Effect of GH/IGF-1 on Bone Metabolism and Osteoporsosis

Vittorio Locatelli, Vittorio E Bianchi, Vittorio Locatelli, Vittorio E Bianchi

Abstract

Background. Growth hormone (GH) and insulin-like growth factor (IGF-1) are fundamental in skeletal growth during puberty and bone health throughout life. GH increases tissue formation by acting directly and indirectly on target cells; IGF-1 is a critical mediator of bone growth. Clinical studies reporting the use of GH and IGF-1 in osteoporosis and fracture healing are outlined. Methods. A Pubmed search revealed 39 clinical studies reporting the effects of GH and IGF-1 administration on bone metabolism in osteopenic and osteoporotic human subjects and on bone healing in operated patients with normal GH secretion. Eighteen clinical studies considered the effect with GH treatment, fourteen studies reported the clinical effects with IGF-1 administration, and seven related to the GH/IGF-1 effect on bone healing. Results. Both GH and IGF-1 administration significantly increased bone resorption and bone formation in the most studies. GH/IGF-1 administration in patients with hip or tibial fractures resulted in increased bone healing, rapid clinical improvements. Some conflicting results were evidenced. Conclusions. GH and IGF-1 therapy has a significant anabolic effect. GH administration for the treatment of osteoporosis and bone fractures may greatly improve clinical outcome. GH interacts with sex steroids in the anabolic process. GH resistance process is considered.

References

    1. Bouillon R, Prodonova A. Growth hormone deficiency and peak bone mass. Journal of Pediatric Endocrinology & Metabolism. 2000;13(supplement 6):1327–1336.
    1. Boot AM, Engels MAMJ, Boerma GJM, Krenning EP, de Muinck Keizer-Schrama SMPF. Changes in bone mineral density, body composition, and lipid metabolism during growth hormone (GH) treatment in children with GH deficiency. Journal of Clinical Endocrinology and Metabolism. 1997;82(8):2423–2428.
    1. Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors, and the skeleton. Endocrine Reviews. 2008;29(5):535–559.
    1. Barrett-Connor E, Goodman-Gruen D. Gender differences in insulin-like growth factor and bone mineral density association in old age: the rancho Bernardo study. Journal of Bone and Mineral Research. 1998;13(8):1343–1349.
    1. Langlois JA, Rosen CJ, Visser M, et al. Association between insulin-like growth factor I and bone mineral density in older women and men: the Framingham heart study. Journal of Clinical Endocrinology and Metabolism. 1998;83(12):4257–4262.
    1. Janssen JAMJL, Burger H, Stolk RP, et al. Gender-specific relationship between serum free and total IGF-I and bone mineral density in elderly men and women. European Journal of Endocrinology. 1998;138(6):627–632.
    1. Johansson AG, Forslund A, Hambraeus L, Blum WF, Ljunghall S. Growth hormone-dependent insulin-like growth factor binding protein is a major determinant of bone mineral density in healthy men. Journal of Bone and Mineral Research. 1994;9(6):915–921.
    1. Sugimoto T, Nishiyama K, Kuribayashi F, Chihara K. Serum levels of insulin-like growth factor (IGF) I, IGF-binding protein (IGFBP)-2, and IGFBP-3 in osteoporotic patients with and without spinal fractures. Journal of Bone and Mineral Research. 1997;12(8):1272–1279.
    1. Garnero P, Sornay-Rendu E, Delmas PD. Low serum IGF-1 and occurrence of osteoporotic fractures in postmenopausal women. The Lancet. 2000;355(9207):898–899.
    1. Ohlsson C, Mellström D, Carlzon D, et al. Older men with low serum IGF-1 have an increased risk of incident fractures: the MrOS Sweden study. Journal of Bone and Mineral Research. 2011;26(4):865–872.
    1. Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Yano S, Sugimoto T. Serum insulin-like growth factor-I level is associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes mellitus. Osteoporosis International. 2007;18(12):1675–1681.
    1. Ebeling PR, Atley LM, Guthrie JR, et al. Bone turnover markers and bone density across the menopausal transition. Journal of Clinical Endocrinology & Metabolism. 1996;81(9):3366–3371.
    1. Ho KY, Evans WS, Blizzard RM, et al. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. Journal of Clinical Endocrinology and Metabolism. 1987;64(1):51–58.
    1. Szulc P, Joly-Pharaboz MO, Marchand F, Delmas PD. Insulin-like growth factor I is a determinant of Hip bone mineral density in men less than 60 years of age: MINOS study. Calcified Tissue International. 2004;74(4):322–329.
    1. Seeman E. Estrogen, androgen, and the pathogenesis of bone fragility in women and men. Current Osteoporosis Reports. 2004;2(3):90–96.
    1. Almeida M, Han L, Martin-Millan M, et al. Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids. Journal of Biological Chemistry. 2007;282(37):27285–27297.
    1. Yakar S, Courtland H, Clemmons D. IGF-1 and bone: new discoveries from mouse models. Journal of Bone and Mineral Research. 2010;25(12):2543–2552.
    1. Fritton JC, Emerton KB, Sun H, et al. Growth hormone protects against ovariectomy-induced bone loss in states of low circulating Insulin-like Growth Factor (IGF-1) Journal of Bone and Mineral Research. 2010;25(2):235–246.
    1. Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocrine Reviews. 1998;19(6):717–797.
    1. Florini JR, Ewton DZ, Coolican SA. Growth hormone and the insulin-like growth factor system in myogenesis. Endocrine Reviews. 1996;17(5):481–517.
    1. Feld S, Hirschberg R. Insulinlike growth factor I and the kidney. Trends in Endocrinology & Metabolism. 1996;7(3):85–93.
    1. Goldspink G, Harridge SDR. Growth factors and muscle ageing. Experimental Gerontology. 2004;39(10):1433–1438.
    1. Aberg D. Role of the growth hormone/insulin-like growth factor 1 axis in neurogenesis. Endocrine Development. 2010;17:63–76.
    1. Ohlsson C, Bengtsson B, Isaksson OGP, Andreassen TT, Slootweg MC. Growth hormone and bone. Endocrine Reviews. 1998;19(1):55–79.
    1. Ballesteros M, Leung K, Ross RJM, Iismaa TP, Ho KKY. Distribution and abundance of messenger ribonucleic acid for growth hormone receptor isoforms in human tissues. Journal of Clinical Endocrinology and Metabolism. 2000;85(8):2865–2871.
    1. Yakar S, Liu J-L, Stannard B, et al. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proceedings of the National Academy of Sciences of the United States of America. 1999;96(13):7324–7329.
    1. Liu J-P, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r) Cell. 1993;75(1):59–72.
    1. Sjögren K, Liu J, Blad K, et al. Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proceedings of the National Academy of Sciences of the United States of America. 1999;96(12):7088–7092.
    1. Holly J, Perks C. The role of insulin-like growth factor binding proteins. Neuroendocrinology. 2006;83(3-4):154–160.
    1. Rosen CJ, Donahue LR, Hunter SJ. Insulin-like growth factors and bone: the osteoporosis connection. Proceedings of the Society for Experimental Biology and Medicine. 1994;206(2):83–102.
    1. Goldenberg N, Barkan A. Factors regulating growth hormone secretion in humans. Endocrinology and Metabolism Clinics of North America. 2007;36(1):37–55.
    1. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocrine Reviews. 1995;16(1):3–34.
    1. Bagi CM, Brommage R, Deleon L, Adams S, Rosen D, Sommer A. Benefit of systemically administered rhIGF-I and rhIGF-I/IGFBP-3 on cancellous bone in ovariectomized rats. Journal of Bone and Mineral Research. 1994;9(8):1301–1312.
    1. Carter-Su C, Smit LS. Signaling via JAK tyrosine kinases: growth hormone receptor as a model system. Recent Progress in Hormone Research. 1998;53:61–83.
    1. Ahmed SF, Farquharson C. The effect of GH and IGF1 on linear growth and skeletal development and their modulation by SOCS proteins. Journal of Endocrinology. 2010;206(3):249–259.
    1. Macrae VE, Horvat S, Pells SC, et al. Increased bone mass, altered trabecular architecture and modified growth plate organization in the growing skeleton of SOCS2 deficient mice. Journal of Cellular Physiology. 2009;218(2):276–284.
    1. Bang P, Westgren M, Schwander J, Blum WF, Rosenfeld RG, Stangenberg M. Ontogeny of insulin-like growth factor-binding protein-1, -2, and -3: quantitative measurements by radioimmunoassay in human fetal serum. Pediatric Research. 1994;36(4):528–536.
    1. Baumann GP. Growth hormone isoforms. Growth Hormone and IGF Research. 2009;19(4):333–340.
    1. Frystyk J, Freda P, Clemmons DR. The current status of IGF-I assays–a 2009 update. Growth Hormone & IGF Research. 2010;20(1):8–18.
    1. Bancos I, Algeciras-Schimnich A, Woodmansee WW, et al. Determination of nadir growth hormone concentration cutoff in patients with acromegaly. Endocrine Practice. 2013;19(6):937–945.
    1. van Toorenenbergen AW. Between-laboratory quality control of automated analysis of IgG antibodies against Aspergillus fumigatus. Diagnostic Microbiology and Infectious Disease. 2012;74(3):278–281.
    1. Faix JD. Principles and pitfalls of free hormone measurements. Best Practice & Research Clinical Endocrinology & Metabolism. 2013;27(5):631–645.
    1. Salmon WD, Jr., Daughaday WH. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. The Journal of Laboratory and Clinical Medicine. 1957;49(6):825–836.
    1. Schlechter NL, Russell SM, Greenberg S, Spencer EM, Nicoll CS. A direct growth effect of growth hormone in rat hindlimb shown by arterial infusion. American Journal of Physiology—Endocrinology and Metabolism. 1986;250(3, part 1):E231–E235.
    1. Green H, Morikawa M, Nixon T. A dual effector theory of growth-hormone action. Differentiation. 1985;29(3):195–198.
    1. Lindahl A, Isgaard J, Nilsson A, Isaksson OGP. Growth hormone potentiates colony formation of epiphyseal chondrocytes in suspension culture. Endocrinology. 1986;118(5):1843–1848.
    1. Ohlsson C, Nilsson A, Isaksson O, Lindahl A. Growth hormone induces multiplication of the slowly cycling germinal cells of the rat tibial growth plate. Proceedings of the National Academy of Sciences of the United States of America. 1992;89(20):9826–9830.
    1. Kassem M, Mosekilde L, Eriksen EF. Growth hormone stimulates proliferation of normal human bone marrow stromal osteoblast precursor cells in vitro. Growth Regulation. 1994;4(3):131–135.
    1. Nilsson A, Swolin D, Enerback S, Ohlsson C. Expression of functional growth hormone receptors in cultured human osteoblast-like cells. The Journal of Clinical Endocrinology & Metabolism. 1995;80(12):3483–3488.
    1. Ernst M, Rodan GA. Increased activity of insulin-like growth factor (IGF) in osteoblastic cells in the presence of growth hormone (GH): positive correlation with the presence of the GH-induced IGF-binding protein BP-3. Endocrinology. 1990;127(2):807–814.
    1. Laron Z, Klinger B. IGF-I treatment of adult patients with Laron syndrome: preliminary results. Clinical Endocrinology. 1994;41(5):631–638.
    1. Ranke MB, Savage MO, Chatelain PG, et al. Insulin-like growth factor I improves height in growth hormone insensitivity: two years' results. Hormone Research. 1995;44(6):253–264.
    1. Walker JL, Van Wyk JJ, Underwood LE. Stimulation of statural growth by recombinant insulin-like growth factor I in a child with growth hormone insensitivity syndrome (Laron type) Journal of Pediatrics. 1992;121(4):641–646.
    1. Guevara-Aguirre J, Rosenbloom AL, Vasconez O, et al. Two-year treatment of growth hormone (GH) receptor deficiency with recombinant insulin-like growth factor I in 22 children: comparison of two dosage levels and to GH-treated GH deficiency. Journal of Clinical Endocrinology and Metabolism. 1997;82(2):629–633.
    1. Collett-Solberg PF, Misra M, Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine The role of recombinant human insulin-like growth factor-I in treating children with short stature. Journal of Clinical Endocrinology & Metabolism. 2008;93(1):10–18.
    1. Rosen CJ, Bilezikian JP. Clinical review 123: anabolic therapy for osteoporosis. The Journal of Clinical Endocrinology & Metabolism. 2001;86(3):957–964.
    1. Isaksson OGP, Jansson JO, Gause IAM. Growth hormone stimulates longitudinal bone growth directly. Science. 1982;216(4551):1237–1239.
    1. Isgaard J, Moller C, Isaksson OGP, Nilsson A, Mathews LS, Norstedt G. Regulation of insulin-like growth factor messenger ribonucleic acid in rat growth plate by growth hormone. Endocrinology. 1988;122(4):1515–1520.
    1. Hunziker EB, Wagner J, Zapf J. Differential effects of insulin-like growth factor I and growth hormone on developmental stages of rat growth plate chondrocytes in vivo . Journal of Clinical Investigation. 1994;93(3):1078–1086.
    1. Guler HP, Zapf J, Scheiwiller E, Froesch ER. Recombinant human insulin-like growth factor I stimulates growth and has distinct effects on organ size in hypophysectomized rats. Proceedings of the National Academy of Sciences of the United States of America. 1988;85(13):4889–4893.
    1. Kupfer SR, Underwood LE, Baxter RC, Clemmons DR. Enhancement of the anabolic effects of growth hormone and insulin-like growth factor I by use of both agents simultaneously. Journal of Clinical Investigation. 1993;91(2):391–396.
    1. Fielder PJ, Mortensen DL, Mallet P, Carlsson B, Baxter RC, Clark RG. Differential long-term effects of insulin-like growth factor-I (IGF-I), growth hormone (GH), and IGF-I plus GH on body growth and IGF binding proteins in hypophysectomized rats. Endocrinology. 1996;137(5):1913–1920.
    1. Hazel SJ, Gillespie CM, Moore RJ, Clark RG, Jureidini KF, Martin AA. Enhanced body growth in uremic rats treated with IGF-I and growth hormone in combination. Kidney International. 1994;46(1):58–68.
    1. Sims NA, Clément-Lacroix P, da Ponte F, et al. Bone homeostasis in growth hormone receptor-null mice is restored by IGF-I but independent of Stat5. The Journal of Clinical Investigation. 2000;106(9):1095–1103.
    1. Courtland H, Elis S, Wu Y, et al. Serum IGF-1 affects skeletal acquisition in a temporal and compartment-specific manner. PLoS ONE. 2011;6(3)e14762
    1. Laviola L, Natalicchio A, Perrini S, Giorgino F. Abnormalities of IGF-I signaling in the pathogenesis of diseases of the bone, brain, and fetoplacental unit in humans. The American Journal of Physiology: Endocrinology and Metabolism. 2008;295(5):E991–E999.
    1. Yakar S, Canalis E, Sun H, et al. Serum IGF-1 determines skeletal strength by regulating subperiosteal expansion and trait interactions. Journal of Bone and Mineral Research. 2009;24(8):1481–1492.
    1. Zhang M, Xuan S, Bouxsein ML, et al. Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. Journal of Biological Chemistry. 2002;277(46):44005–44012.
    1. Yakar S, Rosen CJ, Beamer WG, et al. Circulating levels of IGF-1 directly regulate bone growth and density. Journal of Clinical Investigation. 2002;110(6):771–781.
    1. Uronen-Hansson H, Allen ML, Lichtarowicz-Krynska E, et al. Growth hormone enhances proinflammatory cytokine production by monocytes in whole blood. Growth Hormone and IGF Research. 2003;13(5):282–286.
    1. Renier G, Clément I, Desfaits AC, Lambert A. Direct stimulatory effect of insulin-like growth factor-I on monocyte and macrophage tumor necrosis factor-α production. Endocrinology. 1996;137(11):4611–4618.
    1. Wolf M, Bohm S, Brand M, Kreymann G. Proinflammatory cytokines interleukin 1-β and tumor necrosis factor α inhibit growth hormone stimulation of insulin-like growth factor I synthesis and growth hormone receptor mRNA levels in cultured rat liver cells. European Journal of Endocrinology. 1996;135(6):729–737.
    1. Swolin D, Ohlsson C. Growth hormone increases interleukin-6 produced by human osteoblast- like cells. Journal of Clinical Endocrinology and Metabolism. 1996;81(12):4329–4333.
    1. Yamaguchi T, Kanatani M, Yamauchi M, et al. Serum levels of insulin-like growth factor (IGF); IGF-binding proteins-3, -4, and -5; and their relationships to bone mineral density and the risk of vertebral fractures in postmenopausal women. Calcified Tissue International. 2006;78(1):18–24.
    1. Boonen S, Mohan S, Dequeker J, et al. Down-regulation of the serum stimulatory components of the insulin-like growth factor (IGF) system (IGF-I, IGF-II, IGF binding protein [BP]-3, and IGFBP-5) in age-related (type II) femoral neck osteoporosis. Journal of Bone and Mineral Research. 1999;14(12):2150–2158.
    1. Seck T, Scheidt-Nave C, Leidig-Bruckner G, Ziegler R, Pfeilschifter J. Low serum concentrations of insulin-like growth factor I are associated with femoral bone loss in a population-based sample of postmenopausal women. Clinical Endocrinology. 2001;55(1):101–106.
    1. Krassas GE, Papadopoulou P, Koliakos G, Konstantinidis T, Kalothetou K. Growth hormone, insulin growth factor-1, and IGF binding protein-3 axis relationship with bone mineral density among healthy men. Archives of Andrology. 2003;49(3):191–199.
    1. Yamada PM, Lee KW. Perspectives in mammalian IGFBP-3 biology: local vs. systemic action. The American Journal of Physiology—Cell Physiology. 2009;296(5):C954–C976.
    1. Ali O, Cohen P, Lee K-W. Epidemiology and biology of insulin-like growth factor binding protein-3 (IGFBP-3) as an anti-cancer molecule. Hormone and Metabolic Research. 2003;35(11-12):726–733.
    1. Benini S, Zuntini M, Manara MC, et al. Insulin-like growth factor binding protein 3 as an anticancer molecule in Ewing's sarcoma. International Journal of Cancer. 2006;119(5):1039–1046.
    1. Niemann I, Hannemann A, Nauck M, et al. The association between insulin-like growth factor I and bone turnover markers in the general adult population. Bone. 2013;56(1):184–190.
    1. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocrine Reviews. 2000;21(2):115–137.
    1. Beato M, Klug J. Steroid hormone receptors: an update. Human Reproduction Update. 2000;6(3):225–236.
    1. Manolagas SC, O'Brien CA, Almeida M. The role of estrogen and androgen receptors in bone health and disease. Nature Reviews Endocrinology. 2013;9(12):699–712.
    1. Colvard DS, Eriksen EF, Keeting PE, et al. Identification of androgen receptors in normal human osteoblast-like cells. Proceedings of the National Academy of Sciences of the United States of America. 1989;86(3):854–857.
    1. Ohlsson C, Vandenput LV. The role of estrogens for male bone health. European Journal of Endocrinology. 2009;160(6):883–889.
    1. Kawano H, Kawaguchi H, Kato S. Bone metabolism in androgen receptor-deficient mice. Clinical Calcium. 2003;13(11):1443–1445.
    1. Notini AJ, McManus JF, Moore A, et al. Osteoblast deletion of exon 3 of the androgen receptor gene results in trabecular bone loss in adult male mice. Journal of Bone and Mineral Research. 2007;22(3):347–356.
    1. Callewaert F, Sinnesael M, Gielen E, Boonen S, Vanderschueren D. Skeletal sexual dimorphism: relative contribution of sex steroids, GH-IGF1, and mechanical loading. Journal of Endocrinology. 2010;207(2):127–134.
    1. Kousteni S, Bellido T, Plotkin LI, et al. Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity. Cell. 2001;104(5):719–730.
    1. Benz DJ, Haussler MR, Thomas MA, Speelman B, Komm BS. High-affinity androgen binding and androgenic regulation of α1(I)-procollagen and transforming growth factor-β steady state messenger ribonucleic acid levels in human osteoblast-like osteosarcoma cells. Endocrinology. 1991;128(6):2723–2730.
    1. Bilezikian JP, Morishima A, Bell J, Grumbach MM. Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency. The New England Journal of Medicine. 1998;339(9):599–603.
    1. Coxam V, Bowman BM, Mecham M, Roth CM, Miller MA, Miller SC. Effects of dihydrotestosterone alone and combined with estrogen on bone mineral density, bone growth, and formation rates in ovariectomized rats. Bone. 1996;19(2):107–114.
    1. Tomkinson A, Reeve J, Shaw RW, Noble BS. The death of osteocytes via apoptosis accompanies estrogen withdrawal in human bone. Journal of Clinical Endocrinology and Metabolism. 1997;82(9):3128–3135.
    1. Martin-Millan M, Almeida M, Ambrogini E, et al. The estrogen receptor-α in osteoclasts mediates the protective effects of estrogens on cancellous but not cortical bone. Molecular Endocrinology. 2010;24(2):323–334.
    1. Windahl SH, Saxon L, Börjesson AE, et al. Estrogen receptor-α is required for the osteogenic response to mechanical loading in a ligand-independent manner involving its activation function 1 but not 2. Journal of Bone and Mineral Research. 2013;28(2):291–301.
    1. Marcus R, Leary D, Schneider DL, Shane E, Favus M, Quigley CA. The contribution of testosterone to skeletal development and maintenance: lessons from the androgen insensitivity syndrome. Journal of Clinical Endocrinology and Metabolism. 2000;85(3):1032–1037.
    1. Kawano H, Sato T, Yamada T, et al. Suppressive function of androgen receptor in bone resorption. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(16):9416–9421.
    1. Wiren KM, Semirale AA, Zhang XW, et al. Targeting of androgen receptor in bone reveals a lack of androgen anabolic action and inhibition of osteogenesis : a model for compartment-specific androgen action in the skeleton. Bone. 2008;43(3):440–451.
    1. Khosla S, Oursler MJ, Monroe DG. Estrogen and the skeleton. Trends in Endocrinology and Metabolism. 2012;23(11):576–581.
    1. Falahati-Nini A, Riggs BL, Atkinson EJ, O'Fallon WM, Eastell R, Khosla S. Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. Journal of Clinical Investigation. 2000;106(12):1553–1560.
    1. Mosekilde L, Thomsen JS, Orhii PB, Kalu DN. Growth hormone increases vertebral and femoral bone strength in osteopenic, ovariectomized, aged rats in a dose-dependent and site-specific manner. Bone. 1998;23(4):343–352.
    1. Kasukawa Y, Stabnov L, Miyakoshi N, Baylink DJ, Mohan S. Insulin-like growth factor I effect on the number of osteoblast progenitors is impaired in ovariectomized mice. Journal of Bone and Mineral Research. 2002;17(9):1579–1587.
    1. Yeh JK, Chen M, Aloia JF. Effects of estrogen and growth hormone on skeleton in the ovariectomized rat with hypophysectomy. The American Journal of Physiology —Endocrinology and Metabolism. 1997;273(4):E734–E742.
    1. Kidder LS, Schmidt IU, Evans GL, Turner RT. Effects of growth hormone and low dose estrogen on bone growth and turnover in long bones of hypophysectomized rats. Calcified Tissue International. 1997;61(4):327–335.
    1. Abe T, Chow JWM, Lean JM, Chambers TJ. Estrogen does not restore bone lost after ovariectomy in the rat. Journal of Bone and Mineral Research. 1993;8(7):831–838.
    1. Wakley GK, Evans GL, Turner RT. Short-term effects of high dose estrogen on tibiae of growing male rats. Calcified Tissue International. 1997;60(1):37–42.
    1. Veldhuis JD, Frystyk J, Iranmanesh A, Ørskov H. Testosterone and estradiol regulate free insulin-like growth factor I (IGF-I), IGF binding protein 1 (IGFBP-1), and dimeric IGF-I/IGFBP-1 concentrations. Journal of Clinical Endocrinology and Metabolism. 2005;90(5):2941–2947.
    1. Weissberger AJ, Ho KK, Lazarus L. Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women. Journal of Clinical Endocrinology and Metabolism. 1991;72(2):374–381.
    1. Vandenput L, Boonen S, Van Herck E, Swinnen JV, Bouillon R, Vanderschueren D. Evidence from the aged orchidectomized male rat model that 17β-estradiol is a more effective bone-sparing and anabolic agent than 5α-dihydrotestosterone. Journal of Bone and Mineral Research. 2002;17(11):2080–2086.
    1. Christiansen JJ, Fisker S, Gravholt CH, et al. Discontinuation of estrogen replacement therapy in GH-treated hypopituitary women alters androgen status and IGF-I. European Journal of Endocrinology. 2005;152(5):719–726.
    1. Vanderschueren D, Vandenput L, Boonen S, Lindberg MK, Bouillon R, Ohlsson C. Androgens and bone. Endocrine Reviews. 2004;25(3):389–425.
    1. Kasperk CH, Wergedal JE, Farley JR, Linkhart TA, Turner RT, Baylink DJ. Androgens directly stimulate proliferation of bone cells in vitro. Endocrinology. 1989;124(3):1576–1578.
    1. Bi LX, Wiren KM, Zhang XW, et al. The effect of oxandrolone treatment on human osteoblastic cells. Journal of Burns and Wounds. 2007;6, article e4
    1. Venken K, De Gendt K, Boonen S, et al. Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model. Journal of Bone and Mineral Research. 2006;21(4):576–585.
    1. Prakasam G, Yeh JK, Chen M, Castro-Magana M, Liang CT, Aloia JF. Effects of growth hormone and testosterone on cortical bone formation and bone density in aged orchiectomized rats. Bone. 1999;24(5):491–497.
    1. Weissberger AJ, Ho KKY. Activation of the somatotropic axis by testosterone in adult males: evidence for the role of aromatization. Journal of Clinical Endocrinology and Metabolism. 1993;76(6):1407–1412.
    1. Gleeson HK, Shalet SM. Effect of aromatizable and unaromatizable androgen replacement in hypogonadal men on GH responsiveness. Clinical Endocrinology. 2009;70(1):109–115.
    1. Vanderschueren D, Boonen S, Ederveen AGH, et al. Skeletal effects of estrogen deficiency as induced by an aromatase inhibitor in an aged male rat model. Bone. 2000;27(5):611–617.
    1. Vanderschueren D, Van Herck E, Suiker AMH, Visser WJ, Schot LPC, Bouillon R. Bone and mineral metabolism in aged male rats: short and long term effects of androgen deficiency. Endocrinology. 1992;130(5):2906–2916.
    1. Kearns AE, Khosla S. Potential anabolic effects of androgens on bone. Mayo Clinic Proceedings. 2004;79(4):S14–S18.
    1. Hobbs CJ, Plymate SR, Rosen CJ, Adler RA. Testosterone administration increases insulin-like growth factor-I levels in normal men. The Journal of Clinical Endocrinology & Metabolism. 1993;77(3):776–779.
    1. Liu L, Merriam GR, Sherins RJ. Chronic sex steroid exposure increases mean plasma growth hormone concentration and pulse amplitude in men with isolated hypogonadotropic hypogonadism. Journal of Clinical Endocrinology and Metabolism. 1987;64(4):651–656.
    1. Jørgensen JOL, Vahl N, Hansen TB, et al. Determinants of serum insulin-like growth factor I in growth hormone deficient adults as compared to healthy subjects. Clinical Endocrinology. 1998;48(4):479–486.
    1. Chiang C, Chiu M, Moore AJ, et al. Mineralization and bone resorption are regulated by the androgen receptor in male mice. Journal of Bone and Mineral Research. 2009;24(4):621–631.
    1. Andersen TL, Sondergaard TE, Skorzynska KE, et al. A physical mechanism for coupling bone resorption and formation in adult human bone. The American Journal of Pathology. 2009;174(1):239–247.
    1. Kassem M, Blum W, Ristelli J, Mosekilde L, Eriksen EF. Growth hormone stimulates proliferation and differentiation of normal human osteoblast-like cells in vitro. Calcified Tissue International. 1993;52(3):222–226.
    1. Brixen K, Kassem M, Nielsen HK, Loft AG, Flyvbjerg A, Mosekilde L. Short-term treatment with growth hormone stimulates osteoblastic and osteoclastic activity in osteopenic postmenopausal women: a dose response study. Journal of Bone and Mineral Research. 1995;10(12):1865–1874.
    1. Krishnan V, Bryant HU, MacDougald OA. Regulation of bone mass by Wnt signaling. Journal of Clinical Investigation. 2006;116(5):1202–1209.
    1. Clevers H. Wnt/β-catenin signaling in development and disease. Cell. 2006;127(3):469–480.
    1. Cole MF, Johnstone SE, Newman JJ, Kagey MH, Young RA. Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells. Genes and Development. 2008;22(6):746–755.
    1. Canalis E, Deregowski V, Pereira RC, Gazzerro E. Signals that determine the fate of osteoblastic cells. Journal of Endocrinological Investigation. 2005;28(8):3–7.
    1. Takeuchi M, Kakushi H, Tohkin M. Androgens directly stimulate mineralization and increase androgen receptors in human osteoblast-like osteosarcoma cells. Biochemical and Biophysical Research Communications. 1994;204(2):905–911.
    1. Hou P, Sato T, Hofstetter W, Foged NT. Identification and characterization of the insulin-like growth factor I receptor in mature rabbit osteoclasts. Journal of Bone and Mineral Research. 1997;12(4):534–540.
    1. Niu T, Rosen CJ. The insulin-like growth factor-I gene and osteoporosis: a critical appraisal. Gene. 2005;361(1-2):38–56.
    1. Mazziotti G, Bianchi A, Bonadonna S, et al. Prevalence of vertebral fractures in men with acromegaly. Journal of Clinical Endocrinology and Metabolism. 2008;93(12):4649–4655.
    1. McCarthy TL, Centrella M. Regulation of IGF activity in bone. Advances in Experimental Medicine and Biology. 1993;343:407–414.
    1. Bichell DP, Rotwein P, McCarthy TL. Prostaglandin E2 rapidly stimulates insulin-like growth factor-I gene expression in primary rat osteoblast cultures: Evidence for transcriptional control. Endocrinology. 1993;133(3):1020–1028.
    1. Canalis E, Centrella M, Burch W, McCarthy TL. Insulin-like growth factor I mediates selective anabolic effects of parathyroid hormone in bone cultures. Journal of Clinical Investigation. 1989;83(1):60–65.
    1. Mccarthy TL, Centrella M, Raisz LG, Canalis E. Prostaglandin E2 stimulates insulin-like growth factor I synthesis in osteoblast-enriched cultures from fetal rat bone. Endocrinology. 1991;128(6):2895–2900.
    1. Locklin RM, Khosla S, Turner RT, Riggs BL. Mediators of the biphasic responses of bone to intermittent and continuously administered parathyroid hormone. Journal of Cellular Biochemistry. 2003;89(1):180–190.
    1. Ishizuya T, Yokose S, Hori M, et al. Parathyroid hormone exerts disparate effects on osteoblast differentiation depending on exposure time in rat osteoblastic cells. Journal of Clinical Investigation. 1997;99(12):2961–2970.
    1. Kassem M, Marie PJ. Senescence-associated intrinsic mechanisms of osteoblast dysfunctions. Aging Cell. 2011;10(2):191–197.
    1. Amin S, Riggs BL, Melton LJ, III, Achenbach SJ, Atkinson EJ, Khosla S. High serum IGFBP-2 is predictive of increased bone turnover in aging men and women. Journal of Bone and Mineral Research. 2007;22(6):799–807.
    1. DiGirolamo DJ, Mukherjee A, Fulzele K, et al. Mode of growth hormone action in osteoblasts. The Journal of Biological Chemistry. 2007;282(43):31666–31674.
    1. Rubin CT, Bain SD, McLeod KJ. Suppression of the osteogenic response in the aging skeleton. Calcified Tissue International. 1992;50(4):306–313.
    1. Bass SL, Eser P, Daly R. The effect of exercise and nutrition on the mechanostat. Journal of Musculoskeletal Neuronal Interactions. 2005;5(3):239–254.
    1. Bonjour JP. Protein intake and bone health. International Journal for Vitamin and Nutrition Research. 2011;81(2-3):134–142.
    1. Simkin A, Ayalon J, Leichter I. Increased trabecular bone density due to bone-loading exercises in postmenopausal osteoporotic women. Calcified Tissue International. 1987;40(2):59–63.
    1. Kelley GA, Kelley KS. Exercise and bone mineral density at the femoral neck in postmenopausal women: a meta-analysis of controlled clinical trials with individual patient data. American Journal of Obstetrics and Gynecology. 2006;194(3):760–767.
    1. Martyn-St James M, Carroll S. A meta-analysis of impact exercise on postmenopausal bone loss: the case for mixed loading exercise programmes. British Journal of Sports Medicine. 2009;43(12):898–908.
    1. Borer KT. Physical activity in the prevention and amelioration of osteoporosis in women: Interaction of mechanical, hormonal and dietary factors. Sports Medicine. 2005;35(9):779–830.
    1. Landin-Wilhelmsen K, Lundberg PA, Lappas G, Wilhelmsen L. Insulin-like growth factor I levels in healthy adults. Hormone Research. 2004;62(supplement 1):8–16.
    1. Bennett AE, Wahner HW, Riggs BL, Hintz RL. Insulin-like growth factors I and II: aging and bone density in women. Journal of Clinical Endocrinology and Metabolism. 1984;59(4):701–704.
    1. Callewaert F, Venken K, Kopchick JJ, et al. Sexual dimorphism in cortical bone size and strength but not density is determined by independent and time-specific actions of sex steroids and IGF-1: evidence from pubertal mouse models. Journal of Bone and Mineral Research. 2010;25(3):617–626.
    1. Wu Y, Sun H, Basta-Pljakic J, et al. Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor. Journal of Bone and Mineral Research. 2013;28(7):1575–1586.
    1. Bonadonna S, Burattin A, Nuzzo M, et al. Chronic glucocorticoid treatment alters spontaneous pulsatile parathyroid hormone secretory dynamics in human subjects. European Journal of Endocrinology. 2005;152(2):199–205.
    1. Manolagas SC, Weinstein RS. New developments in the pathogenesis and treatment of steroid-induced osteoporosis. Journal of Bone and Mineral Research. 1999;14(7):1061–1066.
    1. Berneis K, Oehri M, Kraenzlin M, Keller U. Effects of IGF-I combined with GH on glucocorticoid-induced changes of bone and connective tissue turnover in man. Journal of Endocrinology. 1999;162(2):259–264.
    1. Melmed S. Acromegaly. The New England Journal of Medicine. 1990;322(14):966–977.
    1. Ezzat S, Melmed S, Endres D, Eyre DR, Singer FR. Biochemical assessment of bone formation and resorption in acromegaly. Journal of Clinical Endocrinology and Metabolism. 1993;76(6):1452–1457.
    1. Marazuela M, Astigarraga B, Tabuenca MJ, Estrada J, Marin F, Lucas T. Serum bone Gla protein as a marker of bone turnover in acromegaly. Calcified Tissue International. 1993;52(6):419–421.
    1. Scillitani A, Battista C, Chiodini I, et al. Bone mineral density in acromegaly: the effect of gender, disease activity and gonadal status. Clinical Endocrinology. 2003;58(6):725–731.
    1. Kotzmann H, Bernecker P, Hubsch P, et al. Bone mineral density and parameters of bone metabolism in patients with acromegaly. Journal of Bone and Mineral Research. 1993;8(4):459–466.
    1. Lesse GP, Fraser WD, Farquharson R, Hipkin L, Vora JP. Gonadal status is an important determinant of bone density in acromegaly. Clinical Endocrinology. 1998;48(1):59–65.
    1. Kaji H, Sugimoto T, Nakaoka D, et al. Bone metabolism and body composition in Japanese patients with active acromegaly. Clinical Endocrinology. 2001;55(2):175–181.
    1. Ho PJ, Fig LM, Barkan AL, Shapiro B. Bone mineral density of the axial skeleton in acromegaly. Journal of Nuclear Medicine. 1992;33(9):1608–1612.
    1. Kayath MJ, Vieira JGH. Osteopenia occurs in a minority of patients with acromegaly and is predominant in the spine. Osteoporosis International. 1997;7(3):226–230.
    1. Chiodini I, Trischitta V, Carnevale V, Liuzzi A, Scillitani A. Bone mineral density in acromegaly: does growth hormone excess protect against osteoporosis? Journal of Endocrinological Investigation. 2001;24(4):288–291.
    1. Bolanowski M, Wielgus W, Milewicz A, Marciniak R. Axial bone mineral density in patients with acromegaly. Academic Radiology. 2000;7(8):592–594.
    1. Zgliczynski W, Kochman M, Misiorowski W, Zdunowski P. In acromegaly, increased bone mineral density (BMD) is determined by GH-excess, gonadal function and gender. Neuroendocrinology Letters. 2007;28(5):621–628.
    1. Vestergaard P, Mosekilde L. Fracture risk is decreased in acromegaly—a potential beneficial effect of growth hormone. Osteoporosis International. 2004;15(2):155–159.
    1. Biermasz NR, Hamdy NAT, Pereira AM, Romijn JA, Roelfsema F. Long-term maintenance of the anabolic effects of GH on the skeleton in successful treated patients with acromegaly. European Journal of Endocrinology. 2005;152(1):53–60.
    1. Broulik P, Kragstrup J, Mosekilde L, Melsen F. Osteon cross-sectional size in the iliac crest. Variation in normals and patients with osteoporosis, hyperparathyroidism, acromegaly, hypothyroidism and treated epilepsia. Acta Pathologica et Microbiologica Scandinavica A: Pathology. 1982;90(5):339–344.
    1. Halse J, Melsen F, Mosekilde L. Iliac crest bone mass and remodelling in acromegaly. Acta Endocrinologica. 1981;97(1):18–22.
    1. Riggs BL, Randall RV, Wahner HW, Jowsey J, Kelly PJ, Singh M. The nature of the metabolic bone disorder in acromegaly. The Journal of Clinical Endocrinology & Metabolism. 1972;34(6):911–918.
    1. Padova G, Borzì G, Incorvaia L, et al. Prevalence of osteoporosis and vertebral fractures in acromegalic patients. Clinical Cases in Mineral and Bone Metabolism. 2011;8(3):37–43.
    1. Madeira M, Neto LV, de Paula Paranhos Neto F, et al. Acromegaly has a negative influence on trabecular bone, but not on cortical bone, as assessed by high-resolution peripheral quantitative computed tomography. Journal of Clinical Endocrinology and Metabolism. 2013;98(4):1734–1741.
    1. Ueland T, Ebbesen EN, Thomsen JS, et al. Decreased trabecular bone biomechanical competence, apparent density, IGF-II and IGFBP-5 content in acromegaly. European Journal of Clinical Investigation. 2002;32(2):122–128.
    1. Bonadonna S, Mazziotti G, Nuzzo M, et al. Increased prevalence of radiological spinal deformities in active acromegaly: a cross-sectional study in postmenopausal women. Journal of Bone and Mineral Research. 2005;20(10):1837–1844.
    1. Mazziotti G, Bianchi A, Porcelli T, et al. Vertebral fractures in patients with acromegaly: a 3-year prospective study. Journal of Clinical Endocrinology and Metabolism. 2013;98(8):3402–3410.
    1. Claessen KM, Kroon HM, Pereira AM, et al. Progression of vertebral fractures despite long-term biochemical control of acromegaly: a prospective follow-up study. Journal of Clinical Endocrinology & Metabolism. Dec 2013;98(12):4808–4815.
    1. Mazziotti G, Gola M, Bianchi A, et al. Influence of diabetes mellitus on vertebral fractures in men with acromegaly. Endocrine. 2011;40(1):102–108.
    1. Wassenaar MJE, Biermasz NR, Hamdy NAT, et al. High prevalence of vertebral fractures despite normal bone mineral density in patients with long-term controlled acromegaly. European Journal of Endocrinology. 2011;164(4):475–483.
    1. Battista C, Chiodini I, Muscarella S, et al. Spinal volumetric trabecular bone mass in acromegalic patients: a longitudinal study. Clinical Endocrinology. 2009;70(3):378–382.
    1. Boutroy S, Bouxsein ML, Munoz F, Delmas PD. In vivo assessment of trabecular bone microarchitecture by high-resolution peripheral quantitative computed tomography. The Journal of Clinical Endocrinology & Metabolism. 2005;90(12):6508–6515.
    1. Nicks KM, Amin S, Atkinson EJ, Riggs BL, Melton LJ, III, Khosla S. Relationship of age to bone microstructure independent of areal bone mineral density. Journal of Bone and Mineral Research. 2012;27(3):637–644.
    1. Nishiyama KK, Macdonald HM, Buie HR, Hanley DA, Boyd SK. Postmenopausal women with osteopenia have higher cortical porosity and thinner cortices at the distal radius and tibia than women with normal aBMD: an in vivo HR-pQCT study. Journal of Bone and Mineral Research. 2010;25(4):882–890.
    1. Argoud T, Boutroy S, Claustrat B, Chapurlat R, Szulc P. Association between sex steroid levels and bone microarchitecture in men: the STRAMBO study. The Journal of Clinical Endocrinology & Metabolism. 2014;99(4):1400–1410.
    1. Holmes SJ, Whitehouse RW, Swindell R, Economou G, Adams JE, Shalet SM. Effect of growth hormone replacement on bone mass in adults with adult onset growth hormone deficiency. Clinical Endocrinology. 1995;42(6):627–633.
    1. Amato G, Izzo G, La Montagna G, Bellastella A. Low dose recombinant human growth hormone normalizes bone metabolism and cortical bone density and improves trabecular bone density in growth hormone deficient adults without causing adverse effects. Clinical Endocrinology. 1996;45(1):27–32.
    1. Hansen TB, Brixen K, Vahl N, et al. Effects of 12 months of growth hormone (GH) treatment on calciotropic hormones, calcium homeostasis, and bone metabolism in adults with acquired GH deficiency: a double blind, randomized, placebo-controlled study. Journal of Clinical Endocrinology and Metabolism. 1996;81(9):3352–3359.
    1. Thoren M, Soop M, Degerblad M, Saaf M. Preliminary study of the effects of growth hormone substitution therapy on bone mineral density and serum osteocalcin levels in adults with growth hormone deficiency. Acta Endocrinologica, 1993;128(supplement 2):41–43.
    1. Beshyah SA, Kyd P, Thomas E, Fairney A, Johnston DG. The effects of prolonged growth hormone replacement on bone metabolism and bone mineral density in hypopituitary adult. Clinical Endocrinology. 1995;42(3):249–254.
    1. Gómez JM, Gómez N, Fiter J, Soler J. Effects of long-term treatment with GH in the bone mineral density of adults with hypopituitarism and GH deficiency and after discontinuation of GH replacement. Hormone and Metabolic Research. 2000;32(2):66–70.
    1. Kotzmann H, Riedl M, Bernecker P, et al. Effect of long-term growth-hormone substitution therapy on bone mineral density and parameters of bone metabolism in adult patients with growth hormone deficiency. Calcified Tissue International. 1998;62(1):40–46.
    1. Johansson J, Landin K, Johannsson G, Tengborn L, Bengtsson B. Long-term treatment with growth hormone decreases plasminogen activator inhibitor-1 and tissue plasminogen activator in growth hormone-deficient adults. Thrombosis and Haemostasis. 1996;76(3):422–428.
    1. Götherström G, Bengtsson BA, Bossæus I, Johansson G, Svensson J. Ten-year GH replacement increase bone mineral density in hypopituitary patients with adult onset GH deficiency. European Journal of Endocrinology. 2007;156(1):55–64.
    1. Elbornsson M, Götherström G, Bosæus I, Bengtsson B, Johannsson G, Svensson J. Fifteen years of GH replacement increases bone mineral density in hypopituitary patients with adult-onset GH deficiency. European Journal of Endocrinology. 2012;166(5):787–795.
    1. Johannsson G, Rosén T, Bosaeus I, Sjöström L, Bengtsson B. Two years of growth hormone (GH) treatment increases bone mineral content and density in hypopituitary patients with adult-onset GH deficiency. Journal of Clinical Endocrinology and Metabolism. 1996;81(8):2865–2873.
    1. Mazziotti G, Bianchi A, Bonadonna S, et al. Increased prevalence of radiological spinal deformities in adult patients with GH deficiency: influence of GH replacement therapy. Journal of Bone and Mineral Research. 2006;21(4):520–528.
    1. Barake M, Klibanski A, Tritos NA. Effects of recombinant human growth hormone therapy on bone mineral density in adults with growth hormone deficiency: a meta-analysis. The Journal of Clinical Endocrinology & Metabolism. 2014;99(3):852–860.
    1. Cummings SR, Melton LJ., III Epidemiology and outcomes of osteoporotic fractures. The Lancet. 2002;359(9319):1761–1767.
    1. Looker AC, Orwoll ES, Johnston CC, Jr., et al. Prevalence of low femoral bone density in older U.S. adults from NHANES III. Journal of Bone and Mineral Research. 1997;12(11):1761–1768.
    1. Cole ZA, Dennison EM, Cooper C. Osteoporosis epidemiology update. Current Rheumatology Reports. 2008;10(2):92–96.
    1. Raisz LG. Pathogenesis of osteoporosis: concepts, conflicts, and prospects. Journal of Clinical Investigation. 2005;115(12):3318–3325.
    1. Khosla S, Riggs BL. Pathophysiology of age-related bone loss and osteoporosis. Endocrinology and Metabolism Clinics of North America. 2005;34(4):1015–1030.
    1. Perrini S, Laviola L, Carreira MC, Cignarelli A, Natalicchio A, Giorgino F. The GH/IGF1 axis and signaling pathways in the muscle and bone: mechanisms underlying age-related skeletal muscle wasting and osteoporosis. Journal of Endocrinology. 2010;205(3):201–210.
    1. Seeman E. Pathogenesis of bone fragility in women and men. The Lancet. 2002;359(9320):1841–1850.
    1. Khosla S, Melton LJ, III, Riggs BL. The unitary model for estrogen deficiency and the pathogenesis of osteoporosis: is a revision needed? Journal of Bone and Mineral Research. 2011;26(3):441–451.
    1. Garnero P, Sornay-Rendu E, Chapuy MC, Delmas PD. Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis. Journal of Bone and Mineral Research. 1996;11(3):337–349.
    1. Hannan MT, Felson DT, Dawson-Hughes B, et al. Risk factors for longitudinal bone loss in elderly men and women: the Framingham Osteoporosis Study. Journal of Bone and Mineral Research. 2000;15(4):710–720.
    1. Cooper C, Campion G, Melton LJ., III Hip fractures in the elderly: a world-wide projection. Osteoporosis International. 1992;2(6):285–289.
    1. Burger H, van Daele PLA, Grashuis K, et al. Vertebral deformities and functional impairment in men and women. Journal of Bone and Mineral Research. 1997;12(1):152–157.
    1. Thomas-John M, Codd MB, Manne S, Watts NB, Mongey A. Risk factors for the development of osteoporosis and osteoporotic fractures among older men. Journal of Rheumatology. 2009;36(9):1947–1952.
    1. Manolagas SC. From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. Endocrine Reviews. 2010;31(3):266–300.
    1. Ledger GA, Burritt MF, Kao PC, O'Fallon WM, Riggs BL, Khosla S. Role of parathyroid hormone in mediating nocturnal and age-related increases in bone resorption. Journal of Clinical Endocrinology & Metabolism. 1995;80(11):3304–3310.
    1. Nicolas V, Prewett A, Bettica P, et al. Age-related decreases in insulin-like growth factor-I and transforming growth factor-β in femoral cortical bone from both men and women: implications for bone loss with aging. Journal of Clinical Endocrinology and Metabolism. 1994;78(5):1011–1016.
    1. Ljunghall S, Johansson AG, Burman P, Kampe O, Lindh E, Karlsson FA. Low plasma levels of insulin-like growth factor 1 (IGF-1) in male patients with idiopathic osteoporosis. Journal of Internal Medicine. 1992;232(1):59–64.
    1. Maïmoun L, Coste O, Galtier F, et al. Bone mineral density acquisition in peripubertal female rhythmic gymnasts is directly associated with plasma IGF1/IGF-binding protein 3 ratio. European Journal of Endocrinology. 2010;163(1):157–164.
    1. Boonen S, Lesaffre E, Dequeker J, et al. Relationship between baseline insulin-like growth factor-I (IGF-I) and femoral bone density in women aged over 70 years: potential implications for the prevention of age-related bone loss. Journal of the American Geriatrics Society. 1996;44(11):1301–1306.
    1. Wuster C, Blum WF, Schlemilch S, Ranke MB, Ziegler R. Decreased serum levels of insulin-like growth factors and IGF binding protein 3 in osteoporosis. Journal of Internal Medicine. 1993;234(3):249–255.
    1. Khosla S, Atkinson EJ, Melton LJ, III, Riggs BL. Effects of age and estrogen status on serum parathyroid hormone levels and biochemical markers of bone turnover in women: a population-based study. The Journal of Clinical Endocrinology & Metabolism. 1997;82(5):1522–1527.
    1. Span JPT, Pieters GFFM, Sweep CGJ, Hermus ARMM, Smals AGH. Gender difference in insulin-like growth factor I response to growth hormone (GH) treatment in GH-deficient adults: Role of sex hormone replacement. Journal of Clinical Endocrinology and Metabolism. 2000;85(3):1121–1125.
    1. Nindl BC, Santtila M, Vaara J, Hakkinen K, Kyrolainen H. Circulating IGF-I is associated with fitness and health outcomes in a population of 846 young healthy men. Growth Hormone and IGF Research. 2011;21(3):124–128.
    1. Kraemer WJ, Dunn-Lewis C, Comstock BA, Thomas GA, Clark JE, Nindl BC. Growth hormone, exercise, and athletic performance: a continued evolution of complexity. Current Sports Medicine Reports. 2010;9(4):242–252.
    1. Gregory SM, Spiering BA, Alemany JA, et al. Exercise-induced insulin-like growth factor I system concentrations after training in women. Medicine and Science in Sports and Exercise. 2013;45(3):420–428.
    1. Henning PC, Scofield DE, Rarick KR, et al. Effects of acute caloric restriction compared to caloric balance on the temporal response of the IGF-I system. Metabolism: Clinical and Experimental. 2013;62(2):179–187.
    1. Chevalley T, Hoffmeyer P, Bonjour J, Rizzoli R. Early serum IGF-I response to oral protein supplements in elderly women with a recent hip fracture. Clinical Nutrition. 2010;29(1):78–83.
    1. Darling AL, Millward DJ, Torgerson DJ, Hewitt CE, Lanham-New SA. Dietary protein and bone health: a systematic review and meta-analysis. The American Journal of Clinical Nutrition. 2009;90(6):1674–1692.
    1. Franceschi C, Bonafè M, Valensin S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Annals of the New York Academy of Sciences. 2000;908:244–254.
    1. Nanes MS. Tumor necrosis factor-alpha: Molecular and cellular mechanisms in skeletal pathology. Gene. 2003;321(1-2):1–15.
    1. Wahl EC, Aronson J, Liu L, et al. Restoration of regenerative osteoblastogenesis in aged mice: modulation of TNF. Journal of Bone and Mineral Research. 2010;25(1):114–123.
    1. Boonen S, Lesaffre E, Aerssens J, Pelemans W, Dequeker J, Bouillon R. Deficiency of the growth hormone-insulin-like growth factor-1 axis potentially involved in age-related alterations in body composition. Gerontology. 1996;42(6):330–338.
    1. Veldhuis JD, Bowers CY. Human GH pulsatility: an ensemble property regulated by age and gender. Journal of Endocrinological Investigation. 2003;26(9):799–813.
    1. Benbassat CA, Maki KC, Unterman TG. Circulating levels of insulin-like growth factor (IGF) binding protein- 1 and -3 in aging men: relationships to insulin, glucose, IGF, and dehydroepiandrosterone sulfate levels and anthropometric measures. Journal of Clinical Endocrinology and Metabolism. 1997;82(5):1484–1491.
    1. Nasu M, Sugimoto T, Chihara M, Hiraumi M, Kurimoto F, Chihara K. Effect of natural menopause on serum levels of IGF-I and IGF-binding proteins: Relationship with bone mineral density and lipid metabolism in perimenopausal women. European Journal of Endocrinology. 1997;136(6):608–616.
    1. Romagnoli E, Minisola S, Carnevale V, et al. Circulating levels of insulin-like growth factor binding protein 3 (IGFBP-3) and insulin-like growth factor I (IGF-I) in perimenopausal women. Osteoporosis International. 1994;4(6):305–308.
    1. Muñoz-Torres M, Mezquita-Raya P, Lopez-Rodriguez F, Torres-Vela E, de Dios Luna J, Escobar-Jimenez F. The contribution of IGF-I to skeletal integrity in postmenopausal women. Clinical Endocrinology. 2001;55(6):759–766.
    1. Gillberg P, Olofsson H, Mallmin H, Blum WF, Ljunghall S, Nilsson AG. Bone mineral density in femoral neck is positively correlated to circulating insulin-like growth factor (IGF)-I and IGF-binding protein (IGFBP)-3 in Swedish men. Calcified Tissue International. 2002;70(1):22–29.
    1. Kruse HP, Kuhlencordt F. On an attempt to treat primary and secondary osteoporosis with human growth hormone. Hormone and Metabolic Research. 1975;7(6):488–491.
    1. Brixen K, Nielsen HK, Mosekilde L, Flyvbjerg A. A short course of recombinant human growth hormone treatment stimulates osteoblasts and activates bone remodeling in normal human volunteers. Journal of Bone and Mineral Research. 1990;5(6):609–618.
    1. Rudman D, Feller AG, Nagraj HS, et al. Effects of human growth hormone in men over 60 years old. The New England Journal of Medicine. 1990;323(1):1–6.
    1. Holloway L, Butterfield G, Hintz RL, Gesundheit N, Marcus R. Effects of recombinant human growth hormone on metabolic indices, body composition, and bone turnover in healthy elderly women. Journal of Clinical Endocrinology and Metabolism. 1994;79(2):470–479.
    1. Bianda T, Hussain MA, Glatz Y, Bouillon R, Froesch ER, Schmid C. Effects of short-term insulin-like growth factor-I or growth hormone treatment on bone turnover, renal phosphate reabsorption and 1,25 dihydroxyvitamin D3 production in healthy man. Journal of Internal Medicine. 1997;241(2):143–150.
    1. Clemmesen B, Overgaard K, Riis B, Christiansen C. Human growth hormone and growth hormone releasing hormone: a double-masked, placebo-controlled study of their effects on bone metabolism in elderly women. Osteoporosis International. 1993;3(6):330–336.
    1. Kassem M, Brixen K, Blum W, Mosekilde L, Eriksen EF. No evidence for reduced spontaneous or growth-hormone-stimulated serum levels of insulin-like growth factor (IGF)-I, IGF-II or IGF binding protein 3 in women with spinal osteoporosis. European Journal of Endocrinology. 1994;131(2):150–155.
    1. Erdtsieck RJ, Pols HAP, Valk NK, et al. Treatment of post-menopausal osteoporosis with a combination of growth hormone and pamidronate: a placebo controlled trial. Clinical Endocrinology. 1995;43(5):557–565.
    1. Holloway L, Kohlmeier L, Kent K, Marcus R. Skeletal effects of cyclic recombinant human growth hormone and salmon calcitonin in osteopenic postmenopausal women. Journal of Clinical Endocrinology and Metabolism. 1997;82(4):1111–1117.
    1. Kassem M, Brixen K, Mosekilde L, Blum WF, Flyvbjerg A. Effects of growth hormone treatment on serum levels of insulin-like growth factors (IGFs) and IGF binding proteins 1-4 in postmenopausal women. Clinical Endocrinology. 1998;49(6):747–756.
    1. Sugimoto T, Nakaoka D, Nasu M, Kanzawa M, Sugishita T, Chihara K. Effect of recombinant human growth hormone in elderly osteoporotic women. Clinical Endocrinology. 1999;51(6):715–724.
    1. Sääf M, Hilding A, Thorén M, Troell S, Hall K. Growth hormone treatment of osteoporotic postmenopausal women—a one-year placebo-controlled study. European Journal of Endocrinology. 1999;140(5):390–399.
    1. Sugimoto T, Kaji H, Nakaoka D, et al. Effect of low-dose of recombinant human growth hormone on bone metabolism in elderly women with osteoporosis. European Journal of Endocrinology. 2002;147(3):339–348.
    1. Gillberg P, Mallmin H, Petrén-Mallmin M, Ljunghall S, Nilsson AG. Two years of treatment with recombinant human growth hormone increases bone mineral density in men with idiopathic osteoporosis. Journal of Clinical Endocrinology & Metabolism. 2002;87(11):4900–4906.
    1. Landin-Wilhelmsen K, Nilsson A, Bosaeus I, Bengtsson B. Growth hormone increases bone mineral content in postmenopausal osteoporosis: a randomized placebo-controlled trial. Journal of Bone and Mineral Research. 2003;18(3):393–405.
    1. Joseph F, Ahmad AM, Ul-Haq M, et al. Effects of growth hormone administration on bone mineral metabolism, PTH sensitivity and PTH secretory rhythm in postmenopausal women with established osteoporosis. Journal of Bone and Mineral Research. 2008;23(5):721–729.
    1. Johansson AG, Lindh E, Blum WF, Kollerup G, Sørensen OH, Ljunghall S. Effects of growth hormone and insulin-like growth factor I in men with idiopathic osteoporosis. Journal of Clinical Endocrinology and Metabolism. 1996;81(1):44–48.
    1. White HD, Ahmad AM, Durham BH, et al. Growth hormone replacement is important for the restoration of parathyroid hormone sensitivity and improvement in bone metabolism in older adult growth hormone-deficient patients. Journal of Clinical Endocrinology and Metabolism. 2005;90(6):3371–3380.
    1. Ho KKY, Weissberger AJ. Impact of short-term estrogen administration on growth hormone secretion and action: distinct route-dependent effects on connective and bone tissue metabolism. Journal of Bone and Mineral Research. 1992;7(7):821–827.
    1. Marcus R, Butterfield G, Holloway L, et al. Effects of short term administration of recombinant human growth hormone to elderly people. Journal of Clinical Endocrinology and Metabolism. 1990;70(2):519–527.
    1. Bianda TL. Effects of growth hormone (GH) and insulin-like growth factor-I on serum leptin in GH-deficient adults. Diabetologia. 1997;40(3):363–364.
    1. Johansson AG, Lindh E, Ljunghall S. Insulin-like growth factor I stimulates bone turnover in osteoporosis. The Lancet. 1992;339(8809, article 1619)
    1. Ebeling PR, Jones JD, O'Fallon WM, Janes CH, Riggs BL. Short-term effects of recombinant human insulin-like growth factor I on bone turnover in normal women. Journal of Clinical Endocrinology and Metabolism. 1993;77(5):1384–1387.
    1. Rubin CD, Reed B, Sakhaee K, Pak CYC. Treating a patient with the Werner syndrome and osteoporosis using recombinant human insulin-like growth factor. Annals of Internal Medicine. 1994;121(9):665–668.
    1. Grinspoon SK, Baum HBA, Peterson S, Klibanski A. Effects of rhIGF-I administration on bone turnover during short-term fasting. Journal of Clinical Investigation. 1995;96(2):900–906.
    1. Ghiron LJ, Thompson JL, Holloway L, et al. Effects of recombinant insulin-like growth factor-I and growth hormone on bone turnover in elderly women. Journal of Bone and Mineral Research. 1995;10(12):1844–1852.
    1. Grinspoon S, Baum H, Lee K, Anderson E, Herzog D, Klibanski A. Effects of short-term recombinant human insulin-like growth factor I administration on bone turnover in osteopenic women with anorexia nervosa. Journal of Clinical Endocrinology and Metabolism. 1996;81(11):3864–3870.
    1. Mauras N, Doi SQ, Shapiro JR. Recombinant human insulin-like growth factor I, recombinant human growth hormone, and sex steroids: effects on markers of bone turnover in humans. Journal of Clinical Endocrinology and Metabolism. 1996;81(6):2222–2226.
    1. Friedlander AL, Butterfield GE, Moynihan S, et al. One year of insulin-like growth factor I treatment does not affect bone density, body composition, or psychological measures in postmenopausal women. The Journal of Clinical Endocrinology & Metabolism. 2001;86(4):1496–1503.
    1. Boonen S, Rosen C, Bouillon R, et al. Musculoskeletal effects of the recombinant human IGF-I/IGF binding protein-3 complex in osteoporotic patients with proximal femoral fracture: a double-blind, placebo-controlled pilot study. Journal of Clinical Endocrinology and Metabolism. 2002;87(4):1593–1599.
    1. Grinspoon S, Thomas L, Miller K, Herzog D, Klibanski A. Effects of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa. Journal of Clinical Endocrinology and Metabolism. 2002;87(6):2883–2891.
    1. Grinspoon S, Miller K, Herzog D, Clemmons D, Klibanski A. Effects of recombinant human insulin-like growth factor (IGF)-I and estrogen administration on IGF-I, IGF binding protein (IGFBP)-2, and IGFBP-3 in anorexia nervosa: a randomized-controlled study. Journal of Clinical Endocrinology and Metabolism. 2003;88(3):1142–1149.
    1. Misra M, McGrane J, Miller KK, et al. Effects of rhIGF-1 administration on surrogate markers of bone turnover in adolescents with anorexia nervosa. Bone. 2009;45(3):493–498.
    1. van der Lely AJ, Lamberts SW, Jauch KW, et al. Use of human GH in elderly patients with accidental hip fracture. European Journal of Endocrinology. 2000;143(5):585–592.
    1. Yeo A-L, Levy D, Martin FC, et al. Frailty and the biochemical effects of recombinant human growth hormone in women after surgery for hip fracture. Growth Hormone and IGF Research. 2003;13(6):361–370.
    1. Weissberger AJ, Anastasiadis AD, Sturgess I, Martin FC, Smith MA, Sönksen PH. Recombinant human growth hormone treatment in elderly patients undergoing elective total hip replacement. Clinical Endocrinology. 2003;58(1):99–107.
    1. Hedström M, Sääf M, Brosjö E, et al. Positive effects of short-term growth hormone treatment on lean body mass and BMC after a hip fracture: a double-blind placebo-controlled pilot study in 20 patients. Acta Orthopaedica Scandinavica. 2004;75(4):394–401.
    1. Raschke M, Højby Rasmussen M, Govender S, Segal D, Suntum M, Christiansen JS. Effects of growth hormone in patients with tibial fracture: a randomised, double-blind, placebo-controlled clinical trial. European Journal of Endocrinology. 2007;156(3):341–351.
    1. Krusenstjerna-Hafstrøm T, Rasmussen MH, Raschke M, Govender S, Madsen J, Christiansen JS. Biochemical markers of bone turnover in tibia fracture patients randomly assigned to growth hormone (GH) or placebo injections. Implications for detection of GH abuse. Growth Hormone and IGF Research. 2011;21(6):331–335.
    1. Johansson AG, Lindh E, Kollerup G, Ljunghal S. Dose-dependent of IGF-1 on the metabolism of collagen type I in male osteoporosis. Journal of Bone and Mineral Research. 1995;10, article S393
    1. Papavasiliou AV. Histological and biological changes in the epiphyseal plate during fracture healing. Journal of Orthopaedic Science. 2002;7(1):91–96.
    1. Mont MA, Jones LC, Einhorn TA, Hungerford DS, Reddi AH. Osteonecrosis of the femoral head: potential treatment with growth and differentiation factors. Clinical Orthopaedics and Related Research. 1998;(355):S314–S335.
    1. Lissenberg-Thunnissen SN, de Gorter DJJ, Sier CFM, Schipper IB. Use and efficacy of bone morphogenetic proteins in fracture healing. International Orthopaedics. 2011;35(9):1271–1280.
    1. Bail H, Raschke MJ, Kolbeck SF, Weiler A, Haahr PM, Haas NP. Recombinant growth hormone increasus callus maturation time in distraction osteogenesis—a histomorphometric study. Langenbecks Archiv für Chirurgie. 1998;115(supplement I):675–680.
    1. Cook SD, Baffes GC, Wolfe MW, Sampath TK, Rueger DC, Whitecloud TS., III The effect of recombinant human osteogenic protein-1 on healing of large segmental bone defects. Journal of Bone and Joint Surgery A. 1994;76(6):827–838.
    1. Kawaguchi H, Kurokawa T, Hanada K, et al. Stimulation of fracture repair by recombinant human basic fibroblast growth factor in normal and streptozotocin-diabetic rats. Endocrinology. 1994;135(2):774–781.
    1. Nielsen HM, Bak B, Jorgensen PH, Andreassen TT. Growth hormone promotes healing of tibial fractures in the rat. Acta Orthopaedica Scandinavica. 1991;62(3):244–247.
    1. Nash TJ, Howlett CR, Martin C, Steele J, Johnson KA, Hicklin DJ. Effect of platelet-derived growth factor on tibial osteotomies in rabbits. Bone. 1994;15(2):203–208.
    1. Spencer RF. The effect of head injury on fracture healing. A quantitative assessment. Journal of Bone and Joint Surgery B. 1987;69(4):525–528.
    1. Bidner SM, Rubins IM, Desjardins JV, Zukor DJ, Goltzman D. Evidence for a humoral mechanism for enhanced osteogenesis after head injury. Journal of Bone and Joint Surgery. 1990;72(8):1144–1149.
    1. Gazit D, Karmish M, Holzman L, Bab I. Regenerating marrow induces systemic increase in osteo- and chondrogenesis. Endocrinology. 1990;126(5):2607–2613.
    1. Weiss S, Henle P, Bidlingmaier M, Moghaddam A, Kasten P, Zimmermann G. Systemic response of the GH/IGF-I axis in timely versus delayed fracture healing. Growth Hormone and IGF Research. 2008;18(3):205–212.
    1. di Monaco M, Vallero F, Di Monaco R, Tappero R, Cavanna A. Serum levels of insulin-like growth factor-I are positively associated with functional outcome after hip fracture in elderly women. The American Journal of Physical Medicine and Rehabilitation. 2009;88(2):119–125.
    1. Johannsson G, Ohlsson C. Growth hormone therapy and fracture risk in the growth hormone-deficient adult. Bailliere's Clinical Endocrinology and Metabolism. 1998;12(2):233–250.
    1. Yang S, Cao L, Cai S, Yuan J, Wang J. A systematic review of growth hormone for hip fractures. Growth Hormone and IGF Research. 2012;22(3-4):97–101.
    1. Bistrian BR, Schwartz J, Istfan NW. Cytokines, muscle proteolysis, and the catabolic response to infection and inflammation. Proceedings of the Society for Experimental Biology and Medicine. 1992;200(2):220–223.
    1. Wilmore DW. Catabolic illness: Strategies for enhancing recovery. The New England Journal of Medicine. 1991;325(10):695–702.
    1. Cooney RN, Shumate M. The inhibitory effects of interleukin-1 on growth hormone action during catabolic illness. Vitamins & Hormones. 2006;74:317–340.
    1. von Laue S, Ross RJM. Inflammatory cytokines and acquired growth hormone resistance. Growth Hormone and IGF Research. 2000;10(S9):p. S14.
    1. Yumet G, Shumate ML, Bryant DP, Lang CH, Cooney RN. Hepatic growth hormone resistance during sepsis is associated with increased suppressors of cytokine signaling expression and impaired growth hormone signaling. Critical Care Medicine. 2006;34(5):1420–1427.
    1. Yumet G, Shumate ML, Bryant P, Lin C, Lang CH, Cooney RN. Tumor necrosis factor mediates hepatic growth hormone resistance during sepsis. American Journal of Physiology: Endocrinology and Metabolism. 2002;283(3):E472–E481.
    1. Ahmed TA, Buzzelli MD, Lang CH, et al. Interleukin-6 inhibits growth hormone-mediated gene expression in hepatocytes. American Journal of Physiolog: Gastrointestinal and Liver Physiology. 2007;292(6):G1793–G1803.
    1. Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocrine Reviews. 2007;28(1):20–47.
    1. Seccareccia E, Brodt P. The role of the insulin-like growth factor-I receptor in malignancy: an update. Growth Hormone & IGF Research. 2012;22(6):193–199.
    1. Deodati A, Ferroli BB, Cianfarani S. Association between growth hormone therapy and mortality, cancer and cardiovascular risk: systematic review and meta-analysis. Growth Hormone and IGF Research. 2014
    1. Carel JC, Ecosse E, Landier F, et al. Long-term mortality after recombinant growth hormone treatment for isolated growth hormone deficiency or childhood short stature: preliminary report of the French SAGhE study. Journal of Clinical Endocrinology and Metabolism. 2012;97(2):416–425.
    1. Sävendahl L, Maes M, Albertsson-Wikland K, et al. Long-term mortality and causes of death in isolated GHD, ISS, and SGA patients treated with recombinant growth hormone during childhood in Belgium, The Netherlands, and Sweden: Preliminary report of 3 countries participating in the EU SAGhE study. Journal of Clinical Endocrinology and Metabolism. 2012;97(2):E213–E217.
    1. Pekic S, Popovic V. GH therapy and cancer risk in hypopituitarism: what we know from human studies. European Journal of Endocrinology. 2013;169(5):R89–R97.
    1. Ergun-Longmire B, Mertens AC, Mitby P, et al. Growth hormone treatment and risk of second neoplasms in the childhood cancer survivor. Journal of Clinical Endocrinology and Metabolism. 2006;91(9):3494–3498.
    1. Popovic V, Mattsson AF, Gaillard RC, Wilton P, Kołtowska-Häggström M, Ranke MB. Serum insulin-like growth factor I (IGF-I), IGF-binding proteins 2 and 3, and the risk for development of malignancies in adults with growth hormone (GH) deficiency treated with GH: data from KIMS (Pfizer International Metabolic Database) Journal of Clinical Endocrinology and Metabolism. 2010;95(9):4449–4454.
    1. Xiang H, Wang Y, Nie S. Meta-analysis of the association between insulin-like growth factor binding protein 3 genetic polymorphisms and colorectal cancer susceptibility. PLoS ONE. 2013;8(3)e59665
    1. Chihara K, Kato Y, Kohno H, et al. Safety and efficacy of growth hormone (GH) during extended treatment of adult Japanese patients with GH deficiency (GHD) Growth Hormone and IGF Research. 2008;18(4):307–317.
    1. Mauras N, Rogol AD, Haymond MW, Veldhuis JD. Sex steroids, growth hormone, insulin-like growth factor-1: neuroendocrine and metabolic regulation in puberty. Hormone Research. 1996;45(1-2):74–80.
    1. Khosla S, Melton LJ, Riggs BL. Estrogens and bone health in men. Calcified Tissue International. 2001;69(4):189–192.

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