor expressed in rat prostate and ovary”. Proceedings of the National Academy of Sciences of the United States of America, 93(12):5925–30. 73. Kular J, Tickner J, Chim SM, Xu J (2012). “An overview of the regulation of bone remodelling at the cellular level”. Clin Biochem, 45(12):863-73. 74. Landin-Wilhelmsen K, Wilhelmsen L, Bengtsson B-Å (1999). “Postmenopausal osteoporosis is more related to hormonal aberrations than to lifestyle factors”. Clin Endocrinol (Oxf),  51:387–394.  75. Landin-Wilhelmsen K, Nilsson A, Bosaeus I, Bengtsson BA (2003). “Growth hormone increases bone mineral content in postmenopausal osteoporosis: A randomized placebo-controlled trial”. J Bone Miner Res, 18:393–405. 76. Lanning NJ, Carter-Su C (2006). “Recent advances in growth hormone signaling”. Rev Endocr Metab Disord, 7:225–235. 77. Leung K, Rajkovic IA, Peters E, Markus I, Van Wyk JJ, Ho KK (1996). “Insulin-like growth factor I and insulin down-regulate growth hormone (GH) receptors in rat osteoblasts: evidence for a peripheral feedback loop regulating GH action”. Endocrinology, 137:2694–2702. 78. Lindsey RC, Mohan S (2016). “Skeletal Effects of Growth Hormone and Insulin-like Growth Factor-I Therapy”. Molecular and cellular endocrinology, 432:44-55. 79. Little N, Roger B, Flannery M (2011). “Bone formation, remodeling and healing”. Surgery, 29(4): 141-45. 80. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A (1993). “Mice carrying null mutations of the genes encoding insulin-like growth factor I (IGF-1) and type 1 IGF receptor (IGF1R)”. Cell, 75:59–72. 81. Locatelli V, Bianchi VE (2014). “Effect of GH/IGF-1 on Bone Metabolism and Osteoporosis”. Int J Endocrinol, 2014:235060.  82. Mosekilde L, Thomsen JS, Orhii PB, Kalu DN (1998). “Growth hormone increases vertebral and femoral bone strength in osteopenic, ovariectomized, aged rats in a dose-dependent and site-specific manner”. Bone, 23(4):343-52. 83. Martin-Monge E, Tresguerres IF, Clemente C, Tresguerres JA (2017). “Local Application of Growth Hormone to Enhance Osseointegration in Osteoporotic Bones: A Morphometric and Densitometric Study”. Int J Oral Maxillofac Implants, 32(4):751-758. 84. Manolagas SC (2000). “Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis”. Endocr Rev, 21(2):115-37. 85. Manolagas SC, Almeida M (2007). “Gone with the Wnts: beta-catenin, t-cell factor, forkhead box O, and oxidative stress in age-dependent diseases of bone, lipid, and glucose metabolism”. Mol Endocrinol, 21:2605–2614.  86. Manolagas SC, O'Brien CA, Almeida M (2013). “The role of estrogen and androgen receptors in bone health and disease”. Nat Rev Endocrinol, 9: 699–712. 87. Martin-Millan M, Almeida M, Ambrogini E, Han L, Zhao H, Weinstein RS, Jilka RL, O' Brien CA, Manolagas SC (2010). “The estrogen receptor-alpha in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone”. Mol Endocrinol, 24:323–334.88. Matic I, Matthews BG, Wang X, et al (2016). “Quiescent Bone Lining Cells Are a Major Source of Osteoblasts During Adulthood”. Stem Cells, 34(12):2930-2942. 89. Mikami T, Kitagawa H (2013). “Biosynthesis and function of chondroitin sulfate”. Biochim Biophys Acta, 1830(10):4719-33.  90. Mrak E, Villa I, Lanzi R, Losa M, Guidobono F, Rubinacci A (2007). “Growth hormone stimulates osteoprotegerin expression and secretion in human osteoblastlike cells”. J Endocrinol, 192:639–645. 91. Mohan S, Kesavan C (2012). “Role of insulin-like growth factor-1 in the regulation of skeletal growth”. Curr Osteoporos Rep, 10(2):178-86.  92. Morgan S, Poundarik AA, Vashishth D (2015). “Do Non-collagenous Proteins Affect Skeletal Mechanical Properties?” Calcif Tissue Int, 97(3):281-91. 93. Murshed M (2018). “Mechanism of Bone Mineralization”. Cold Spring Harb Perspect Med, pii: a031229. 94. Nakamura T, Imai Y, Matsumoto T, Sato S, Takeuchi K, Igarashi K, et al (2007). “Estrogen prevents bone loss via estrogen receptor alpha and induction of fas ligand in osteoclasts”. Cell, 130:811–823. 95. O'Brien CA, Nakashima T, Takayanagi, H (2013). “Osteocyte control of osteoclastogenesis”. Bone, 54: 258-6. 96. Ohlsson C, Nilsson A, Isaksson O, Lindahl A (1992). “Growth hormone induces multiplication of the slowly cycling germinal cells of the rat tibial growth plate”. Proc Natl Acad Sci USA, 89:9826–9830. 97. Okman-Kilic T (2015). “Estrogen deficiency and osteoporosis”. In: Advances in Osteoporosis. Ed. Yannis Dionyssiotis, 7-18.  98. Pacifici R (2008). “Estrogen deficiency, T cells and bone loss”. Cell Immunol, 252(1– 2):68–80. 99. Prideaux M, Findlay DM, Atkins GJ (2016). “Osteocytes: The master cells in bone remodeling”. Curr Opin Pharmacol,  28:24-30. 100. Prieto L, Prieto S (2010). Fisiología del hueso. Fisiología humana. En: Tresguerres JAF, editor. Fisiología humana. 4ª Ed. México DF: Mc Graw Hill, p. 1015-1030.   101. Prisby RD (2017). “Mechanical, hormonal and metabolic influences on blood vessels, blood flow and bone”. J Endocrinol, 235(3):R77-R100. 102. Riggs BL, Khosla S, Melton LJ (1998). “A unitary model for involutional osteoporosis: Estrogen deficiency causes Type I and Type II osteoporosis in postmenopausal women and contributes to bone loss in aging men”. J Bone Miner Res, 13:763-73. 103. Rizzoli R (2014). “Nutritional aspects of bone health”. Best Pract Res Clin Endocrinol Metab, 28(6):795-808. 104. Roggia C, Gao Y, Cenci S, Weitzmann MN, Toraldo G, Isaia G, Pacifici R (2001). “Up-regulation of TNF-producing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo”. Proc Natl Acad Sci, 98:13960– 13965. 105. Romanillos JO, Rodríguez EC (2003). Ultimas investigaciones ortopédicas sobre osteoporosis y sus posibles aplicaciones prácticas. En: Rodríguez Merchan EC, Ortega Andreu M, Alonso Carro G, eds. Fracturas osteoporóticas. Prevención y tratamiento. Madrid: Médica Panamericana, 167-97.  106. Rosen CJ, Donahue LR, Hunter SJ (1994). “Insulin-like growth factors and bone: the osteoporosis connection”. Proc Soc Exp Biol Med, 206(2):83-102.  107. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J (2002). “Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial”. JAMA, 288:321–333. 108. Rubin J, Ackert-Bicknell CL, Zhu L, Fan X, Murphy TC, Nanes MS, Marcus R, Holloway L, Beamer WG, Rosen CJ (2002). “IGF-I regulates osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand in vitro and OPG in vivo”. J Clin Endocrinol Metab, 87:4273–4279. 109. Ruggiero SL, Dodson TB, Fantasia K, Goodday R, Aghaloo T, Mehrotra B, et al (2014). “American Associaton of Oral and Maxillofacial Surgeons Position Paper on Medication-Related Osteonecrosis of the Jaw-2014 Update”. J Oral Maxillofac Surg, 72(10) 1938-56. 110. Sassarini J, Lumsden MA (2015). “Oestrogen replacement in postmenopausal women”. Age Ageing, 44: 551–558.  111. Sapir-Koren R, Livshits G (2011). “Bone mineralization and regulation of phosphate homeostasis”. Int Bone Miner Soc, 8: 286-300. 112. Schurman L, Bagur A, Claus-Hermberg H, Messina OD, Negri AL, Sánchez A, et al (2013). “2012 Guidelines for the diagnosis, prevention and treatment of osteoporosis”. Medicina, 73(1):55-74.  113. Sengupta P (2013). “The Laboratory rat: relating its age with human’s”. International Journal of Preventive Medicine, 4(6):624-630. 114. Sims NA, Martin TJ (2015). “Coupling signals between the osteoclast and osteoblast: how are messages transmitted between these temporary visitors to the bone surface?” Front Endocrinol, 6:41.  115. Sosa Henriquez M (2003). “Protocolos de osteoporosis”. Sociedad Española de Medicina Interna (SEMI). 116. Spalding M, Ferreira Amschlinger P, de Vasconcellos LM, de Morais Gouvêa Lima G, Kerbauy WD, Balducci I, Carvalho YR (2014). “Evaluation of different periods of estrogen replacement onset in the tibia of ovariectomized rats”. Aging Clin Exp Res, 26(5):465-71.  117. Sroga GE, Vashishth D (2012). “Effects of Bone Matrix Proteins on Fracture and Fragility in Osteoporosis”. Current Osteoporosis Reports, 10(2):141-150.  118. Strachna O, Torrecilla D, Reumann MK, et al (2014). “Molecular Imaging of Expression of Vascular Endothelial Growth Factor A (VEGF A) in Femoral Bone Grafts Transplanted Into Living Mice”. Cell Transplantation, 23(7):901-912.  119. Sun X, Liang J, Wang C, Cao S, Hu Y, Xu X (2015). “Transient Effect of 17βestradiol on Osteoporosis in Ovariectomized Rats Accompanied with Unilateral Disuse in the Early Phase”. Int J Med Sci,  23;12(5):423-31. 120. Takeda K, Akira S (2000). “STAT family of transcription factors in cytokinemediated biological responses”. Cytokine Growth Factor Rev, 11:199–207. 121. Toogood AA, O’Neill PA, Shalet SM (1996). “Beyond the somatopause: Growth hormone deficiency in adults over the age of 60 years”. J Clin Endocrinol Metab,  81:460–465. 122. Tresguerres JAF. “Somatomedinas (IGFs) y sus proteínas transportadoras”. En: B Moreno Esteban y JAF Tresguerres, editor. Retrasos del crecimiento. 2ªEd. Madrid: Díaz de Santos SA; 1996. p. 71-72 123. Tritos NA, Klibanski A (2016). “Effects of Growth Hormone on Bone”. Prog Mol Biol Transl, 138:193-211.  124. Truong MD, Choi BH, Kim YJ, Kim MS, Min BH (2017). “Granulocyte macrophage-colony stimulating factor (GM-CSF) significantly enhances articular cartilage repair potential by microfracture”. Osteoarthritis Cartilage, 25(8):13451352. 125. Tsuji K, Bandyopadhyay A, Harfe BD, Cox K, Kakar S, Gerstenfeld L, Einhorn T, Tabin CJ, Rosen V (2006). “BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing”. Nat Genet, 38:1424– 1429.  126. Turner RT, Maran A, Lotinum S, Hefferan T, Evans GL, Zhang M, Sibonga JD (2001). “Animal models for osteoporosis”. Rev Endocr Metab Disord, 2(1): 117-27.  127. Turner RT, Riggs BL, Spelsberg TC (1994). “Skeletal effects of estrogen”. Endocr Rev, 15:275–300. 128. Unal M, Creecy A, Nyman JS (2018). “The Role of Matrix Composition in the Mechanical Behavior of Bone”. Curr Osteoporos Rep, 16(3):205-215. 129. Vahle JL, Long GG, Sandusky G, Westmore M, Ma YL, Sato M (2004). “Bone neoplasms in F344 rats given teriparatide [rhPTH (1-34)] are dependet on duration of treatment and dose”. Toxicol Pathol, 32(4): 426-38.  130. Vigetti D, Karousou E, Viola M, Deleonibus S, De Luca G, Passi A (2014). “Hyaluronan: biosynthesis and signaling”. Biochim Biophys Acta, 1840(8):2452-9.  131. Walsh, J (2015). “Normal bone physiology, remodelling and its hormonal regulation”. Surgery, 33(1); 1-6.  132. Wang L, Orhii PB, Banu J, Kalu DN (2001). “Effects of separate and combined therapy with growth hormone and parathyroid hormone on lumbar vertebral bone in aged ovariectomized osteopenic rats”. Bone, 28(2):202-7. 133. Wang Y, Jia L, Zheng Y, Li W (2018). “Bone remodeling induced by mechanical forces is regulated by miRNAs”. Bioscience Reports, 38(4): BSR20180448. 134. Wend K, Wend P, Krum SA (2012). “Tissue-Specific Effects of Loss of Estrogen during Menopause and Aging”. Front Endocrinol, 3:19. 135. White J, Wilson G, Tucci MA, Benghuzzi HA (2014). “The effects of sustained delivery of estrogen on bone strength and cardiovascular panels in osteoporotic female rats”. Biomed Sci Instrum, 50:336-44. 136. Wüster C, Härle U, Rehn U, et al (1998). “Benefits of growth hormone treatment on bone metabolism, bone density and bone strength in growth hormone deficiency and osteoporosis”. Growth Horm IGF Res, 8:87–94.  137. Xing W, Govoni KE, Donahue LR, Kesavan C, Wergedal J, Long C, Bassett JHD, Gogakos A, Wojcicka A, Williams GR, Mohan S (2012). “Genetic evidence that thyroid hormone is indispensable for prepubertal insulin-like growth factor-I expression and bone acquisition in mice”. J Bone Miner Res, 27:1067–1079.  138. Xu X, Zheng L, Yuan Q, Zhen G, Crane JL, Zhou X, Cao X (2018). “Transforming growth factor-β in stem cells and tissue homeostasis”. Bone Research, 6:2.  139. Yakar S, Courtland HW, Clemmons D (2010). “IGF-1 and bone: New discoveries from mouse models”. J Bone Miner Res, 25(12):2543-52 140. You L, Temiyasathit S, Lee P, Kim CH, Tummala P, Yao W, et al (2008). “Osteocytes as mechanosensors in the inhibition of bone resorption due to mechanical loading”. Bone, 42: 172-79. 141. Zhang X, Tamasi J, Lu X, Zhu J, Chen H, Tian X, Lee TC, Threadgill DW, Kream BE, Kang Y, Partridge NC, Qin L (2011). “Epidermal Growth Factor Receptor Plays an Anabolic Role in Bone Metabolism In Vivo”. Journal of Bone and Mineral Research, 26(5):1022-1034. 142. Zhu J, Shimizu E, Zhang X, Partridge NC, Qin L (2011). “EGFR signaling suppresses osteoblast differentiation and inhibits expression of master osteoblastic transcription factors Runx2 and Osterix”. J Cell Biochem, 112(7):1749-60.
DS Docta Complutense
RD 3 dic 2023