Skip to main content
SpringerLink
Log in

Predictors of Bone Responsiveness to Growth Hormone (GH) Replacement in Adult GH-Deficient Patients

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Growth hormone (GH) replacement in adulthood results in variable bone responses as a function of the gonadic hormonal milieu. We performed a retrospective analysis of a large cohort of adult males and females with confirmed GH deficiency (GHD) prior to treatment and during 3 years of replacement therapy. Potential confounders and effect modifiers were taken into account. Sixty-four adult patients with GHD (20 females and 44 males; mean age 34 years, range 18–64) were included in the analysis. GH replacement induced a different effect on bone in males compared to females. Bone mineral content increased in males and decreased in females at the lumbar spine, total femur, and femoral neck; bone mineral density showed a similar trend at the lumbar spine and femoral neck. There was no significant gender difference in bone area at any measured bone site. In both sexes we observed a similar trend for serum markers of bone remodeling. Sex predicted bone outcome on multivariate analysis, as did age, onset of GHD (childhood/adulthood), pretreatment bone mass, baseline body mass index (BMI), and BMI change during GH replacement. Serum IGF-I levels during treatment did not show any relationship with bone outcome at any measured site. This study confirms that bone responsiveness to GH replacement in adult GHD varies as a function of sex even after controlling for potential confounders and highlights the importance of other cofactors that may affect the interaction between GH replacement therapy and bone remodeling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. de Boer H, Blok GJ, van Lingen A, Teule GJ, Lips P, van der Veen EA (1994) Consequences of childhood-onset growth hormone deficiency for adult bone mass. J Bone Miner Res 9:1319–1326

    Article  PubMed  Google Scholar 

  2. Rosen T, Wilhelmsen L, Landin-Wilhelmsen K, Lappas G, Bengtsson BA (1997) Increased fracture frequency in adult patients with hypopituitarism and GH deficiency. Eur J Endocrinol 137:240–245

    Article  PubMed  CAS  Google Scholar 

  3. Mazziotti G, Bianchi A, Bonadonna S, Nuzzo M, Cimino V, Fusco A, De Marinis L, Giustina A (2006) Increased prevalence of radiological spinal deformities in adult patients with GH deficiency: influence of GH replacement therapy. J Bone Miner Res 21:520–528

    Article  PubMed  CAS  Google Scholar 

  4. Holmes SJ, Economou G, Whitehouse RW, Adams JE, Shalet SM (1994) Reduced bone mineral density in patients with adult onset growth hormone deficiency. J Clin Endocrinol Metab 78:669–674

    Article  PubMed  CAS  Google Scholar 

  5. Rosen T, Hansson T, Granhed H, Szucs J, Bengtsson BA (1993) Reduced bone mineral content in adult patients with growth hormone deficiency. Acta Endocrinol (Copenh) 129:201–206

    CAS  Google Scholar 

  6. Beshyah SA, Freemantle C, Thomas E, Rutherford O, Page B, Murphy M, Johnston DG (1995) Abnormal body composition and reduced bone mass in growth hormone deficient hypopituitary adults. Clin Endocrinol (Oxf) 42:179–189

    Article  CAS  Google Scholar 

  7. Hitz MF, Jensen JE, Eskildsen PC (2006) Bone mineral density in patients with growth hormone deficiency: does a gender difference exist? Clin Endocrinol (Oxf) 65:783–791

    Article  CAS  Google Scholar 

  8. Holmer H, Svensson J, Rylander L, Johannsson G, Rosen T, Bengtsson BA, Thoren M, Hoybye C, Degerblad M, Bramnert M, Hagg E, Engstrom BE, Ekman B, Thorngren KG, Hagmar L, Erfurth EM (2007) Fracture incidence in GH-deficient patients on complete hormone replacement including GH. J Bone Miner Res 22:1842–1850

    Article  PubMed  Google Scholar 

  9. Johannsson G, Rosen T, Bosaeus I, Sjostrom L, Bengtsson BA (1996) Two years of growth hormone (GH) treatment increases bone mineral content and density in hypopituitary patients with adult-onset GH deficiency. J Clin Endocrinol Metab 81:2865–2873

    Article  PubMed  CAS  Google Scholar 

  10. Valimaki MJ, Salmela PI, Salmi J, Viikari J, Kataja M, Turunen H, Soppi E (1999) Effects of 42 months of GH treatment on bone mineral density and bone turnover in GH-deficient adults. Eur J Endocrinol 140:545–554

    Article  PubMed  CAS  Google Scholar 

  11. Blok GJ, de Boer H, Gooren LJ, van der Veen EA (1997) Growth hormone substitution in adult growth hormone-deficient men augments androgen effects on the skin. Clin Endocrinol (Oxf) 47:29–36

    Article  CAS  Google Scholar 

  12. Gatford KL, Egan AR, Clarke IJ, Owens PC (1998) Sexual dimorphism of the somatotrophic axis. J Endocrinol 157:373–389

    Article  PubMed  CAS  Google Scholar 

  13. Vanderschueren D, Venken K, Ophoff J, Bouillon R, Boonen S (2006) Sex steroids and the periosteum—reconsidering the roles of androgens and estrogens in periosteal expansion. J Clin Endocrinol Metab 91:378–382

    Article  PubMed  CAS  Google Scholar 

  14. Burman P, Johansson AG, Siegbahn A, Vessby B, Karlsson FA (1997) Growth hormone (GH)-deficient men are more responsive to GH replacement therapy than women. J Clin Endocrinol Metab 82:550–555

    Article  PubMed  CAS  Google Scholar 

  15. Gotherstrom G, Svensson J, Koranyi J, Alpsten M, Bosaeus I, Bengtsson B, Johannsson G (2001) A prospective study of 5 years of GH replacement therapy in GH-deficient adults: sustained effects on body composition, bone mass, and metabolic indices. J Clin Endocrinol Metab 86:4657–4665

    Article  PubMed  CAS  Google Scholar 

  16. Johansson AG, Engstrom BE, Ljunghall S, Karlsson FA, Burman P (1999) Gender differences in the effects of long term growth hormone (GH) treatment on bone in adults with GH deficiency. J Clin Endocrinol Metab 84:2002–2007

    Article  PubMed  CAS  Google Scholar 

  17. Johansson AG (1999) Gender difference in growth hormone response in adults. J Endocrinol Invest 22:58–60

    PubMed  CAS  Google Scholar 

  18. Drake WM, Rodriguez-Arnao J, Weaver JU, James IT, Coyte D, Spector TD, Besser GM, Monson JP (2001) 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) 54:525–532

    Article  CAS  Google Scholar 

  19. Bex M, Abs R, Maiter D, Beckers A, Lamberigts G, Bouillon R (2002) The effects of growth hormone replacement therapy on bone metabolism in adult-onset growth hormone deficiency: a 2-year open randomized controlled multicenter trial. J Bone Miner Res 17:1081–1094

    Article  PubMed  CAS  Google Scholar 

  20. Snyder PJ, Biller BM, Zagar A, Jackson I, Arafah BM, Nippoldt TB, Cook DM, Mooradian AD, Kwan A, Scism-Bacon J, Chipman JJ, Hartman ML (2007) Effect of growth hormone replacement on BMD in adult-onset growth hormone deficiency. J Bone Miner Res 22:762–770

    Article  PubMed  CAS  Google Scholar 

  21. Rota F, Savanelli MC, Tauchmanova L, Savastano S, Lombardi G, Colao A, Di Somma C (2008) Bone density and turnover in young adult patients with growth hormone deficiency after 2-year growth hormone replacement according with gender. J Endocrinol Invest 31:94–102

    PubMed  CAS  Google Scholar 

  22. Baim S, Binkley N, Bilezikian JP, Kendler DL, Hans DB, Lewiecki EM, Silverman S (2008) Official positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Position Development Conference. J Clin Densitom 11:75–91

    Article  PubMed  Google Scholar 

  23. Roelfsema F, Janssen YJ (1999) Influence of gender on response to growth hormone substitution therapy in adults with growth hormone deficiency. In: Veldhuis J, Giustina A (eds) Sex steroid interactions with growth hormone. Springer, New York, pp 209–218

    Google Scholar 

  24. Koranyi J, Svensson J, Gotherstrom G, Sunnerhagen KS, Bengtsson B, Johannsson G (2001) Baseline characteristics and the effects of five years of GH replacement therapy in adults with GH deficiency of childhood or adulthood onset: a comparative, prospective study. J Clin Endocrinol Metab 86:4693–4699

    Article  PubMed  CAS  Google Scholar 

  25. Giustina A, Mazziotti G, Canalis E (2008) Growth hormone, insulin-like growth factors, and the skeleton. Endocr Rev 29:535–559

    Article  PubMed  CAS  Google Scholar 

  26. Abrahamsen B, Hangaard J, Horn HC, Hansen TB, Gregersen G, Hansen-Nord M, Vahl N, Junker P, Andersen M, Hagen C (2002) Evaluation of the optimum dose of growth hormone (GH) for restoring bone mass in adult-onset GH deficiency: results from two 12-month randomized studies. Clin Endocrinol (Oxf) 57:273–281

    Article  CAS  Google Scholar 

  27. Biermasz NR, Hamdy NA, Pereira AM, Romijn JA, Roelfsema F (2004) Long-term skeletal effects of recombinant human growth hormone (rhGH) alone and rhGH combined with alendronate in GH-deficient adults: a seven-year follow-up study. Clin Endocrinol (Oxf) 60:568–575

    Article  CAS  Google Scholar 

  28. Ueland T, Bollerslev J, Flyvbjerg A, Hansen TB, Vahl N, Mosekilde L (2002) Effects of 12 months of GH treatment on cortical and trabecular bone content of IGFs and OPG in adults with acquired GH deficiency: a double-blind, randomized, placebo-controlled study. J Clin Endocrinol Metab 87:2760–2763

    Article  PubMed  CAS  Google Scholar 

  29. Ueland T, Bollerslev J, Hansen TB, Ebbesen EN, Mosekilde L, Brixen K, Flyvbjerg A, Djoseland O (1999) Increased cortical bone content of insulin-like growth factors in acromegalic patients. J Clin Endocrinol Metab 84:123–127

    Article  PubMed  CAS  Google Scholar 

  30. Lanzi R, Losa M, Villa I, Gatti E, Sirtori M, Dal FC, Rubinacci A (2003) GH replacement therapy increases plasma osteoprotegerin levels in GH-deficient adults. Eur J Endocrinol 148:185–191

    Article  PubMed  CAS  Google Scholar 

  31. Mrak E, Villa I, Lanzi R, Losa M, Guidobono F, Rubinacci A (2007) Growth hormone stimulates osteoprotegerin expression and secretion in human osteoblast-like cells. J Endocrinol 192:639–645

    Article  PubMed  CAS  Google Scholar 

  32. Leung KC, Johannsson G, Leong GM, Ho KK (2004) Estrogen regulation of growth hormone action. Endocr Rev 25:693–721

    Article  PubMed  CAS  Google Scholar 

  33. Klefter O, Feldt-Rasmussen U (2009) Is increase in bone mineral content caused by increase in skeletal muscle mass/strength in adult patients with GH-treated GH deficiency? A systematic literature analysis. Eur J Endocrinol 161:213–221

    Article  PubMed  CAS  Google Scholar 

  34. Roemmler J, Kuenkler M, Otto B, Arafat AM, Bidlingmaier M, Schopohl J (2009) Influence of long-term growth hormone replacement on leptin and ghrelin in GH deficiency before and after glucose load. Regul Pept 158:40–46

    Article  PubMed  CAS  Google Scholar 

  35. Eden EB, Burman P, Holdstock C, Karlsson FA (2003) Effects of growth hormone (GH) on ghrelin, leptin, and adiponectin in GH-deficient patients. J Clin Endocrinol Metab 88:5193–5198

    Article  Google Scholar 

  36. Thomas T, Burguera B, Melton LJ III, Atkinson EJ, O’Fallon WM, Riggs BL, Khosla S (2001) Role of serum leptin, insulin, and estrogen levels as potential mediators of the relationship between fat mass and bone mineral density in men versus women. Bone 29:114–120

    Article  PubMed  CAS  Google Scholar 

  37. Weiss LA, Barrett-Connor E, von Mühlen D, Clark P (2006) Leptin predicts BMD and bone resorption in older women but not older men: the Rancho Bernardo study. J Bone Miner Res 21:758–764

    Article  PubMed  CAS  Google Scholar 

  38. Clegg DJ, Brown LM, Woods SC, Benoit SC (2006) Gonadal hormones determine sensitivity to central leptin and insulin. Diabetes 55:978–987

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Endocrinology Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy

    Alessandro Rossini, Roberto Lanzi, Elisa Gatti, Sara Madaschi, Chiara Molinari & Marina Scavini

  2. Neurosurgery Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy

    Marco Losa

  3. Bone Metabolic Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy

    Marcella Sirtori, Isabella Villa & Alessandro Rubinacci

Authors
  1. Alessandro Rossini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roberto Lanzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marco Losa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marcella Sirtori
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Elisa Gatti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sara Madaschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chiara Molinari
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Isabella Villa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marina Scavini
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alessandro Rubinacci
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alessandro Rubinacci.

Additional information

The authors have stated that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rossini, A., Lanzi, R., Losa, M. et al. Predictors of Bone Responsiveness to Growth Hormone (GH) Replacement in Adult GH-Deficient Patients. Calcif Tissue Int 88, 304–313 (2011). https://doi.org/10.1007/s00223-010-9459-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-010-9459-8

Keywords

Search

Navigation