Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Skeletal disorders associated with the growth hormone–insulin-like growth factor 1 axis

Abstract

Growth hormone (GH) and insulin-like growth factor 1 (IGF1) are important regulators of bone remodelling and metabolism and have an essential role in the achievement and maintenance of bone mass throughout life. Evidence from animal models and human diseases shows that both GH deficiency (GHD) and excess are associated with changes in bone remodelling and cause profound alterations in bone microstructure. The consequence is an increased risk of fractures in individuals with GHD or acromegaly, a condition of GH excess. In addition, functional perturbations of the GH–IGF1 axis, encountered in individuals with anorexia nervosa and during ageing, result in skeletal fragility and osteoporosis. The effect of interventions used to treat GHD and acromegaly on the skeleton is variable and dependent on the duration of the disease, the pre-existing skeletal state, coexistent hormone alterations (such as those occurring in hypogonadism) and length of therapy. This variability could also reflect the irreversibility of the skeletal structural defect occurring during alterations of the GH–IGF1 axis. Moreover, the effects of the treatment of GHD and acromegaly on locally produced IGF1 and IGF binding proteins are uncertain and in need of further study. This Review highlights the pathophysiological, clinical and therapeutic aspects of skeletal fragility associated with perturbations in the GH–IGF1 axis.

Key points

  • Most of the actions of the growth hormone (GH)–insulin-like growth factor 1 (IGF1) axis on the skeleton are mediated by IGF1, either synthesized by the liver or locally produced by skeletal cells.

  • In GH deficiency (GHD) caused by pituitary disease, osteoblastogenesis is impaired and bone strength is decreased, with a consequent increase in the risk of vertebral and non-vertebral fractures.

  • In patients with GHD, replacement therapy with recombinant GH decreases the risk of fractures prior to the onset of changes in bone mineral density.

  • In individuals with uncontrolled acromegaly, a deterioration of bone architecture and increase in the risk of vertebral fractures occurs due to long-term exposure to excess GH and IGF1.

  • Biochemical control of GH hypersecretion in acromegaly does not necessarily restore normal bone architecture and the risk of fractures can persist.

  • Specific scenarios associated with dysregulation of the GH–IGF1 axis (for example, anorexia nervosa and ageing) are associated with skeletal fragility and increased risk of fracture.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Physiological actions of the GH–IGF1 axis in bone.
Fig. 2: The role of the GH–IGF1 axis in disease-driven alterations in bone structure.
Fig. 3: Managing skeletal fragility in individuals with suspected disorders of the GH–IGF1 axis.

Similar content being viewed by others

References

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mazziotti, G., Frara, S. & Giustina, A. Pituitary diseases and bone. Endocr. Rev. 39, 440–488 (2018).

    Article  PubMed  Google Scholar 

  3. Schorr, M. & Miller, K. K. The endocrine manifestations of anorexia nervosa: mechanisms and management. Nat. Rev. Endocrinol. 13, 174–186 (2017).

    Article  CAS  PubMed  Google Scholar 

  4. Canalis, E., Centrella, M., Burch, W. & McCarthy, T. L. Insulin-like growth factor I mediates selective anabolic effects of parathyroid hormone in bone cultures. J. Clin. Invest. 83, 60–65 (1989). The seminal study shows that IGF1 mediates the skeletal effects of PTH.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Miyakoshi, N., Kasukawa, Y., Linkhart, T. A., Baylink, D. J. & Mohan, S. Evidence that anabolic effects of PTH on bone require IGF-I in growing mice. Endocrinology 142, 4349–4356 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Playford, M. P., Bicknell, D., Bodmer, W. F. & Macaulay, V. M. Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of beta-catenin. Proc. Natl Acad. Sci. USA 97, 12103–12108 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Canalis, E., Rydziel, S., Delany, A. M., Varghese, S. & Jeffrey, J. J. Insulin-like growth factors inhibit interstitial collagenase synthesis in bone cell cultures. Endocrinology 136, 1348–1354 (1995).

    Article  CAS  PubMed  Google Scholar 

  8. Ueland, T. GH/IGF-I and bone resorption in vivo and in vitro. Eur. J. Endocrinol. 152, 327–332 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Wang, Y. et al. Role of IGF-I signaling in regulating osteoclastogenesis. J. Bone Miner. Res. 21, 1350–1358 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Zhang, M. 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. J. Biol. Chem. 277, 44005–44012 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Liu, Z. et al. Mitochondrial function is compromised in cortical bone osteocytes of long-lived growth hormone receptor null mice. J. Bone Miner. Res. 34, 106–122 (2019).

    Article  CAS  PubMed  Google Scholar 

  12. Yakar, S. et al. Serum IGF-1 determines skeletal strength by regulating subperiosteal expansion and trait interactions. J. Bone Miner. Res. 24, 1481–1492 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lim, S. V. et al. Excessive growth hormone expression in male GH transgenic mice adversely alters bone architecture and mechanical strength. Endocrinology 156, 1362–1371 (2015). A study performed in GH transgenic mice demonstrating that GH and IGF1 excess causes alterations in bone microstructure.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Liao, L. et al. Liver-specific overexpression of the insulin-like growth factor-I enhances somatic growth and partially prevents the effects of growth hormone deficiency. Endocrinology 147, 3877–3888 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Zhao, G. et al. Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. Endocrinology 141, 2674–2682 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Hwa, V., Oh, Y. & Rosenfeld, R. G. The insulin-like growth factor-binding protein (IGFBP) superfamily. Endocr. Rev. 20, 761–787 (1999).

    CAS  PubMed  Google Scholar 

  17. DeMambro, V. E. et al. Gender-specific changes in bone turnover and skeletal architecture in IGFBP-2-null mice. Endocrinology 149, 2051–2061 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Xi, G., Wai, C., DeMambro, V., Rosen, C. J. & Clemmons, D. R. IGFBP-2 directly stimulates osteoblast differentiation. J. Bone Miner. Res. 29, 2427–2438 (2014). This study provides evidence that IGFBP2 has direct effects on osteoblasts that are independent of IGF1.

    Article  CAS  PubMed  Google Scholar 

  19. DeMambro, V. E. et al. Insulin-like growth factor-binding protein-2 is required for osteoclast differentiation. J. Bone Miner. Res. 27, 390–400 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. DeMambro, V. E. et al. Igfbp2 deletion in ovariectomized mice enhances energy expenditure but accelerates bone loss. Endocrinology 156, 4129–4140 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Xi, G., Wai, C., Rosen, C. J. & Clemmons, D. R. A peptide containing the receptor binding site of insulin-like growth factor binding protein-2 enhances bone mass in ovariectomized rats. Bone Res. 6, 23 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Zhang, M. et al. Paracrine overexpression of IGFBP-4 in osteoblasts of transgenic mice decreases bone turnover and causes global growth retardation. J. Bone Miner. Res. 18, 836–843 (2003). A study providing evidence that IGFBP4 has direct effects on bone remodelling that are independent of IGF1.

    Article  CAS  PubMed  Google Scholar 

  23. Maridas, D. E. et al. IGFBP-4 regulates adult skeletal growth in a sex-specific manner. J. Endocrinol. 233, 131–144 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Durant, D., Pereira, R. M. & Canalis, E. Overexpression of insulin-like growth factor binding protein-5 decreases osteoblastic function in vitro. Bone 35, 1256–1262 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Miyakoshi, N. et al. Systemic administration of insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) increases bone formation parameters in mice by increasing IGF bioavailability via an IGFBP-4 protease-dependent mechanism. Endocrinology 142, 2641–2648 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Domené, H. M., Bengolea, S. V., Jasper, H. G. & Boisclair, Y. R. Acid-labile subunit deficiency: phenotypic similarities and differences between human and mouse. J. Endocrinol. Invest. 28, 43–46 (2005).

    PubMed  Google Scholar 

  27. Fritton, J. C. et al. The insulin-like growth factor-1 binding protein acid-labile subunit alters mesenchymal stromal cell fate. J. Biol. Chem. 285, 4709–4714 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Yakar, S. et al. Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism. FASEB J. 23, 709–719 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pereira, R. C. & Canalis, E. Parathyroid hormone increases mac25/insulin-like growth factor-binding protein-related protein-1 expression in cultured osteoblasts. Endocrinology 140, 1998–2003 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Zhang, W. et al. IGFBP7 regulates the osteogenic differentiation of bone marrow-derived mesenchymal stem cells via Wnt/β-catenin signaling pathway. FASEB J. 32, 2280–2291 (2018).

    Article  CAS  PubMed  Google Scholar 

  31. Ye, C. et al. IGFBP7 acts as a negative regulator of RANKL-induced osteoclastogenesis and oestrogen deficiency-induced bone loss. Cell Prolif. 53, e12752 (2020).

    Article  PubMed  Google Scholar 

  32. Kanzaki, S., Hilliker, S., Baylink, D. J. & Mohan, S. Evidence that human bone cells in culture produce insulin-like growth factor-binding protein-4 and -5 proteases. Endocrinology 134, 383–392 (1994).

    Article  CAS  PubMed  Google Scholar 

  33. Qin, X. et al. Pregnancy-associated plasma protein-A increases osteoblast proliferation in vitro and bone formation in vivo. Endocrinology 147, 5653–5661 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Tanner, S. J., Hefferan, T. E., Rosen, C. J. & Conover, C. A. Impact of pregnancy-associated plasma protein-a deletion on the adult murine skeleton. J. Bone Miner. Res. 23, 655–662 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Miller, B. S. et al. Pregnancy associated plasma protein-A is necessary for expeditious fracture healing in mice. J. Endocrinol. 192, 505–513 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Christians, J. K., Amiri, N., Schipilow, J. D., Zhang, S. W. & May-Rashke, K. I. Pappa2 deletion has sex- and age-specific effects on bone in mice. Growth Horm. IGF Res. 44, 6–10 (2019).

    Article  CAS  PubMed  Google Scholar 

  37. Tencerova, M., Okla, M. & Kassem, M. Insulin signaling in bone marrow adipocytes. Curr. Osteoporos. Rep. 17, 446–454 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Tencerova, M. & Kassem, M. The bone marrow-derived stromal cells: commitment and regulation of adipogenesis. Front. Endocrinol. 7, 127 (2016).

    Article  Google Scholar 

  39. Kudo, O. et al. Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone 32, 1–7 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Ferraù, F. et al. High bone marrow fat in patients with Cushing’s syndrome and vertebral fractures. Endocrine 67, 172–179 (2020).

    Article  PubMed  CAS  Google Scholar 

  41. Akune, T. et al. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J. Clin. Invest. 113, 846–855 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vikman, K., Carlsson, B., Billig, H. & Edén, S. Expression and regulation of growth hormone (GH) receptor messenger ribonucleic acid (mRNA) in rat adipose tissue, adipocytes, and adipocyte precursor cells: GH regulation of GH receptor mRNA. Endocrinology 129, 1155–1161 (1991).

    Article  CAS  PubMed  Google Scholar 

  43. Davies, J. S. et al. Adiposity profile in the dwarf rat: an unusually lean model of profound growth hormone deficiency. Am. J. Physiol. Endocrinol. Metab. 292, E1483–E1494 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Menagh, P. J. et al. Growth hormone regulates the balance between bone formation and bone marrow adiposity. J. Bone Miner. Res. 25, 757–768 (2010).

    CAS  PubMed  Google Scholar 

  45. Gevers, E. F., Loveridge, N. & Robinson, I. C. Bone marrow adipocytes: a neglected target tissue for growth hormone. Endocrinology 143, 4065–4073 (2002).

    Article  CAS  PubMed  Google Scholar 

  46. Kamenicky, P., Mazziotti, G., Lombes, M., Giustina, A. & Chanson, P. Growth hormone, insulin-like growth factor-1, and the kidney: pathophysiological and clinical implications. Endocr. Rev. 35, 234–281 (2014).

    Article  CAS  PubMed  Google Scholar 

  47. Chiavistelli, S., Giustina, A. & Mazziotti, G. Parathyroid hormone pulsatility: physiological and clinical aspects. Bone Res. 3, 14049 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Philippou, A. et al. Expression of IGF-1 isoforms after exercise-induced muscle damage in humans: characterization of the MGF E peptide actions in vitro. In vivo 23, 567–575 (2009).

    CAS  PubMed  Google Scholar 

  49. Yoshida, T. & Delafontaine, P. Mechanisms of IGF-1-mediated regulation of skeletal muscle hypertrophy and atrophy. Cells 9, 1970 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  50. McPherron, A. C., Lawler, A. M. & Lee, S. J. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 387, 83–90 (1997).

    Article  CAS  PubMed  Google Scholar 

  51. Morissette, M. R., Cook, S. A., Buranasombati, C., Rosenberg, M. A. & Rosenzweig, A. Myostatin inhibits IGF-I-induced myotube hypertrophy through Akt. Am. J. Physiol. Cell Physiol. 297, C1124–C1132 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Hennebry, A. et al. IGF1 stimulates greater muscle hypertrophy in the absence of myostatin in male mice. J. Endocrinol. 234, 187–200 (2017).

    Article  CAS  PubMed  Google Scholar 

  53. Liu, J. P., Baker, J., Perkins, A. S., Robertson, E. J. & Efstratiadis, A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75, 59–72 (1993).

    CAS  PubMed  Google Scholar 

  54. Wuster, C. et al. 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. 16, 398–405 (2001). The seminal study demonstrates the central role of GH deficiency in determining skeletal fragility and the high risk of fractures in adults with hypopituitarism.

    Article  CAS  PubMed  Google Scholar 

  55. Colao, A. et al. Bone loss is correlated to the severity of growth hormone deficiency in adult patients with hypopituitarism. J. Clin. Endocrinol. Metab. 84, 1919–1924 (1999).

    CAS  PubMed  Google Scholar 

  56. Bravenboer, N., Holzmann, P., de Boer, H., Blok, G. J. & Lips, P. Histomorphometric analysis of bone mass and bone metabolism in growth hormone deficient adult men. Bone 18, 551–557 (1996).

    Article  CAS  PubMed  Google Scholar 

  57. Murray, R. D., Columb, B., Adams, J. E. & Shalet, S. M. Low bone mass is an infrequent feature of the adult growth hormone deficiency syndrome in middle-age adults and the elderly. J. Clin. Endocrinol. Metab. 89, 1124–1130 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Hogler, W. & Shaw, N. Childhood growth hormone deficiency, bone density, structures and fractures: scrutinizing the evidence. Clin. Endocrinol. 72, 281–289 (2010).

    Article  CAS  Google Scholar 

  59. Li, L. et al. Association between visceral fat and bone mineral density in both male and female patients with adult growth hormone deficiency. Biochem. Res. Int. 2020, 5079625 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Yang, H. et al. Bone microarchitecture and volumetric bone density impairment in young male adults with childhood-onset growth hormone deficiency. Eur. J. Endocrinol. 180, 145–153 (2019).

    Article  PubMed  Google Scholar 

  61. Gracia-Marco, L. et al. 3D DXA hip differences in patients with acromegaly or adult growth hormone deficiency. J. Clin. Med. 10, 657 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Silva, P. P. B. et al. Bone microarchitecture and estimated bone strength in men with active acromegaly. Eur. J. Endocrinol. 177, 409–420 (2017).

    Article  CAS  PubMed  Google Scholar 

  63. Souza, A. H. et al. Lifetime, untreated isolated GH deficiency due to a GH-releasing hormone receptor mutation has beneficial consequences on bone status in older individuals, and does not influence their abdominal aorta calcification. Endocrine 47, 191–197 (2014).

    CAS  PubMed  Google Scholar 

  64. Mazziotti, G. et al. Increased prevalence of radiological spinal deformities in adult patients with GH deficiency: influence of GH replacement therapy. J. Bone Miner. Res. 21, 520–528 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Mirza, F. & Canalis, E. Management of endocrine disease: Secondary osteoporosis: pathophysiology and management. Eur. J. Endocrinol. 173, R131–R151 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tritos, N. A. et al. Unreplaced sex steroid deficiency, corticotropin deficiency, and lower IGF-I are associated with lower bone mineral density in adults with growth hormone deficiency: a KIMS database analysis. J. Clin. Endocrinol. Metab. 96, 1516–1523 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mazziotti, G. et al. Incidence of morphometric vertebral fractures in adult patients with growth hormone deficiency. Endocrine 52, 103–110 (2016).

    Article  CAS  PubMed  Google Scholar 

  68. Jørgensen, J. O. L. & Juul, A. Therapy of endocrine disease: Growth hormone replacement therapy in adults: 30 years of personal clinical experience. Eur. J. Endocrinol. https://doi.org/10.1530/eje-18-0306 (2018).

    Article  PubMed  Google Scholar 

  69. Cuneo, R. C., Salomon, F., Wiles, C. M., Hesp, R. & Sonksen, P. H. Growth hormone treatment in growth hormone-deficient adults. I. Effects on muscle mass and strength. J. Appl. Physiol. 70, 688–694 (1991).

    Article  CAS  PubMed  Google Scholar 

  70. Ohlsson, C., Bengtsson, B. A., Isaksson, O. G., Andreassen, T. T. & Slootweg, M. C. Growth hormone and bone. Endocr. Rev. 19, 55–79 (1998).

    CAS  PubMed  Google Scholar 

  71. Abrahamsen, B. et al. 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. 57, 273–281 (2002).

    Article  CAS  Google Scholar 

  72. Ueland, T. et al. Increased serum and bone matrix levels of the secreted Wnt antagonist DKK-1 in patients with growth hormone deficiency in response to growth hormone treatment. J. Clin. Endocrinol. Metab. 100, 736–743 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Bex, M. et al. 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 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Ahmad, A. M. et al. Effects of growth hormone replacement on parathyroid hormone sensitivity and bone mineral metabolism. J. Clin. Endocrinol. Metab. 88, 2860–2868 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Barake, M., Klibanski, A. & Tritos, N. A. Effects of recombinant human growth hormone therapy on bone mineral density in adults with growth hormone deficiency: a meta-analysis. J. Clin. Endocrinol. Metab. 99, 852–860 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Appelman-Dijkstra, N. M., Claessen, K. M., Hamdy, N. A., Pereira, A. M. & Biermasz, N. R. Effects of up to 15 years of recombinant human GH (rhGH) replacement on bone metabolism in adults with growth hormone deficiency (GHD): the Leiden Cohort Study. Clin. Endocrinol. 81, 727–735 (2014).

    Article  CAS  Google Scholar 

  77. Holmer, H. et al. Fracture incidence in GH-deficient patients on complete hormone replacement including GH. J. Bone Miner. Res. 22, 1842–1850 (2007).

    Article  PubMed  Google Scholar 

  78. Mo, D. et al. Fracture risk in adult patients treated with growth hormone replacement therapy for growth hormone deficiency: a prospective observational cohort study. Lancet Diabetes Endocrinol. 3, 331–338 (2015). The first prospective study reporting a favourable effect of recombinant GH in decreasing the risk of fractures in adults with GHD.

    Article  CAS  PubMed  Google Scholar 

  79. van Varsseveld, N. C. et al. Fractures in pituitary adenoma patients from the dutch national registry of growth hormone treatment in adults. Pituitary 19, 381–390 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Barake, M. et al. Effects of growth hormone therapy on bone density and fracture risk in age-related osteoporosis in the absence of growth hormone deficiency: a systematic review and meta-analysis. Endocrine 59, 39–49 (2018).

    Article  CAS  PubMed  Google Scholar 

  81. Yang, H. et al. Effects of 24 weeks of growth hormone treatment on bone microstructure and volumetric bone density in patients with childhood-onset adult GH deficiency. Int. J. Endocrinol. 2020, 9201979 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Rosenfeld, R. G., Rosenbloom, A. L. & Guevara-Aguirre, J. Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr. Rev. 15, 369–390 (1994).

    Article  CAS  PubMed  Google Scholar 

  83. Benbassat, C. A., Eshed, V., Kamjin, M. & Laron, Z. Are adult patients with Laron syndrome osteopenic? A comparison between dual-energy X-ray absorptiometry and volumetric bone densities. J. Clin. Endocrinol. Metab. 88, 4586–4589 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Baroncelli, G. I., Bertelloni, S., Galli, L., Sodini, F. & Saggese, G. Are adult patients with laron syndrome osteopenic? A comparison between dual-energy X-ray absorptiometry and volumetric bone densities. J. Clin. Endocrinol. Metab. 89, 2506–2507 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Bachrach, L. K. et al. Bone mineral, histomorphometry, and body composition in adults with growth hormone receptor deficiency. J. Bone Miner. Res. 13, 415–421 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Shaw, N. J., Fraser, N. C., Rose, S., Crabtree, N. J. & Boivin, C. M. Bone density and body composition in children with growth hormone insensitivity syndrome receiving recombinant IGF-I. Clin. Endocrinol. 59, 487–491 (2003).

    Article  CAS  Google Scholar 

  87. Dauber, A. et al. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Mol. Med. 8, 363–374 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cabrera-Salcedo, C. et al. Pharmacokinetics of IGF-1 in PAPP-A2-deficient patients, growth response, and effects on glucose and bone density. J. Clin. Endocrinol. Metab. 102, 4568–4577 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Hawkins-Carranza, F. G. et al. rhIGF-1 treatment increases bone mineral density and trabecular bone structure in children with PAPP-A2 deficiency. Horm. Res. Paediatr. 89, 200–204 (2018).

    Article  CAS  PubMed  Google Scholar 

  90. Löwe, B. et al. Long-term outcome of anorexia nervosa in a prospective 21-year follow-up study. Psychol. Med. 31, 881–890 (2001).

    Article  PubMed  Google Scholar 

  91. Miller, K. K. et al. Medical findings in outpatients with anorexia nervosa. Arch. Intern. Med. 165, 561–566 (2005).

    Article  PubMed  Google Scholar 

  92. Singhal, V. et al. Impaired bone strength estimates at the distal tibia and its determinants in adolescents with anorexia nervosa. Bone 106, 61–68 (2018).

    Article  PubMed  Google Scholar 

  93. Fazeli, P. K. & Klibanski, A. The paradox of marrow adipose tissue in anorexia nervosa. Bone 118, 47–52 (2019).

    Article  CAS  PubMed  Google Scholar 

  94. Wei, W. et al. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor γ. Proc. Natl Acad. Sci. USA 109, 3143–3148 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Inagaki, T. et al. Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab. 8, 77–83 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Fazeli, P. K., Misra, M., Goldstein, M., Miller, K. K. & Klibanski, A. Fibroblast growth factor-21 may mediate growth hormone resistance in anorexia nervosa. J. Clin. Endocrinol. Metab. 95, 369–374 (2010).

    Article  CAS  PubMed  Google Scholar 

  97. Gutefeldt, K. et al. Dysregulated growth hormone-insulin-like growth factor-1 axis in adult type 1 diabetes with long duration. Clin. Endocrinol. https://doi.org/10.1111/cen.13810 (2018).

    Article  Google Scholar 

  98. Hotta, M. et al. The relationship between bone turnover and body weight, serum insulin-like growth factor (IGF) I, and serum IGF-binding protein levels in patients with anorexia nervosa. J. Clin. Endocrinol. Metab. 85, 200–206 (2000).

    CAS  PubMed  Google Scholar 

  99. Viapiana, O. et al. Marked increases in bone mineral density and biochemical markers of bone turnover in patients with anorexia nervosa gaining weight. Bone 40, 1073–1077 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Bachmann, K. N. et al. Vertebral strength and estimated fracture risk across the BMI spectrum in women. J. Bone Miner. Res. 31, 281–288 (2016).

    Article  PubMed  Google Scholar 

  101. Fazeli, P. K. et al. IGF-1 is associated with estimated bone strength in anorexia nervosa. Osteoporos. Int. 31, 259–265 (2020). A clinical study supporting the role of low levels of IGF1 in determining skeletal fragility in individuals with anorexia nervosa.

    Article  CAS  PubMed  Google Scholar 

  102. Lawson, E. A. et al. Hormone predictors of abnormal bone microarchitecture in women with anorexia nervosa. Bone 46, 458–463 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Misra, M. et al. Bone metabolism in adolescent boys with anorexia nervosa. J. Clin. Endocrinol. Metab. 93, 3029–3036 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Faje, A. T. et al. Fracture risk and areal bone mineral density in adolescent females with anorexia nervosa. Int. J. Eat. Disord. 47, 458–466 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Rigotti, N. A., Neer, R. M., Skates, S. J., Herzog, D. B. & Nussbaum, S. R. The clinical course of osteoporosis in anorexia nervosa. A longitudinal study of cortical bone mass. JAMA 265, 1133–1138 (1991).

    Article  CAS  PubMed  Google Scholar 

  106. Vestergaard, P. et al. Fractures in patients with anorexia nervosa, bulimia nervosa, and other eating disorders — a nationwide register study. Int. J. Eat. Disord. 32, 301–308 (2002). A population-based study demonstrating a high risk of fractures in individuals with anorexia nervosa.

    Article  PubMed  Google Scholar 

  107. Divasta, A. D., Feldman, H. A. & Gordon, C. M. Vertebral fracture assessment in adolescents and young women with anorexia nervosa: a case series. J. Clin. Densitom. 17, 207–211 (2014).

    Article  PubMed  Google Scholar 

  108. Lucas, A. R., Melton, L. J. III, Crowson, C. S. & O’Fallon, W. M. Long-term fracture risk among women with anorexia nervosa: a population-based cohort study. Mayo Clin. Proc. 74, 972–977 (1999).

    Article  CAS  PubMed  Google Scholar 

  109. Counts, D. R., Gwirtsman, H., Carlsson, L. M., Lesem, M. & Cutler, G. B. Jr. The effect of anorexia nervosa and refeeding on growth hormone-binding protein, the insulin-like growth factors (IGFs), and the IGF-binding proteins. J. Clin. Endocrinol. Metab. 75, 762–767 (1992).

    CAS  PubMed  Google Scholar 

  110. Fazeli, P. K. et al. Effects of recombinant human growth hormone in anorexia nervosa: a randomized, placebo-controlled study. J. Clin. Endocrinol. Metab. 95, 4889–4897 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Misra, M. et al. Hormonal determinants of regional body composition in adolescent girls with anorexia nervosa and controls. J. Clin. Endocrinol. Metab. 90, 2580–2587 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Grinspoon, S. et al. Effects of short-term recombinant human insulin-like growth factor I administration on bone turnover in osteopenic women with anorexia nervosa. J. Clin. Endocrinol. Metab. 81, 3864–3870 (1996).

    CAS  PubMed  Google Scholar 

  113. Misra, M. et al. Effects of rhIGF-1 administration on surrogate markers of bone turnover in adolescents with anorexia nervosa. Bone 45, 493–498 (2009). A study reporting favourable effects of recombinant IGF1 on the skeleton of adolescents with anorexia nervosa.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. 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. J. Clin. Endocrinol. Metab. 87, 2883–2891 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Strokosch, G. R., Friedman, A. J., Wu, S. C. & Kamin, M. Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in adolescent females with anorexia nervosa: a double-blind, placebo-controlled study. J. Adolesc. Health 39, 819–827 (2006).

    Article  PubMed  Google Scholar 

  116. Kam, G. Y., Leung, K. C., Baxter, R. C. & Ho, K. K. Estrogens exert route- and dose-dependent effects on insulin-like growth factor (IGF)-binding protein-3 and the acid-labile subunit of the IGF ternary complex. J. Clin. Endocrinol. Metab. 85, 1918–1922 (2000).

    CAS  PubMed  Google Scholar 

  117. Misra, M. et al. Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa. J. Bone Miner. Res. 26, 2430–2438 (2011).

    Article  CAS  PubMed  Google Scholar 

  118. Resulaj, M. et al. Transdermal estrogen in women with anorexia nervosa: an exploratory pilot study. JBMR Plus 4, e10251 (2020).

    Article  CAS  PubMed  Google Scholar 

  119. Junnila, R. K., List, E. O., Berryman, D. E., Murrey, J. W. & Kopchick, J. J. The GH/IGF-1 axis in ageing and longevity. Nat. Rev. Endocrinol. 9, 366–376 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. van Varsseveld, N. C., Sohl, E., Drent, M. L. & Lips, P. Gender-specific associations of serum insulin-like growth factor-1 with bone health and fractures in older persons. J. Clin. Endocrinol. Metab. 100, 4272–4281 (2015).

    Article  PubMed  CAS  Google Scholar 

  121. Ohlsson, C. et al. Older men with low serum IGF-1 have an increased risk of incident fractures: the MrOS Sweden study. J. Bone Miner. Res. 26, 865–872 (2011). A study reporting an association between low IGF1 values and osteoporotic fractures in older men.

    Article  CAS  PubMed  Google Scholar 

  122. Garnero, P., Sornay-Rendu, E. & Delmas, P. D. Low serum IGF-1 and occurrence of osteoporotic fractures in postmenopausal women. Lancet 355, 898–899 (2000). A study reporting an association between low IGF1 values and osteoporotic fractures in postmenopausal women.

    Article  CAS  PubMed  Google Scholar 

  123. Perrini, S. et al. The GH/IGF1 axis and signaling pathways in the muscle and bone: mechanisms underlying age-related skeletal muscle wasting and osteoporosis. J. Endocrinol. 205, 201–210 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. Krantz, E., Trimpou, P. & Landin-Wilhelmsen, K. Effect of growth hormone treatment on fractures and quality of life in postmenopausal osteoporosis: a 10-year follow-up study. J. Clin. Endocrinol. Metab. 100, 3251–3259 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Mazziotti, G. et al. Bone turnover, bone mineral density, and fracture risk in acromegaly: a meta-analysis. J. Clin. Endocrinol. Metab. 100, 384–394 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Jensen, E. D., Gopalakrishnan, R. & Westendorf, J. J. Regulation of gene expression in osteoblasts. BioFactors 36, 25–32 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Belaya, Z. et al. Effects of active acromegaly on bone mRNA and microRNA expression patterns. Eur. J. Endocrinol. 178, 353–364 (2018).

    Article  CAS  PubMed  Google Scholar 

  128. Pekkolay, Z., Kılınç, F., Gozel, N., Önalan, E. & Tuzcu, A. K. Increased serum sclerostin levels in patients with active acromegaly. J. Clin. Endocrinol. Metab. 105, dgz254 (2020).

    Article  PubMed  Google Scholar 

  129. Silva, P. P. B. et al. Impaired bone microarchitecture in premenopausal women with acromegaly: the possible role of Wnt signaling. J. Clin. Endocrinol. Metab. 106, 2690–2706 (2021).

    Article  PubMed  Google Scholar 

  130. Canalis, E. Wnt signalling in osteoporosis: mechanisms and novel therapeutic approaches. Nat. Rev. Endocrinol. 9, 575–583 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. Madeira, M. et al. Acromegaly has a negative influence on trabecular bone, but not on cortical bone, as assessed by high-resolution peripheral quantitative computed tomography. J. Clin. Endocrinol. Metab. 98, 1734–1741 (2013).

    Article  CAS  PubMed  Google Scholar 

  132. Dalle Carbonare, L. et al. Bone histomorphometry in acromegaly patients with fragility vertebral fractures. Pituitary 21, 56–64 (2018).

    Article  CAS  PubMed  Google Scholar 

  133. Calatayud, M. et al. Trabecular bone score and bone mineral density in patients with long-term controlled acromegaly. Clin. Endocrinol. 95, 58–64 (2021).

    Article  CAS  Google Scholar 

  134. Kuzma, M. et al. Non-invasive DXA-derived bone structure assessment of acromegaly patients: a cross-sectional study. Eur. J. Endocrinol. 180, 201–211 (2019).

    Article  CAS  PubMed  Google Scholar 

  135. Bonadonna, S. et al. Increased prevalence of radiological spinal deformities in active acromegaly: a cross-sectional study in postmenopausal women. J. Bone Miner. Res. 20, 1837–1844 (2005). The seminal study reporting high risk of vertebral fractures in individuals with acromegaly.

    Article  PubMed  Google Scholar 

  136. Wassenaar, M. J. et al. High prevalence of vertebral fractures despite normal bone mineral density in patients with long-term controlled acromegaly. Eur. J. Endocrinol. 164, 475–483 (2011).

    Article  CAS  PubMed  Google Scholar 

  137. Mazziotti, G. et al. Vertebral fractures in patients with acromegaly: a 3-year prospective study. J. Clin. Endocrinol. Metab. 98, 3402–3410 (2013).

    Article  CAS  PubMed  Google Scholar 

  138. Mazziotti, G. et al. Treatment of acromegalic osteopathy in real-life clinical practice: the BAAC (Bone Active Drugs in Acromegaly) study. J. Clin. Endocrinol. Metab. 105, dgaa363 (2020). The first study evaluating the effectiveness of bone-active agents in preventing the risk of vertebral fractures in individuals with acromegaly.

    Article  PubMed  Google Scholar 

  139. Cellini, M. et al. Vertebral fractures associated with spinal sagittal imbalance and quality of life in acromegaly: a radiographic study with EOS 2D/3D technology. Neuroendocrinology 111, 775–785 (2021).

    Article  CAS  PubMed  Google Scholar 

  140. Plard, C. et al. Acromegaly is associated with vertebral deformations but not vertebral fractures: results of a cross-sectional monocentric study. Joint Bone Spine 87, 618–624 (2020).

    Article  PubMed  Google Scholar 

  141. Maffezzoni, F. et al. High-resolution-cone beam tomography analysis of bone microarchitecture in patients with acromegaly and radiological vertebral fractures. Endocrine 54, 532–542 (2016).

    Article  CAS  PubMed  Google Scholar 

  142. Mazziotti, G., Lania, A. & Canalis, E. Management of endocrine disease: bone disorders associated with acromegaly: mechanisms and treatment. Eur. J. Endocrinol. 181, R45–R56 (2019).

    Article  CAS  PubMed  Google Scholar 

  143. Füchtbauer, L. et al. Muscle strength in patients with acromegaly at diagnosis and during long-term follow-up. Eur. J. Endocrinol. 177, 217–226 (2017).

    Article  PubMed  Google Scholar 

  144. Godang, K. et al. Hip structure analyses in acromegaly: decrease of cortical bone thickness after treatment: a longitudinal cohort study. JBMR Plus 3, e10240 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Vitali, E. et al. Direct effects of octreotide on osteoblast cell proliferation and function. J. Endocrinol. Invest. https://doi.org/10.1007/s40618-022-01740-7 (2022).

    Article  PubMed  Google Scholar 

  146. Chiloiro, S. et al. Effects of pegvisomant and pasireotide LAR on vertebral fractures in acromegaly resistant to first-generation SRLs. J. Clin. Endocrinol. Metab. 105, dgz054 (2020).

    Article  PubMed  Google Scholar 

  147. Pelsma, I. C. M. et al. Progression of vertebral fractures in long-term controlled acromegaly: a 9-year follow-up study. Eur. J. Endocrinol. 183, 427–437 (2020).

    Article  CAS  PubMed  Google Scholar 

  148. Cosman, F. et al. Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1-34)] in postmenopausal osteoporosis. J. Bone Miner. Res. 26, 503–511 (2011).

    Article  CAS  PubMed  Google Scholar 

  149. White, H. D. et al. Effect of oral phosphate and alendronate on bone mineral density when given as adjunctive therapy to growth hormone replacement in adult growth hormone deficiency. J. Clin. Endocrinol. Metab. 96, 726–736 (2011).

    Article  CAS  PubMed  Google Scholar 

  150. Biermasz, N. R., Hamdy, N. A., Pereira, A. M., Romijn, J. A. & Roelfsema, F. 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. 60, 568–575 (2004).

    Article  CAS  Google Scholar 

  151. Miller, K. K. et al. Effects of risedronate and low-dose transdermal testosterone on bone mineral density in women with anorexia nervosa: a randomized, placebo-controlled study. J. Clin. Endocrinol. Metab. 96, 2081–2088 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Kilbane, M. T., Crowley, R. K., Twomey, P. J., Maher, C. & McKenna, M. J. Anorexia nervosa with markedly high bone turnover and hyperphosphatemia during refeeding rectified by denosumab. Osteoporos. Int. 31, 1395–1398 (2020).

    Article  CAS  PubMed  Google Scholar 

  153. Golden, N. H. et al. Alendronate for the treatment of osteopenia in anorexia nervosa: a randomized, double-blind, placebo-controlled trial. J. Clin. Endocrinol. Metab. 90, 3179–3185 (2005).

    Article  CAS  PubMed  Google Scholar 

  154. Fazeli, P. K. et al. Teriparatide increases bone formation and bone mineral density in adult women with anorexia nervosa. J. Clin. Endocrinol. Metab. 99, 1322–1329 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Milos, G. et al. Positive effect of teriparatide on areal bone mineral density in young women with anorexia nervosa: a pilot study. Calcif. Tissue Int. 108, 595–604 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Schousboe, J. T., Shepherd, J. A., Bilezikian, J. P. & Baim, S. Executive summary of the 2013 international society for clinical densitometry position development conference on bone densitometry. J. Clin. Densitom. 16, 455–466 (2013).

    Article  PubMed  Google Scholar 

  157. Griffith, J. F. & Genant, H. K. New advances in imaging osteoporosis and its complications. Endocrine 42, 39–51 (2012).

    Article  CAS  PubMed  Google Scholar 

  158. de Bakker, C. M. J., Tseng, W. J., Li, Y., Zhao, H. & Liu, X. S. Clinical evaluation of bone strength and fracture risk. Curr. Osteoporos. Rep. 15, 32–42 (2017).

    Article  PubMed  Google Scholar 

  159. Pistoia, W. et al. Estimation of distal radius failure load with micro-finite element analysis models based on three-dimensional peripheral quantitative computed tomography images. Bone 30, 842–848 (2002).

    Article  CAS  PubMed  Google Scholar 

  160. Winzenrieth, R. et al. Effects of osteoporosis drug treatments on cortical and trabecular bone in the femur using DXA-based 3D modeling. Osteoporos. Int. 29, 2323–2333 (2018).

    Article  CAS  PubMed  Google Scholar 

  161. Ulivieri, F. M. et al. Utility of the trabecular bone score (TBS) in secondary osteoporosis. Endocrine 47, 435–448 (2014).

    Article  CAS  PubMed  Google Scholar 

  162. Mazziotti, G., Bilezikian, J., Canalis, E., Cocchi, D. & Giustina, A. New understanding and treatments for osteoporosis. Endocrine 41, 58–69 (2012).

    Article  CAS  PubMed  Google Scholar 

  163. Genant, H. K. et al. Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis The Study of Osteoporotic Fractures Research Group. J. Bone Miner. Res. 11, 984–996 (1996).

    Article  CAS  PubMed  Google Scholar 

  164. Clark, E. M., Carter, L., Gould, V. C., Morrison, L. & Tobias, J. H. Vertebral fracture assessment (VFA) by lateral DXA scanning may be cost-effective when used as part of fracture liaison services or primary care screening. Osteoporos. Int. 25, 953–964 (2014).

    Article  CAS  PubMed  Google Scholar 

  165. Canalis, E. Management of endocrine disease: novel anabolic treatments for osteoporosis. Eur. J. Endocrinol. 178, R33–R44 (2018).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank G. R. Hargis and C. Bonin, at UConn Health, for help with the first versions of the figures.

Author information

Authors and Affiliations

Authors

Contributions

G.M. researched data for the article. A.G.L. and E.C. contributed substantially to discussion of the content. G.M. and E.C. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Gherardo Mazziotti.

Ethics declarations

Competing interests

G.M. received consultant fees from Eli Lilly, Ipsen and Novartis and lecture fees from Abiogen and Amgen. A.G.L. received grants from Pfizer and consultant fees from Ipsen. E.C. declares no competing interests.

Peer review

Peer review information

Nature Reviews Endocrinology thanks S. Ahmed and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mazziotti, G., Lania, A.G. & Canalis, E. Skeletal disorders associated with the growth hormone–insulin-like growth factor 1 axis. Nat Rev Endocrinol 18, 353–365 (2022). https://doi.org/10.1038/s41574-022-00649-8

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-022-00649-8

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing