Osteoporosis International

, Volume 17, Issue 5, pp 783–790 | Cite as

Relationship between insulin-like growth factor I, dehydroepiandrosterone sulfate and proresorptive cytokines and bone density in cystic fibrosis

  • C. M. Gordon
  • E. Binello
  • M. S. LeBoff
  • M. E. Wohl
  • C. J. Rosen
  • A. A. Colin
Original Article
First Online:
Received:
Accepted:

Abstract

Introduction

Patients with cystic fibrosis (CF) are known to be at risk for early osteoporosis, and the mechanisms that mediate bone loss are still being delineated. The aim of the present investigation was to investigate if a correlation exists in these patients between skeletal measurements by dual-energy x-ray absorptiometry (DXA) and two anabolic factors, dehydroepiandrosterone (DHEA) and insulin-like growth factor I (IGF-I), and proresorptive factors such as the cytokines interleukin-1β, tumor necrosis factor α, and interleukin-6.

Methods

We studied 32 outpatients (18 females; mean age: 26.2 ± 7.9 years) at a tertiary care medical center. The subjects had venous samples obtained, underwent anthropometric and bone mineral density (BMD) measurements, and completed a health survey. Serum IGF-I concentrations were below the age-adjusted mean in 78% of the participants, and DHEA sulfate (DHEAS) concentrations were low in 72%. Serum concentrations of all cytokines were on the low side of normal; nonetheless, there was a modest inverse correlation between IL-1β and BMD at all sites.

Results

In univariate analyses, IGF-I and DHEAS were significant correlates of BMD or bone mineral content. In final multivariate models controlling for anthropometric and other variables of relevance to bone density, only IGF-I was identified as a significant independent skeletal predictor. While alterations in DHEAS, IGF-I, and specific cytokines may contribute to skeletal deficits in patients with CF, of these factors a low IGF-I concentration appears to be most strongly correlated with BMD.

Conclusions

These findings may have therapeutic implications for enhancing bone density in these patients.

Keywords

Bone mineral density Cystic fibrosis Dual-energy x-ray absorptiometry Insulin-like growth factor I Osteoporosis Pediatrics 
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Notes

Acknowledgements

We wish to thank our patients for their participation, and the skilled and dedicated nurses in the General Clinical Research Center for their excellent patient care. We also gratefully acknowledge Suzanne Muggeo, BA and Julie Burgess, BS, for technical support, Avery LeBoff Williams for editorial assistance, and Henry A. Feldman, PhD for biostatistical advice. This work was funded by NIH Grant MO1-RR-2172 and Project 5-T71-MC-0000-10-S1-RO from the Maternal and Child Health Bureau.

References

  1. 1.
    Bachrach LK, Loutit CW, Moss RB (1994) Osteopenia in adults with cystic fibrosis. Am J Med 96:27–34CrossRefPubMedGoogle Scholar
  2. 2.
    Bhudhikanok GS, Wang MC, Marcus R, Harkins A, Moss RB, Bachrach LK (1998) Bone acquisition and loss in children and adults with cystic fibrosis. J Pediatr 133:18–27CrossRefPubMedGoogle Scholar
  3. 3.
    Gibbens DT, Gilsanz V, Boechat MI, Dufer D, Carlson ME, Wang CI (1988) Osteoporosis in cystic fibrosis. J Pediatr 133:295–300Google Scholar
  4. 4.
    DeSchepper J, Smitz J, Dab I, Piepsz A, Jonckheer M, Bergmann P (1993) Low serum bone gammacarboxyglutamic acid protein concentrations in patients with cystic fibrosis: correlation with hormonal parameters and bone mineral density. Horm Res 39:197–201PubMedGoogle Scholar
  5. 5.
    Henderson RC, Madsen CD (1996) Bone density in children and adolescents with cystic fibrosis. J Pediatr 128:28–34CrossRefPubMedGoogle Scholar
  6. 6.
    Bhudhikanok GS, Lim J, Marcus R, Harkins A, Moss RB, Bachrach LK (1996) Correlates of osteopenia in patients with cystic fibrosis. Pediatrics 97:103–111PubMedGoogle Scholar
  7. 7.
    Baroncelli GI, De Luca F, Maguzzu G, Arrigo T, Sferlazzas C, Catena C, Bertelloni S, Saggese G (1997) Bone demineralization in cystic fibrosis: Evidence of imbalance between bone formation and degradation. Pediatr Res 41:397–403PubMedCrossRefGoogle Scholar
  8. 8.
    Buntain HM, Greer RM, Schluter PJ, Wong JC, Batch JA, Potter JM, Lewindon PJ, Powell E, Wainwright CE, Bell SC (2004) Bone mineral density in Australian children, adolescents and adults with cystic fibrosis: a controlled cross sectional study. Thorax 59:149–155CrossRefPubMedGoogle Scholar
  9. 9.
    Grey AB, Ames RW, Matthews RD, Reid IR (1993) Bone mineral density and body composition in adult patients with cystic fibrosis. Thorax 48:589–593PubMedGoogle Scholar
  10. 10.
    Elkin SL, Fairney A, Burnett S, Kemp M, Kyd P, Burgess J, Compston JE, Hodson ME (2001) Vertebral deformities and low bone density in adults with cystic fibrosis: a cross-sectional study. Osteoporos Int 12:366–372CrossRefPubMedGoogle Scholar
  11. 11.
    Henderson RC, Specter BB (1994) Kyphosis and fractures in children and young adults with cystic fibrosis. J Pediatr 125:208–212CrossRefPubMedGoogle Scholar
  12. 12.
    Donovan DS Jr, Papadopoulos A, Staron RB, Addesso V, Schulman L, McGregor C, Cosman F, Lindsay RL, Shane E (1998) Bone mass and vitamin D deficiency in adults with advanced cystic fibrosis lung disease. Am J Respir Crit Care Med 157:1892–1899PubMedGoogle Scholar
  13. 13.
    Salamoni F, Roulet M, Gudinchet F, Pilet M, Thiébaud D, Burckhardt P (1996) Bone mineral content in cystic fibrosis patients: correlation with fat-free mass. Arch Dis Child 74:314–318PubMedGoogle Scholar
  14. 14.
    Haworth CS, Selby PL, Webb AK et al (1999) Low bone mineral density in adults with cystic fibrosis. Thorax 54:961–967PubMedCrossRefGoogle Scholar
  15. 15.
    Conway SP, Morton AM, Oldroyd B et al (2000) Osteoporosis and osteopenia in adults and adolescents with cystic fibrosis: prevalence and associated factors. Thorax 55:798–804CrossRefPubMedGoogle Scholar
  16. 16.
    Gordon CM, Goodman E, Emans SJ, Grace E, Becker KA, Rosen CJ, Gundberg CM, LeBoff MS (2002) Physiologic regulators of bone turnover in young women with anorexia nervosa. J Pediatr 141:64–70CrossRefPubMedGoogle Scholar
  17. 17.
    Soyka LA, Grinspoon S, Levitsky LL, Herzog DB, Klibanski A (1999) The effects of anorexia nervosa on bone metabolism in female adolescents. J Clin Endocrinol Metab 84:4489–4496CrossRefPubMedGoogle Scholar
  18. 18.
    Greendale GA, Edelstein S, Barrett-Connor E (1997) Endogenous sex steroids and bone mineral density in older women and men: The Rancho Bernardo Study. J Bone Miner Res 12:1833–1843PubMedCrossRefGoogle Scholar
  19. 19.
    Labrie F, Diamond P, Cussan L, Gomez JL, Belanger A, Candas B (1997) Effect of 12-month dehydroepiandrosterone replacement therapy on bone, vagina and endometrium in postmenopausal women. J Clin Endocrinol Metab 82:3498–3505CrossRefPubMedGoogle Scholar
  20. 20.
    Gordon CM, Goodman E, Emans SJ, Grace E, Becker KA, Rosen CJ, Gundberg CM, LeBoff MS (2002) Effects of oral DHEA on bone density in young women with anorexia nervosa: a randomized trial. J Clin Endocrinol Metab 87:4935–4941PubMedCrossRefGoogle Scholar
  21. 21.
    Van Hollenhoven RF, Park JL, Genovese MC, West JP (1999) A double-blind placebo-controlled clinical trial of dehydroepiandrosterone in severe systemic lupus erythematosis. Lupus 8:181–187CrossRefPubMedGoogle Scholar
  22. 22.
    Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, Liu JL, Ooi GT, Setser J, Frystyk J, Boisclair YR, LeRoith D (2002) Circulating levels of IGF-I directly regulate bone growth density. J Clin Invest 2002 110:771–781CrossRefGoogle Scholar
  23. 23.
    Mohan S, Baylink DJ (1991) Bone growth factors. Clin Orthop 263:30–48PubMedGoogle Scholar
  24. 24.
    Ueland T (2005) GH/IGF-I and bone resorption in vivo and in vitro. Eur J Endocrinol 152:327–332CrossRefPubMedGoogle Scholar
  25. 25.
    Laursen EM, Juul A, Lanng S, Hoiby N, Koch C, Muller J, Shakkebaek NE (1995) Diminished concentrations of insulin-like growth factor I in cystic fibrosis. Arch Dis Child 72:494–497PubMedCrossRefGoogle Scholar
  26. 26.
    Sermet-Gaudelus I, Souberbielle JC, Azhar I, Ruiz JC, Magnine P, Colomb V, Le Bihan C, Folio D, Lenoir G (2003) Insulin-like growth factor I correlates with lean body mass in cystic fibrosis patients. Arch Dis Child 88:956–961CrossRefPubMedGoogle Scholar
  27. 27.
    Casson PR, Santoro N, Elkind-Hirsch K, Carson SA, Hornsby PJ, Abraham G, Buster JE (1998) Post menopausal dehydroepiandrosterone administration increases free insulin like growth factor-I and decreases high-density lipoprotein: a six-month trial. Fertil Steril 70:107–110CrossRefPubMedGoogle Scholar
  28. 28.
    Manolagas SC, Jilka RLL (1995) Bone marrow, cytokines and bone remodeling. N Engl J Med 332:305–311CrossRefPubMedGoogle Scholar
  29. 29.
    Pffefer KD, Huecksteadt TP, Hoidal JR (1993) Expression and resolution of tumor necrosis factor in macrophages from cystic fibrosis patients. Am J Respir Cell Mol Biol 9:511–519PubMedGoogle Scholar
  30. 30.
    Bonfeld TL, Panuska JR, Konstan MW, Hillard KA, Hillard JB, Ghnaim H, Berger M (1995) Inflammatory cytokines in cystic fibrosis lungs. Am J Respir Crit Care Med 152:2111–2118PubMedGoogle Scholar
  31. 31.
    Teramoto S, Matsuse T, Ouchi Y (1997) Increased production of TNF-alpha may play a role in osteoporosis in cystic fibrosis patients. Chest 112:574PubMedCrossRefGoogle Scholar
  32. 32.
    Noah TL, Black HR, Cheng PQ, Wood RE, Leigh MQ (1997) Nasal and bronchoalveolar lavage fluid cytokines in early cystic fibrosis. J Infect Dis 175:638–647PubMedGoogle Scholar
  33. 33.
    Nixon LS, Yung B, Bell SC, Elborn JS, Shale DJ (1998) Circulating immunoreactive interleukin-6 in cystic fibrosis. Am J Respir Crit Care Med 157:1764–1769PubMedGoogle Scholar
  34. 34.
    Haworth CS, Selby Pl, Webb Ak et al (2004) Inflammatory related changes in bone mineral content in adults with cystic fibrosis. Thorax 59:613–617CrossRefPubMedGoogle Scholar
  35. 35.
    Daynes RA, Araneo BA, Ershler WB, Maloneyu C, Li GZ, Ryu SY (1993) Altered regulation of IL-6 production with normal aging: Possible linkage to the age associated decline in DHEA and its sulphated derivative. J Immunol 150:5219–5230PubMedGoogle Scholar
  36. 36.
    Gordon CM, LeBoff MS, Glowacki J (2001) Adrenal and gonadal steroids inhibit IL-6 secretion by human marrow cells. Cytokine 16:178–186CrossRefPubMedGoogle Scholar
  37. 37.
    Aris RM, Stephens AR, Ontjes DA, Denene Blackwood A, Lark RK, Hensler MB, Neuringer IP, Lester GE (2000) Adverse alterations in bone metabolism are associated with lung infection in adults with cystic fibrosis. Am J Respir Crit Care Med 162:1674–1678PubMedGoogle Scholar
  38. 38.
    Kelly TL (1990) Bone mineral density reference databases for American men and women. J Bone Miner Res 5:S249CrossRefGoogle Scholar
  39. 39.
    Looker AC, Wahner HW, Dunn WL, Calvo MS, Harris TB, Heyse SP, Johnston CC Jr, Lindsay RL (1995) Proximal femur bone mineral levels of US adults. Osteoporos Int 5:389–409CrossRefPubMedGoogle Scholar
  40. 40.
    Zemel BS (2004) Reference data for the whole body, lumbar spine and proximal femur for American children relative to age, gender, and body size. J Bone Miner Res 1:S231Google Scholar
  41. 41.
    Hardin DS (2002) Growth problems and growth hormone treatment in children with cystic fibrosis. J Pediatr Endocrinol Metab 15:731–735PubMedGoogle Scholar
  42. 42.
    Grinspoon SK, Baum HB, Peterson S, Klibanski A (1995) Effects of rhIGF-I administration on bone turnover during short-term fasting. J Clin Invest 96:900–906PubMedGoogle Scholar
  43. 43.
    Gordon CM, Grace E, Emans SJ, Goodman E, Crawford MH, LeBoff MS (1999) Changes in bone turnover markers and menstrual function after short-term oral DHEA in young women with anorexia nervosa. J Bone Miner Res 14:136–145PubMedCrossRefGoogle Scholar
  44. 44.
    Sin DD, Lacy P, York E, Man SF (2004) Effects of fluticasone on systemic markers of inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 170:721–722CrossRefPubMedGoogle Scholar
  45. 45.
    Wojtczak HA, Kerby GS, Wagener JS et al (2001) Beclomethasone diproprionate reduced airway inflammation with adrenal suppression in young children with cystic fibrosis: a pilot study. Pediatr Pulmonol 32:293–302CrossRefPubMedGoogle Scholar
  46. 46.
    Aris RM, Merkel PA, Bachrach LK et al (2005) Guide to bone health and disease in cystic fibrosis (e-publication). J Clin Endocrinol Metab 90:1888–1896CrossRefPubMedGoogle Scholar
  47. 47.
    Hahn TJ, Squires AE, Halstead LR, Strominger DB (1979) Reduced serum 25-hydroxyvitamin D concentration and disordered mineral metabolism in patients with cystic fibrosis. J Pediatr 94:38–42CrossRefPubMedGoogle Scholar
  48. 48.
    Stead RJ, Houlder S, Agnew J, Thomas M, Hodson ME, Batten JC, Dadona P (1998) Vitamin D and parathyroid hormone and bone mineralization in adults with cystic fibrosis. Thorax 43:190–194Google Scholar
  49. 49.
    Reiter EO, Brugman SM, Pike JW, Pitt M, Dokoh S, Haussler MR, Gerstle RS, Taussig LM (1985) Vitamin D metabolites in adolescents and young adults with cystic fibrosis: effects of sun and season. J Pediatr 106:21–26CrossRefPubMedGoogle Scholar
  50. 50.
    Thompson GN (1987) Determinants of serum vitamin D levels in preadolescent cystic fibrosis children. Acta Paediatr Scand 76:962–965PubMedCrossRefGoogle Scholar
  51. 51.
    Hubbard VS, Farrell PM, di Sant’Agnese PA (1979) 25-Hydroxycholecalciferol levels in patients with cystic fibrosis. J Pediatr 94:84–86CrossRefPubMedGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2006

Authors and Affiliations

  • C. M. Gordon
    • 1
    • 4
  • E. Binello
    • 1
  • M. S. LeBoff
    • 2
  • M. E. Wohl
    • 1
  • C. J. Rosen
    • 3
  • A. A. Colin
    • 1
  1. 1.Children’s HospitalBostonUSA
  2. 2.Brigham and Women’s HospitalBostonUSA
  3. 3.St. Joseph HospitalBangorUSA
  4. 4.Children’s HospitalDivision of EndocrinologyBostonUSA

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