Horm Metab Res 2011; 43(1): 55-61
DOI: 10.1055/s-0030-1268006
Humans, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Inhibition of Growth Hormone Receptor Activation by Pegvisomant may Increase Bone Density in Acromegaly

C. Jimenez1 , M. Ayala-Ramirez1 , J. Liu2 , R. Nunez3 , R. F. Gagel1
  • 1Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
  • 2Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
  • 3Department of Nuclear Medicine, The M.D. Anderson Cancer Center, Madrid, Spain
Further Information

Publication History

received 05.06.2010

accepted 20.10.2010

Publication Date:
22 November 2010 (online)

Abstract

Treatment of acromegaly with pegvisomant lowers serum IGF-1 and raises serum growth hormone. As both IGF-1 and GH are important for bone growth and remodeling, we were concerned that lowering of IGF-1 could cause loss of bone. To evaluate the effects of treatment of acromegaly with pegvisomant on bone mineral density (BMD) we developed an observational, prospective study. 7 acromegaly patients participated in the study. Male and female subjects aged 18 years or more were eligible to participate. Patients were eugonadal or on adequate gonadal replacement therapy for at least 3 years before participating in the study. These patients were treated with a mean dosage of 20 mg of pegvisomant daily for up to 7 years. Bone mineral density (BMD) was evaluated by dual X-ray absorbtiometry (DXA) at baseline, 8, and 18 months as a part of a prospective trial and periodically thereafter. Baseline mean serum insulin-like growth factor-1 (IGF-1) concentration±SD was elevated in all patients (679.86±138.21 ng/ml). The IGF-1 concentrations at 18 months decreased significantly from baseline (p=0.016). Wilcoxon signed-rank tests showed significant increases in the spine BMD from baseline to 18 months (p=0.016) and significant increases in the right hip BMD from baseline to 18 months (p=0.032). The range of the increases was 4.3–17.8% at 7 years. It is concluded that successful treatment of acromegaly with pegvisomant increases BMD.

References

  • 1 Sjogren K, Bohlooly YM, Olsson B, Coschigano K, Tornell J, Mohan S, Isaksson OG, Baumann G, Kopchick J, Ohlsson C. Disproportional skeletal growth and markedly decreased bone mineral content in growth hormone receptor -/- mice.  Biochem Biophy Res Commun. 2000;  267 603-608
  • 2 Zhang M, Xuan S, Bouxsein ML, von Stechow D, Akeno N, Faugere MC, Malluche H, Zhao G, Rosen CJ, Efstratiadis A, Clemens TL. Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization.  J Biol Chem. 2002;  277 44005-44012
  • 3 Lupu F, Terwilliger JD, Lee K, Segre GV, Efstratiadis A. Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth.  Develop Biol. 2001;  229 141-162
  • 4 Rosen T, Wilhelmsen L, Landin-Wilhelmsen K, Lappas G, Bengtsson BA. Increased fracture frequency in adult patients with hypopituitarism and GH deficiency.  Eur J Endocrinol. 1997;  137 240-245
  • 5 Wuster C, Abs R, Bengtsson BA, Bennmarker H, Feldt-Rasmussen U, Hernberg-Stahl E, Monson JP, Westberg B, Wilton P. The influence of growth hormone deficiency, growth hormone replacement therapy, and other aspects of hypopituitarism on fracture rate and bone mineral density.  J Bone Miner Res. 2001;  16 398-405
  • 6 Brixen K, Hansen TB, Hauge E, Vahl N, Jorgensen JO, Christiansen JS, Mosekilde L, Hagen C, Melsen F. Growth hormone treatment in adults with adult-onset growth hormone deficiency increases iliac crest trabecular bone turnover: a 1-year, double-blind, randomized, placebo-controlled study.  J Bone Miner Res. 2000;  15 293-300
  • 7 Landin-Wilhelmsen K, Nilsson A, Bosaeus I, Bengtsson BA. Growth hormone increases bone mineral content in postmenopausal osteoporosis: a randomized placebo-controlled trial.  J Bone Miner Res. 2003;  18 393-405
  • 8 Scillitani A, Battista C, Chiodini I, Carnevale V, Fusilli S, Ciccarelli E, Terzolo M, Oppizzi G, Arosio M, Gasperi M, Arnaldi G, Colao A, Baldelli R, Ghiggi MR, Gaia D, Di Somma C, Trischitta V, Liuzzi A. Bone mineral density in acromegaly: the effect of gender, disease activity and gonadal status.  Clin Endocrinol (Oxf). 2003;  58 725-731
  • 9 Vestergaard P, Mosekilde L. Fracture risk is decreased in acromegaly – a potential beneficial effect of growth hormone.  Osteoporos Int. 2004;  15 155-159
  • 10 Mazziotti G, Bianchi A, Bonadonna S, Cimino V, Patelli I, Fusco A, Pontecorvi A, De Marinis L, Giustina A. Prevalence of vertebral fractures in men with acromegaly.  J Clin Endocrinol Metab. 2008;  93 4649-4655
  • 11 Bonadonna S, Mazziotti G, Nuzzo M, Bianchi A, Fusco A, De Marinis L, Giustina A. Increased prevalence of radiological spinal deformities in active acromegaly: a cross-sectional study in postmenopausal women.  J Bone Miner Res. 2005;  20 1837-1844
  • 12 Melmed S, Colao A, Barkan A, Molitch M, Grossman AB, Kleinberg D, Clemmons D, Chanson P, Laws E, Schlechte J, Vance ML, Ho K, Giustina A. Guidelines for acromegaly management: an update.  J Clin Endocrinol Metab. 2009;  94 1509-1517
  • 13 Castinetti F, Morange I, Dubois N, Albarel F, Conte-Devolx B, Dufour H, Brue T. Does first-line surgery still have its place in the treatment of acromegaly?.  Ann Endocrinol (Paris). 2009;  70 107-112
  • 14 Jenkins PJ, Bates P, Carson MN, Stewart PM, Wass JA. Conventional pituitary irradiation is effective in lowering serum growth hormone and insulin-like growth factor-I in patients with acromegaly.  J Clin Endocrinol Metab. 2006;  91 1239-1245
  • 15 Mullan K, Sanabria C, Abram P, McConnell M, Courtney H, Hunter S, McCance D, Leslie H, Sheridan B, Atkinson B. Long term effect of external pituitary irradiation on IGF1 levels in patients with acromegaly free of adjunctive treatment.  Eur J Endocrinol. 2009;  161 547-551
  • 16 Luque-Ramirez M, Portoles GR, Varela C, Albero R, Halperin I, Moreiro J, Soto A, Casamitjana R. The efficacy of octreotide LAR as firstline therapy for patients with newly diagnosed acromegaly is independent of tumor extension: predictive factors of tumor and biochemical response.  Horm Metab Res. 2010;  42 38-44
  • 17 van der Lely AJ, Hutson RK, Trainer PJ, Besser GM, Barkan AL, Katznelson L, Klibanski A, Herman-Bonert V, Melmed S, Vance ML, Freda PU, Stewart PM, Friend KE, Clemmons DR, Johannsson G, Stavrou S, Cook DM, Phillips LS, Strasburger CJ, Hackett S, Zib KA, Davis RJ, Scarlett JA, Thorner MO. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist.  Lancet. 2001;  358 1754-1759
  • 18 Kopchick JJ, Parkinson C, Stevens EC, Trainer PJ. Growth hormone receptor antagonists: discovery, development, and use in patients with acromegaly.  Endocr Rev. 2002;  23 623-646
  • 19 Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely AJ, Dimaraki EV, Stewart PM, Friend KE, Vance ML, Besser GM, Scarlett JA, Thorner MO, Parkinson C, Klibanski A, Powell JS, Barkan AL, Sheppard MC, Malsonado M, Rose DR, Clemmons DR, Johannsson G, Bengtsson BA, Stavrou S, Kleinberg DL, Cook DM, Phillips LS, Bidlingmaier M, Strasburger CJ, Hackett S, Zib K, Bennett WF, Davis RJ. Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant.  N Engl J Med. 2000;  342 1171-1177
  • 20 Schreiber I, Buchfelder M, Droste M, Forssmann K, Mann K, Saller B, Strasburger CJ. Treatment of acromegaly with the GH receptor antagonist pegvisomant in clinical practice: safety and efficacy evaluation from the German Pegvisomant Observational Study.  Eur J Endocrinol. 2007;  156 75-82
  • 21 Strasburger CJ, Buchfelder M, Droste M, Mann K, Stalla GK, Saller B. Experience from the German pegvisomant observational study.  Horm Res. 2007;  68 (S 05) 70-73
  • 22 Barkan AL, Burman P, Clemmons DR, Drake WM, Gagel RF, Harris PE, Trainer PJ, van der Lely AJ, Vance ML. Glucose homeostasis and safety in patients with acromegaly converted from long-acting octreotide to pegvisomant.  J Clin Endocrinol Metab. 2005;  90 5684-5691
  • 23 Higham CE, Rowles S, Russell-Jones D, Umpleby AM, Trainer PJ. Pegvisomant improves insulin sensitivity and reduces overnight free fatty acid concentrations in patients with acromegaly.  J Clin Endocrinol Metab. 2009;  94 2459-2463
  • 24 Colao A, Pivonello R, Auriemma RS, De Martino MC, Bidlingmaier M, Briganti F, Tortora F, Burman P, Kourides IA, Strasburger CJ, Lombardi G. Efficacy of 12-month treatment with the GH receptor antagonist pegvisomant in patients with acromegaly resistant to long-term, high-dose somatostatin analog treatment: effect on IGF-I levels, tumor mass, hypertension and glucose tolerance.  Eur J Endocrinol. 2006;  154 467-477
  • 25 Fairfield WP, Sesmilo G, Katznelson L, Pulaski K, Freda PU, Stavrou S, Kleinberg D, Klibanski A. Effects of a growth hormone receptor antagonist on bone markers in acromegaly.  Clin Endocrinol (Oxf). 2002;  57 385-390
  • 26 Parkinson C, Kassem M, Heickendorff L, Flyvbjerg A, Trainer PJ. Pegvisomant-induced serum insulin-like growth factor-I normalization in patients with acromegaly returns elevated markers of bone turnover to normal.  J Clin Endocrinol Metab. 2003;  88 5650-5655
  • 27 Drake WM, Rodriguez-Arnao J, Weaver JU, James IT, Coyte D, Spector TD, Besser GM, Monson JP. The influence of gender on the short and long-term effects of growth hormone replacement on bone metabolism and bone mineral density in hypopituitary adults: a 5-year study.  Clin Endocrinol (Oxf). 2001;  54 525-532
  • 28 Jimenez C, Burman P, Abs R, Clemmons DR, Drake WM, Hutson KR, Messig M, Thorner MO, Trainer PJ, Gagel RF. Follow-up of pituitary tumor volume in patients with acromegaly treated with pegvisomant in clinical trials.  Eur J Endocrinol. 2008;  159 517-523
  • 29 Mode A, Tollet P, Wells T, Carmignac DF, Clark RG, Chen WY, Kopchick JJ, Robinson IC. The human growth hormone (hGH) antagonist G120RhGH does not antagonize GH in the rat, but has paradoxical agonist activity, probably via the prolactin receptor.  Endocrinology. 1996;  137 447-454
  • 30 Pekhletsky RI, Chernov BK, Rubtsov PM. Variants of the 5′-untranslated sequence of human growth hormone receptor mRNA.  Mol Cell Endocrinol. 1992;  90 103-109
  • 31 Clement-Lacroix P, Ormandy C, Lepescheux L, Ammann P, Damotte D, Goffin V, Bouchard B, Amling M, Gaillard-Kelly M, Binart N, Baron R, Kelly PA. Osteoblasts are a new target for prolactin: analysis of bone formation in prolactin receptor knockout mice.  Endocrinology. 1999;  140 96-105
  • 32 Nilsson A, Swolin D, Enerback S, Ohlsson C. Expression of functional growth hormone receptors in cultured human osteoblast-like cells.  J Clin Endocrinol Metab. 1995;  80 3483-3488
  • 33 Morel G, Chavassieux P, Barenton B, Dubois PM, Meunier PJ, Boivin G. Evidence for a direct effect of growth hormone on osteoblasts.  Cell Tissue Res. 1993;  273 279-286
  • 34 Slootweg MC, Salles JP, Ohlsson C, de Vries CP, Engelbregt MJ, Netelenbos JC. Growth hormone binds to a single high affinity receptor site on mouse osteoblasts: modulation by retinoic acid and cell differentiation.  J Endocrinol. 1996;  150 465-472
  • 35 Hill PA, Tumber A, Meikle MC. Multiple extracellular signals promote osteoblast survival and apoptosis.  Endocrinology. 1997;  138 3849-3858
  • 36 Guicheux J, Heymann D, Rousselle AV, Gouin F, Pilet P, Yamada S, Daculsi G. Growth hormone stimulatory effects on osteoclastic resorption are partly mediated by insulin-like growth factor I: an in vitro study.  Bone. 1998;  22 25-31
  • 37 Giustina A, Mazziotti G, Canalis E. Growth hormone, insulin-like growth factors, and the skeleton.  Endocr Rev. 2008;  29 535-559
  • 38 Piovesan A, Terzolo M, Reimondo G, Pia A, Codegone A, Osella G, Boccuzzi A, Paccotti P, Angeli A. Biochemical markers of bone and collagen turnover in acromegaly or Cushing's syndrome.  Horm Metab Res. 1994;  26 234-237

Correspondence

Asst. Prof. Camilo Jimenez
MD, Prof. Robert F. GagelMD 

Department of Endocrine Neoplasia

and Hormonal Disorders

Unit 1461

The University of Texas M. D.

Anderson Cancer Center

1400 Pressler Street

Houston 77030

Texas

USA

Phone: +1/713/792 2841

Fax: +1/713/794 4065

Email: cjimenez@mdanderson.org

Email: rgagel@mdanderson.org

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