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. 1995 Aug;96(2):900–906. doi: 10.1172/JCI118137

Effects of rhIGF-I administration on bone turnover during short-term fasting.

S K Grinspoon 1, H B Baum 1, S Peterson 1, A Klibanski 1
PMCID: PMC185277  PMID: 7543494

Abstract

Insulin-like growth factor-I (IGF-I) is a nutritionally dependent bone trophic hormone which stimulates osteoblast function and collagen synthesis in vivo and in vitro. We hypothesized that in the fasting state, IGF-I levels would decline significantly and would establish a model in which we could investigate the effects of IGF-I administration on bone turnover. We therefore studied 14 normal women ages 19-33 (mean, 24 +/- 4 [SD] years) during a complete 10-d fast. After 4 d of fasting, subjects were randomized to receive rhIGF-I or placebo subcutaneously twice a day for 6 d. Bone turnover was assessed using specific markers of formation (osteocalcin and type I procollagen carboxyl-terminal propeptide [PICP]) and resorption (pyridinoline, deoxypyridinoline, type I collagen crosslinked N-telopeptide [N-telopeptide] and hydroxyproline). Serum levels of PICP and osteocalcin decreased from 143 +/- 52 to 60 +/- 28 ng/ml (P = 0.001) and from 7.6 +/- 5.4 to 4.2 +/- 3.1 ng/ml (P = 0.001) respectively with 4 d of fasting. Urinary excretion of pyridinoline and deoxypyridinoline decreased from 96 +/- 63 to 47 +/- 38 nmol/mmol creatinine (P < 0.05) and from 28 +/- 17 to 14 +/- 11 nmol/mmol creatinine (P < 0.05) respectively. Mean IGF-I levels decreased from 310 +/- 81 to 186 +/- 78 ng/ml (P = 0.001). In the second part of the experimental protocol, serum osteocalcin and PICP levels increased 5- and 3-fold, respectively with rhIGF-I administration and were significantly elevated compared with the placebo group at the end of treatment (20.9 +/- 17.3 vs. 5.9 +/- 6.4 ng/ml for osteocalcin [P < 0.05] and 188 +/- 45 vs. 110 +/- 37 ng/ml for PICP [P < 0.05]). In contrast, all four markers of bone resorption, including urinary pyridinoline, deoxypyridinoline, N-telopeptide and hydroxyproline were unchanged with rhIGF-I administration. This report is the first to demonstrate that bone turnover falls rapidly with acute caloric deprivation in normal women. RhIGF-I administration uncouples bone formation in this setting by significantly increasing bone formation, but not resorption. These data suggest a novel use of rhIGF-I to selectively stimulate bone formation in states of undernutrition and low bone turnover.

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Selected References

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  1. Bagi C. M., 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. J Bone Miner Res. 1994 Aug;9(8):1301–1312. doi: 10.1002/jbmr.5650090820. [DOI] [PubMed] [Google Scholar]
  2. Bennett A., Chen T., Feldman D., Hintz R. L., Rosenfeld R. G. Characterization of insulin-like growth factor I receptors on cultured rat bone cells: regulation of receptor concentration by glucocorticoids. Endocrinology. 1984 Oct;115(4):1577–1583. doi: 10.1210/endo-115-4-1577. [DOI] [PubMed] [Google Scholar]
  3. Biller B. M., Saxe V., Herzog D. B., Rosenthal D. I., Holzman S., Klibanski A. Mechanisms of osteoporosis in adult and adolescent women with anorexia nervosa. J Clin Endocrinol Metab. 1989 Mar;68(3):548–554. doi: 10.1210/jcem-68-3-548. [DOI] [PubMed] [Google Scholar]
  4. Bird T. A., Spanheimer R. G., Peterkofsky B. Coordinate regulation of collagen and proteoglycan synthesis in costal cartilage of scorbutic and acutely fasted, vitamin C-supplemented guinea pigs. Arch Biochem Biophys. 1986 Apr;246(1):42–51. doi: 10.1016/0003-9861(86)90447-9. [DOI] [PubMed] [Google Scholar]
  5. Branca F., Robins S. P., Ferro-Luzzi A., Golden M. H. Bone turnover in malnourished children. Lancet. 1992 Dec 19;340(8834-8835):1493–1496. doi: 10.1016/0140-6736(92)92754-4. [DOI] [PubMed] [Google Scholar]
  6. Bushinsky D. A., Sessler N. E. Critical role of bicarbonate in calcium release from bone. Am J Physiol. 1992 Sep;263(3 Pt 2):F510–F515. doi: 10.1152/ajprenal.1992.263.3.F510. [DOI] [PubMed] [Google Scholar]
  7. 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. 1989 Jan;83(1):60–65. doi: 10.1172/JCI113885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Canalis E. Effect of insulinlike growth factor I on DNA and protein synthesis in cultured rat calvaria. J Clin Invest. 1980 Oct;66(4):709–719. doi: 10.1172/JCI109908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Clemmons D. R., Klibanski A., Underwood L. E., McArthur J. W., Ridgway E. C., Beitins I. Z., Van Wyk J. J. Reduction of plasma immunoreactive somatomedin C during fasting in humans. J Clin Endocrinol Metab. 1981 Dec;53(6):1247–1250. doi: 10.1210/jcem-53-6-1247. [DOI] [PubMed] [Google Scholar]
  10. Clemmons D. R., Underwood L. E., Dickerson R. N., Brown R. O., Hak L. J., MacPhee R. D., Heizer W. D. Use of plasma somatomedin-C/insulin-like growth factor I measurements to monitor the response to nutritional repletion in malnourished patients. Am J Clin Nutr. 1985 Feb;41(2):191–198. doi: 10.1093/ajcn/41.2.191. [DOI] [PubMed] [Google Scholar]
  11. Condamine L., Menaa C., Vrtovsnik F., Vztovsnik F., Friedlander G., Garabédian M. Local action of phosphate depletion and insulin-like growth factor 1 on in vitro production of 1,25-dihydroxyvitamin D by cultured mammalian kidney cells. J Clin Invest. 1994 Oct;94(4):1673–1679. doi: 10.1172/JCI117512. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Conover C. A. Potentiation of insulin-like growth factor (IGF) action by IGF-binding protein-3: studies of underlying mechanism. Endocrinology. 1992 Jun;130(6):3191–3199. doi: 10.1210/endo.130.6.1375895. [DOI] [PubMed] [Google Scholar]
  13. 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. 1992 Sep;75(3):762–767. doi: 10.1210/jcem.75.3.1381372. [DOI] [PubMed] [Google Scholar]
  14. Daughaday W. H., Rotwein P. Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev. 1989 Feb;10(1):68–91. doi: 10.1210/edrv-10-1-68. [DOI] [PubMed] [Google Scholar]
  15. Ebeling P. R., Jones J. D., O'Fallon W. M., Janes C. H., Riggs B. L. Short-term effects of recombinant human insulin-like growth factor I on bone turnover in normal women. J Clin Endocrinol Metab. 1993 Nov;77(5):1384–1387. doi: 10.1210/jcem.77.5.8077337. [DOI] [PubMed] [Google Scholar]
  16. Ernst M., Heath J. K., Rodan G. A. Estradiol effects on proliferation, messenger ribonucleic acid for collagen and insulin-like growth factor-I, and parathyroid hormone-stimulated adenylate cyclase activity in osteoblastic cells from calvariae and long bones. Endocrinology. 1989 Aug;125(2):825–833. doi: 10.1210/endo-125-2-825. [DOI] [PubMed] [Google Scholar]
  17. Ernst M., Rodan G. A. Estradiol regulation of insulin-like growth factor-I expression in osteoblastic cells: evidence for transcriptional control. Mol Endocrinol. 1991 Aug;5(8):1081–1089. doi: 10.1210/mend-5-8-1081. [DOI] [PubMed] [Google Scholar]
  18. Ernst M., Rodan G. A. 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 Aug;127(2):807–814. doi: 10.1210/endo-127-2-807. [DOI] [PubMed] [Google Scholar]
  19. Fonseca V. A., D'Souza V., Houlder S., Thomas M., Wakeling A., Dandona P. Vitamin D deficiency and low osteocalcin concentrations in anorexia nervosa. J Clin Pathol. 1988 Feb;41(2):195–197. doi: 10.1136/jcp.41.2.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Goad D. L., Tashjian A. H., Jr Insulin-like growth factor-I inhibits parathyroid hormone-stimulated and enhances prostaglandin E2-stimulated adenosine 3',5'-monophosphate production by human osteoblast-like SaOS-2 cells. Endocrinology. 1993 Oct;133(4):1585–1592. doi: 10.1210/endo.133.4.8404598. [DOI] [PubMed] [Google Scholar]
  21. Gosiewska A., Wilson S., Kwon D., Peterkofsky B. Evidence for an in vivo role of insulin-like growth factor-binding protein-1 and -2 as inhibitors of collagen gene expression in vitamin C-deficient and fasted guinea pigs. Endocrinology. 1994 Mar;134(3):1329–1339. doi: 10.1210/endo.134.3.7509738. [DOI] [PubMed] [Google Scholar]
  22. Guler H. P., Eckardt K. U., Zapf J., Bauer C., Froesch E. R. Insulin-like growth factor I increase glomerular filtration rate and renal plasma flow in man. Acta Endocrinol (Copenh) 1989 Jul;121(1):101–106. doi: 10.1530/acta.0.1210101. [DOI] [PubMed] [Google Scholar]
  23. Hochberg Z., Hertz P., Colin V., Ish-Shalom S., Yeshurun D., Youdim M. B., Amit T. The distal axis of growth hormone (GH) in nutritional disorders: GH-binding protein, insulin-like growth factor-I (IGF-I), and IGF-I receptors in obesity and anorexia nervosa. Metabolism. 1992 Jan;41(1):106–112. doi: 10.1016/0026-0495(92)90198-j. [DOI] [PubMed] [Google Scholar]
  24. Hock J. M., Centrella M., Canalis E. Insulin-like growth factor I has independent effects on bone matrix formation and cell replication. Endocrinology. 1988 Jan;122(1):254–260. doi: 10.1210/endo-122-1-254. [DOI] [PubMed] [Google Scholar]
  25. Ingram R. T., Park Y. K., Clarke B. L., Fitzpatrick L. A. Age- and gender-related changes in the distribution of osteocalcin in the extracellular matrix of normal male and female bone. Possible involvement of osteocalcin in bone remodeling. J Clin Invest. 1994 Mar;93(3):989–997. doi: 10.1172/JCI117106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Isaksson O. G., Lindahl A., Nilsson A., Isgaard J. Mechanism of the stimulatory effect of growth hormone on longitudinal bone growth. Endocr Rev. 1987 Nov;8(4):426–438. doi: 10.1210/edrv-8-4-426. [DOI] [PubMed] [Google Scholar]
  27. Isley W. L., Underwood L. E., Clemmons D. R. Changes in plasma somatomedin-C in response to ingestion of diets with variable protein and energy content. JPEN J Parenter Enteral Nutr. 1984 Jul-Aug;8(4):407–411. doi: 10.1177/0148607184008004407. [DOI] [PubMed] [Google Scholar]
  28. Kupfer S. R., Underwood L. E., Baxter R. C., Clemmons D. R. Enhancement of the anabolic effects of growth hormone and insulin-like growth factor I by use of both agents simultaneously. J Clin Invest. 1993 Feb;91(2):391–396. doi: 10.1172/JCI116212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Laron Z., Klinger B., Jensen L. T., Erster B. Biochemical and hormonal changes induced by one week of administration of rIGF-I to patients with Laron type dwarfism. Clin Endocrinol (Oxf) 1991 Aug;35(2):145–150. doi: 10.1111/j.1365-2265.1991.tb03513.x. [DOI] [PubMed] [Google Scholar]
  30. LeRoith D., Clemmons D., Nissley P., Rechler M. M. NIH conference. Insulin-like growth factors in health and disease. Ann Intern Med. 1992 May 15;116(10):854–862. doi: 10.7326/0003-4819-116-10-854. [DOI] [PubMed] [Google Scholar]
  31. Lewitt M. S., Saunders H., Baxter R. C. Bioavailability of insulin-like growth factors (IGFs) in rats determined by the molecular distribution of human IGF-binding protein-3. Endocrinology. 1993 Oct;133(4):1797–1802. doi: 10.1210/endo.133.4.7691582. [DOI] [PubMed] [Google Scholar]
  32. Linkhart T. A., Mohan S. Parathyroid hormone stimulates release of insulin-like growth factor-I (IGF-I) and IGF-II from neonatal mouse calvaria in organ culture. Endocrinology. 1989 Sep;125(3):1484–1491. doi: 10.1210/endo-125-3-1484. [DOI] [PubMed] [Google Scholar]
  33. Martínez A. J., Pascual M., Larralde J. Acute effects of insulin-like growth factor-I (IGF-I) on bone protein synthesis in rats. Biochim Biophys Acta. 1994 Jan 5;1199(1):101–103. doi: 10.1016/0304-4165(94)90103-1. [DOI] [PubMed] [Google Scholar]
  34. McCarthy T. L., Centrella M., Canalis E. Regulatory effects of insulin-like growth factors I and II on bone collagen synthesis in rat calvarial cultures. Endocrinology. 1989 Jan;124(1):301–309. doi: 10.1210/endo-124-1-301. [DOI] [PubMed] [Google Scholar]
  35. Merimee T. J., Zapf J., Froesch E. R. Insulin-like growth factors in the fed and fasted states. J Clin Endocrinol Metab. 1982 Nov;55(5):999–1002. doi: 10.1210/jcem-55-5-999. [DOI] [PubMed] [Google Scholar]
  36. Mochizuki H., Hakeda Y., Wakatsuki N., Usui N., Akashi S., Sato T., Tanaka K., Kumegawa M. Insulin-like growth factor-I supports formation and activation of osteoclasts. Endocrinology. 1992 Sep;131(3):1075–1080. doi: 10.1210/endo.131.3.1505451. [DOI] [PubMed] [Google Scholar]
  37. Peterkofsky B., Palka J., Wilson S., Takeda K., Shah V. Elevated activity of low molecular weight insulin-like growth factor-binding proteins in sera of vitamin C-deficient and fasted guinea pigs. Endocrinology. 1991 Apr;128(4):1769–1779. doi: 10.1210/endo-128-4-1769. [DOI] [PubMed] [Google Scholar]
  38. Pottratz S. T., Bellido T., Mocharla H., Crabb D., Manolagas S. C. 17 beta-Estradiol inhibits expression of human interleukin-6 promoter-reporter constructs by a receptor-dependent mechanism. J Clin Invest. 1994 Mar;93(3):944–950. doi: 10.1172/JCI117100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Saggese G., Bertelloni S., Baroncelli G. I., Di Nero G. Serum levels of carboxyterminal propeptide of type I procollagen in healthy children from 1st year of life to adulthood and in metabolic bone diseases. Eur J Pediatr. 1992 Oct;151(10):764–768. doi: 10.1007/BF01959087. [DOI] [PubMed] [Google Scholar]
  40. Sartorio A., Conti A., Monzani M., Morabito F., Faglia G. Growth hormone treatment in adults with GH deficiency: effects on new biochemical markers of bone and collagen turnover. J Endocrinol Invest. 1993 Dec;16(11):893–898. doi: 10.1007/BF03348952. [DOI] [PubMed] [Google Scholar]
  41. Scheven B. A., Hamilton N. J. Longitudinal bone growth in vitro: effects of insulin-like growth factor I and growth hormone. Acta Endocrinol (Copenh) 1991 May;124(5):602–607. doi: 10.1530/acta.0.1240602. [DOI] [PubMed] [Google Scholar]
  42. Schoenle E., Zapf J., Humbel R. E., Froesch E. R. Insulin-like growth factor I stimulates growth in hypophysectomized rats. Nature. 1982 Mar 18;296(5854):252–253. doi: 10.1038/296252a0. [DOI] [PubMed] [Google Scholar]
  43. Sebastian A., Harris S. T., Ottaway J. H., Todd K. M., Morris R. C., Jr Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate. N Engl J Med. 1994 Jun 23;330(25):1776–1781. doi: 10.1056/NEJM199406233302502. [DOI] [PubMed] [Google Scholar]
  44. Slootweg M. C., Most W. W., van Beek E., Schot L. P., Papapoulos S. E., Löwik C. W. Osteoclast formation together with interleukin-6 production in mouse long bones is increased by insulin-like growth factor-I. J Endocrinol. 1992 Mar;132(3):433–438. doi: 10.1677/joe.0.1320433. [DOI] [PubMed] [Google Scholar]
  45. Spanheimer R. G., Peterkofsky B. A specific decrease in collagen synthesis in acutely fasted, vitamin C-supplemented, guinea pigs. J Biol Chem. 1985 Apr 10;260(7):3955–3962. [PubMed] [Google Scholar]
  46. Stracke H., Schulz A., Moeller D., Rossol S., Schatz H. Effect of growth hormone on osteoblasts and demonstration of somatomedin-C/IGF I in bone organ culture. Acta Endocrinol (Copenh) 1984 Sep;107(1):16–24. doi: 10.1530/acta.0.1070016. [DOI] [PubMed] [Google Scholar]
  47. Suwanickul A., Morris S. L., Powell D. R. Identification of an insulin-responsive element in the promoter of the human gene for insulin-like growth factor binding protein-1. J Biol Chem. 1993 Aug 15;268(23):17063–17068. [PubMed] [Google Scholar]
  48. Turner R. T., Riggs B. L., Spelsberg T. C. Skeletal effects of estrogen. Endocr Rev. 1994 Jun;15(3):275–300. doi: 10.1210/edrv-15-3-275. [DOI] [PubMed] [Google Scholar]
  49. Uebelhart D., Gineyts E., Chapuy M. C., Delmas P. D. Urinary excretion of pyridinium crosslinks: a new marker of bone resorption in metabolic bone disease. Bone Miner. 1990 Jan;8(1):87–96. doi: 10.1016/0169-6009(91)90143-n. [DOI] [PubMed] [Google Scholar]
  50. Wergedal J. E., Mohan S., Lundy M., Baylink D. J. Skeletal growth factor and other growth factors known to be present in bone matrix stimulate proliferation and protein synthesis in human bone cells. J Bone Miner Res. 1990 Feb;5(2):179–186. doi: 10.1002/jbmr.5650050212. [DOI] [PubMed] [Google Scholar]

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