Advertisement

Low Bone Mineral Density in Anorexia Nervosa: Treatments and Challenges

  • Pouneh K. FazeliEmail author
Treating Bone Loss in Challenging Situations
Part of the following topical collections:
  1. Treating Bone loss in challenging situations

Abstract

Anorexia nervosa, a psychiatric disease predominantly affecting women, is characterized by self-induced starvation and a resultant low-weight state. During starvation, a number of hormonal adaptations—including hypothalamic amenorrhea and growth hormone resistance—allow for decreased energy expenditure during periods of decreased nutrient intake, but these very same adaptations also contribute to the medical complications associated with chronic starvation, including low bone mass. Almost 90% of women with anorexia nervosa have bone mineral density (BMD) values more than one-standard deviation below the mean of healthy women at peak bone mineral density, and this disease is associated with a significantly increased risk of fracture. Although multiple therapies have been studied for the treatment of low bone mass in anorexia nervosa, there are currently no approved therapies and few promising long-term therapeutic options. This review will outline the mediators of low bone mass in anorexia nervosa, discuss therapies that have been studied for the treatment of low BMD in this disorder, and highlight the important challenges that remain, including the differences in bone modeling in adolescents with anorexia nervosa as compared to adults, necessitating that potential therapies be tested in these two populations separately, and the paucity of long-term therapeutic strategies for treating bone loss in this disorder.

Keywords

Anorexia nervosa Bone mineral density Estrogen 

Notes

Acknowledgements

This project was supported by NIH grant R03 DK106410. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding

This project was supported by NIH grant R03 DK106410.

Compliance with Ethical Standards

Conflict of Interest

The author declares that she has no conflict of interest.

Ethical Approval

Not applicable.

Informed Consent

Not applicable.

Disclosures

No disclosures.

References

  1. 1.
    Lucas AR, Crowson CS, O'Fallon WM, Melton LJ 3rd. The ups and downs of anorexia nervosa. Int J Eat Disord. 1999;26(4):397–405.CrossRefGoogle Scholar
  2. 2.
    Keski-Rahkonen A, Hoek HW, Susser ES, Linna MS, Sihvola E, Raevuori A, et al. Epidemiology and course of anorexia nervosa in the community. Am J Psychiatry. 2007;164(8):1259–65.  https://doi.org/10.1176/appi.ajp.2007.06081388.CrossRefPubMedGoogle Scholar
  3. 3.
    Lowe B, Zipfel S, Buchholz C, Dupont Y, Reas DL, Herzog W. Long-term outcome of anorexia nervosa in a prospective 21-year follow-up study. Psychol Med. 2001;31(5):881–90.CrossRefGoogle Scholar
  4. 4.
    Eddy KT, Tabri N, Thomas JJ, Murray HB, Keshaviah A, Hastings E, et al. Recovery from anorexia nervosa and bulimia nervosa at 22-year follow-up. J Clin Psychiatry. 2017;78(2):184–9.  https://doi.org/10.4088/JCP.15m10393.CrossRefPubMedGoogle Scholar
  5. 5.
    Miller KK, Grinspoon SK, Ciampa J, Hier J, Herzog D, Klibanski A. Medical findings in outpatients with anorexia nervosa. Arch Intern Med. 2005;165(5):561–6.  https://doi.org/10.1001/archinte.165.5.561.CrossRefPubMedGoogle Scholar
  6. 6.
    Grinspoon S, Thomas E, Pitts S, Gross E, Mickley D, Miller K, et al. Prevalence and predictive factors for regional osteopenia in women with anorexia nervosa. Ann Intern Med. 2000;133(10):790–4.CrossRefGoogle Scholar
  7. 7.
    Rigotti NA, Neer RM, Skates SJ, Herzog DB, Nussbaum SR. The clinical course of osteoporosis in anorexia nervosa. A longitudinal study of cortical bone mass. JAMA. 1991;265(9):1133–8.CrossRefGoogle Scholar
  8. 8.
    Vestergaard P, Emborg C, Stoving RK, Hagen C, Mosekilde L, Brixen K. Fractures in patients with anorexia nervosa, bulimia nervosa, and other eating disorders—a nationwide register study. Int J Eat Disord. 2002;32(3):301–8.  https://doi.org/10.1002/eat.10101.CrossRefPubMedGoogle Scholar
  9. 9.
    Faje AT, Fazeli PK, Miller KK, Katzman DK, Ebrahimi S, Lee H, et al. Fracture risk and areal bone mineral density in adolescent females with anorexia nervosa. Int J Eat Disord. 2014;47(5):458–66.  https://doi.org/10.1002/eat.22248.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Nagata JM, Golden NH, Leonard MB, Copelovitch L, Denburg MR. Assessment of sex differences in fracture risk among patients with anorexia nervosa: a population-based cohort study using the health improvement network. J Bone Miner Res Off J Am Soc Bone Miner Res. 2017;32(5):1082–9.  https://doi.org/10.1002/jbmr.3068.CrossRefGoogle Scholar
  11. 11.
    Lucas AR, Melton LJ 3rd, Crowson CS, O'Fallon WM. Long-term fracture risk among women with anorexia nervosa: a population-based cohort study. Mayo Clin Proc. 1999;74(10):972–7.  https://doi.org/10.4065/74.10.972.CrossRefPubMedGoogle Scholar
  12. 12.
    Grinspoon S, Thomas L, Miller K, Pitts S, Herzog D, Klibanski A. Changes in regional fat redistribution and the effects of estrogen during spontaneous weight gain in women with anorexia nervosa. Am J Clin Nutr. 2001;73(5):865–9.  https://doi.org/10.1093/ajcn/73.5.865.CrossRefPubMedGoogle Scholar
  13. 13.
    Mayer L, Walsh BT, Pierson RN Jr, Heymsfield SB, Gallagher D, Wang J, et al. Body fat redistribution after weight gain in women with anorexia nervosa. Am J Clin Nutr. 2005;81(6):1286–91.  https://doi.org/10.1093/ajcn/81.6.1286.CrossRefPubMedGoogle Scholar
  14. 14.
    Kooh SW, Noriega E, Leslie K, Muller C, Harrison JE. Bone mass and soft tissue composition in adolescents with anorexia nervosa. Bone. 1996;19(2):181–8.CrossRefGoogle Scholar
  15. 15.
    Grinspoon S, Miller K, Coyle C, Krempin J, Armstrong C, Pitts S, et al. Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea. J Clin Endocrinol Metab. 1999;84(6):2049–55.  https://doi.org/10.1210/jcem.84.6.5792.CrossRefPubMedGoogle Scholar
  16. 16.
    Turner JM, Bulsara MK, McDermott BM, Byrne GC, Prince RL, Forbes DA. Predictors of low bone density in young adolescent females with anorexia nervosa and other dieting disorders. Int J Eat Disord. 2001;30(3):245–51.CrossRefGoogle Scholar
  17. 17.
    DiVasta AD, Beck TJ, Petit MA, Feldman HA, LeBoff MS, Gordon CM. Bone cross-sectional geometry in adolescents and young women with anorexia nervosa: a hip structural analysis study. Osteoporos Int. 2007;18(6):797–804.  https://doi.org/10.1007/s00198-006-0308-6.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Soyka LA, Misra M, Frenchman A, Miller KK, Grinspoon S, Schoenfeld DA, et al. Abnormal bone mineral accrual in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab. 2002;87(9):4177–85.  https://doi.org/10.1210/jc.2001-011889.CrossRefPubMedGoogle Scholar
  19. 19.
    Miller KK, Lee EE, Lawson EA, Misra M, Minihan J, Grinspoon SK, et al. Determinants of skeletal loss and recovery in anorexia nervosa. J Clin Endocrinol Metab. 2006;91(8):2931–7.  https://doi.org/10.1210/jc.2005-2818.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Rigotti NA, Nussbaum SR, Herzog DB, Neer RM. Osteoporosis in women with anorexia nervosa. N Engl J Med. 1984;311(25):1601–6.  https://doi.org/10.1056/NEJM198412203112503.CrossRefPubMedGoogle Scholar
  21. 21.
    Seeman E, Szmukler GI, Formica C, Tsalamandris C, Mestrovic R. Osteoporosis in anorexia nervosa: the influence of peak bone density, bone loss, oral contraceptive use, and exercise. J Bone Miner Res Off J Am Soc Bone Miner Res. 1992;7(12):1467–74.  https://doi.org/10.1002/jbmr.5650071215.CrossRefGoogle Scholar
  22. 22.
    Gordon CM, Goodman E, Emans SJ, Grace E, Becker KA, Rosen CJ, et al. Physiologic regulators of bone turnover in young women with anorexia nervosa. J Pediatr. 2002;141(1):64–70.  https://doi.org/10.1067/mpd.2002.125003.CrossRefPubMedGoogle Scholar
  23. 23.
    DiVasta AD, Feldman HA, O'Donnell JM, Long J, Leonard MB, Gordon CM. Effect of exercise and antidepressants on skeletal outcomes in adolescent girls with anorexia nervosa. J Adolesc Health. 2017;60(2):229–32.  https://doi.org/10.1016/j.jadohealth.2016.10.003.CrossRefPubMedGoogle Scholar
  24. 24.
    Nagata JM, Carlson JL, Golden NH, Murray SB, Long J, Leonard MB, et al. Associations between exercise, bone mineral density, and body composition in adolescents with anorexia nervosa. Eat Weight Disord. 2018.  https://doi.org/10.1007/s40519-018-0521-2.
  25. 25.
    Biller BM, Saxe V, Herzog DB, Rosenthal DI, Holzman S, Klibanski A. Mechanisms of osteoporosis in adult and adolescent women with anorexia nervosa. J Clin Endocrinol Metab. 1989;68(3):548–54.  https://doi.org/10.1210/jcem-68-3-548.CrossRefPubMedGoogle Scholar
  26. 26.
    Bachrach LK, Guido D, Katzman D, Litt IF, Marcus R. Decreased bone density in adolescent girls with anorexia nervosa. Pediatrics. 1990;86(3):440–7.PubMedGoogle Scholar
  27. 27.
    Soyka LA, Grinspoon S, Levitsky LL, Herzog DB, Klibanski A. The effects of anorexia nervosa on bone metabolism in female adolescents. J Clin Endocrinol Metab. 1999;84(12):4489–96.  https://doi.org/10.1210/jcem.84.12.6207.CrossRefPubMedGoogle Scholar
  28. 28.
    Joyce JM, Warren DL, Humphries LL, Smith AJ, Coon JS. Osteoporosis in women with eating disorders: comparison of physical parameters, exercise, and menstrual status with SPA and DPA evaluation. J Nucl Med. 1990;31(3):325–31.PubMedGoogle Scholar
  29. 29.
    Frisch RE, Gotz-Welbergen AV, McArthur JW, Albright T, Witschi J, Bullen B, et al. Delayed menarche and amenorrhea of college athletes in relation to age of onset of training. JAMA. 1981;246(14):1559–63.CrossRefGoogle Scholar
  30. 30.
    Grinspoon S, Gulick T, Askari H, Landt M, Lee K, Anderson E, et al. Serum leptin levels in women with anorexia nervosa. J Clin Endocrinol Metab. 1996;81(11):3861–3.PubMedGoogle Scholar
  31. 31.
    Misra M, Miller KK, Kuo K, Griffin K, Stewart V, Hunter E, et al. Secretory dynamics of leptin in adolescent girls with anorexia nervosa and healthy adolescents. Am J Physiol Endocrinol Metab. 2005;289(3):E373–81.  https://doi.org/10.1152/ajpendo.00041.2005.CrossRefPubMedGoogle Scholar
  32. 32.
    Chou SH, Chamberland JP, Liu X, Matarese G, Gao C, Stefanakis R, et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc Natl Acad Sci U S A. 2011;108(16):6585–90.  https://doi.org/10.1073/pnas.1015674108.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med. 2004;351(10):987–97.  https://doi.org/10.1056/NEJMoa040388.CrossRefPubMedGoogle Scholar
  34. 34.
    Fazeli PK, Bredella MA, Misra M, Meenaghan E, Rosen CJ, Clemmons DR, et al. Preadipocyte factor-1 is associated with marrow adiposity and bone mineral density in women with anorexia nervosa. J Clin Endocrinol Metab. 2010;95(1):407–13.  https://doi.org/10.1210/jc.2009-1152.CrossRefPubMedGoogle Scholar
  35. 35.
    Legroux-Gerot I, Vignau J, Biver E, Pigny P, Collier F, Marchandise X, et al. Anorexia nervosa, osteoporosis and circulating leptin: the missing link. Osteoporos Int. 2010;21(10):1715–22.  https://doi.org/10.1007/s00198-009-1120-x.CrossRefPubMedGoogle Scholar
  36. 36.
    Bredella MA, Fazeli PK, Miller KK, Misra M, Torriani M, Thomas BJ, et al. Increased bone marrow fat in anorexia nervosa. J Clin Endocrinol Metab. 2009;94(6):2129–36.  https://doi.org/10.1210/jc.2008-2532.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Ecklund K, Vajapeyam S, Feldman HA, Buzney CD, Mulkern RV, Kleinman PK, et al. Bone marrow changes in adolescent girls with anorexia nervosa. J Bone Miner Res Off J Am Soc Bone Miner Res. 2010;25(2):298–304.  https://doi.org/10.1359/jbmr.090805.CrossRefGoogle Scholar
  38. 38.
    Fazeli PK, Bredella MA, Freedman L, Thomas BJ, Breggia A, Meenaghan E, et al. Marrow fat and preadipocyte factor-1 levels decrease with recovery in women with anorexia nervosa. J Bone Miner Res Off J Am Soc Bone Miner Res. 2012;27(9):1864–71.  https://doi.org/10.1002/jbmr.1640.CrossRefGoogle Scholar
  39. 39.
    Fazeli PK, Faje A, Bredella MA, Polineni S, Russell S, Resulaj M, et al. Changes in marrow adipose tissue with short-term changes in weight in premenopausal women with anorexia nervosa. Eur J Endocrinol. 2018.  https://doi.org/10.1530/EJE-18-0824.
  40. 40.
    Schellinger D, Lin CS, Hatipoglu HG, Fertikh D. Potential value of vertebral proton MR spectroscopy in determining bone weakness. AJNR Am J Neuroradiol. 2001;22(8):1620–7.PubMedGoogle Scholar
  41. 41.
    Singhal V, Tulsiani S, Campoverde KJ, Mitchell DM, Slattery M, Schorr M, et al. Impaired bone strength estimates at the distal tibia and its determinants in adolescents with anorexia nervosa. Bone. 2018;106:61–8.  https://doi.org/10.1016/j.bone.2017.07.009.CrossRefPubMedGoogle Scholar
  42. 42.
    Misra M, Tsai P, Anderson EJ, Hubbard JL, Gallagher K, Soyka LA, et al. Nutrient intake in community-dwelling adolescent girls with anorexia nervosa and in healthy adolescents. Am J Clin Nutr. 2006;84(4):698–706.CrossRefGoogle Scholar
  43. 43.
    Haagensen AL, Feldman HA, Ringelheim J, Gordon CM. Low prevalence of vitamin D deficiency among adolescents with anorexia nervosa. Osteoporosis International. 2008;19(3):289–94.  https://doi.org/10.1007/s00198-007-0476-z.CrossRefPubMedGoogle Scholar
  44. 44.
    Garn SM, Rohmann CG, Behar M, Viteri F, Guzman MA. Compact bone deficiency in protein-calorie malnutrition. Science. 1964;145(3639):1444–5.CrossRefGoogle Scholar
  45. 45.
    Fontana L, Shew JL, Holloszy JO, Villareal DT. Low bone mass in subjects on a long-term raw vegetarian diet. Arch Intern Med. 2005;165(6):684–9.  https://doi.org/10.1001/archinte.165.6.684.CrossRefPubMedGoogle Scholar
  46. 46.
    Fernstrom MH, Weltzin TE, Neuberger S, Srinivasagam N, Kaye WH. Twenty-four-hour food intake in patients with anorexia nervosa and in healthy control subjects. Biol Psychiatry. 1994;36(10):696–702.CrossRefGoogle Scholar
  47. 47.
    Misra M, Miller KK, Tsai P, Gallagher K, Lin A, Lee N, et al. Elevated peptide YY levels in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab. 2006;91(3):1027–33.  https://doi.org/10.1210/jc.2005-1878.CrossRefGoogle Scholar
  48. 48.
    Gatti D, El Ghoch M, Viapiana O, Ruocco A, Chignola E, Rossini M, et al. Strong relationship between vitamin D status and bone mineral density in anorexia nervosa. Bone. 2015;78:212–5.  https://doi.org/10.1016/j.bone.2015.05.014.CrossRefPubMedGoogle Scholar
  49. 49.
    Mehler PS, Blalock DV, Walden K, Kaur S, McBride J, Walsh K, et al. Medical findings in 1,026 consecutive adult inpatient-residential eating disordered patients. Int J Eat Disord. 2018;51(4):305–13.  https://doi.org/10.1002/eat.22830.CrossRefPubMedGoogle Scholar
  50. 50.
    Verbalis JG, Barsony J, Sugimura Y, Tian Y, Adams DJ, Carter EA, et al. Hyponatremia-induced osteoporosis. J Bone Miner Res Off J Am Soc Bone Miner Res. 2010;25(3):554–63.  https://doi.org/10.1359/jbmr.090827.CrossRefGoogle Scholar
  51. 51.
    Kinsella S, Moran S, Sullivan MO, Molloy MG, Eustace JA. Hyponatremia independent of osteoporosis is associated with fracture occurrence. Clin J Am Soc Nephrol. 2010;5(2):275–80.  https://doi.org/10.2215/CJN.06120809.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Jamal SA, Arampatzis S, Harrison SL, Bucur RC, Ensrud K, Orwoll ES, et al. Hyponatremia and fractures: findings from the MrOS study. J Bone Miner Res Off J Am Soc Bone Miner Res. 2015;30(6):970–5.  https://doi.org/10.1002/jbmr.2383.CrossRefGoogle Scholar
  53. 53.
    Lawson EA, Fazeli PK, Calder G, Putnam H, Misra M, Meenaghan E, et al. Plasma sodium level is associated with bone loss severity in women with anorexia nervosa: a cross-sectional study. J Clin Psychiatry. 2012;73(11):e1379–83.  https://doi.org/10.4088/JCP.12m07919.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5). 5th ed. Washington, DC; 2013.Google Scholar
  55. 55.
    Miller KK, Lawson EA, Mathur V, Wexler TL, Meenaghan E, Misra M, et al. Androgens in women with anorexia nervosa and normal-weight women with hypothalamic amenorrhea. J Clin Endocrinol Metab. 2007;92(4):1334–9.  https://doi.org/10.1210/jc.2006-2501.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Lawson EA, Miller KK, Bredella MA, Phan C, Misra M, Meenaghan E, et al. Hormone predictors of abnormal bone microarchitecture in women with anorexia nervosa. Bone. 2010;46(2):458–63.  https://doi.org/10.1016/j.bone.2009.09.005.CrossRefPubMedGoogle Scholar
  57. 57.
    Lawson EA, Donoho D, Miller KK, Misra M, Meenaghan E, Lydecker J, et al. Hypercortisolemia is associated with severity of bone loss and depression in hypothalamic amenorrhea and anorexia nervosa. J Clin Endocrinol Metab. 2009;94(12):4710–6.  https://doi.org/10.1210/jc.2009-1046.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Fazeli PK, Faje AT, Cross EJ, Lee H, Rosen CJ, Bouxsein ML, et al. Serum FGF-21 levels are associated with worsened radial trabecular bone microarchitecture and decreased radial bone strength in women with anorexia nervosa. Bone. 2015;77:6–11.  https://doi.org/10.1016/j.bone.2015.04.001.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Misra M, Prabhakaran R, Miller KK, Goldstein MA, Mickley D, Clauss L, et al. Prognostic indicators of changes in bone density measures in adolescent girls with anorexia nervosa-II. J Clin Endocrinol Metab. 2008;93(4):1292–7.  https://doi.org/10.1210/jc.2007-2419.CrossRefPubMedGoogle Scholar
  60. 60.
    Utz AL, Lawson EA, Misra M, Mickley D, Gleysteen S, Herzog DB, et al. Peptide YY (PYY) levels and bone mineral density (BMD) in women with anorexia nervosa. Bone. 2008;43(1):135–9.  https://doi.org/10.1016/j.bone.2008.03.007.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Lawson EA, Donoho DA, Blum JI, Meenaghan EM, Misra M, Herzog DB, et al. Decreased nocturnal oxytocin levels in anorexia nervosa are associated with low bone mineral density and fat mass. J Clin Psychiatry. 2011;72(11):1546–51.  https://doi.org/10.4088/JCP.10m06617.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Wiegelmann W, Solbach HG. Effects of LH-RH on plasma levels of LH and FSH in anorexia nervosa. Horm Metab Res. 1972;4(5):404.  https://doi.org/10.1055/s-0028-1097104.CrossRefPubMedGoogle Scholar
  63. 63.
    Mecklenburg RS, Loriaux DL, Thompson RH, Andersen AE, Lipsett MB. Hypothalamic dysfunction in patients with anorexia nervosa. Medicine. 1974;53(2):147–59.CrossRefGoogle Scholar
  64. 64.
    Travaglini P, Beck-Peccoz P, Ferrari C, Ambrosi B, Paracchi A, Severgnini A, et al. Some aspects of hypothalamic-pituitary function in patients with anorexia nervosa. Acta Endocrinol. 1976;81(2):252–62.CrossRefGoogle Scholar
  65. 65.
    Nillius SJ, Fries H, Wide L. Successful induction of follicular maturation and ovulation by prolonged treatment with LH-releasing hormone in women with anorexia nervosa. Am J Obstet Gynecol. 1975;122(8):921–8.CrossRefGoogle Scholar
  66. 66.
    Boyar RM, Katz J, Finkelstein JW, Kapen S, Weiner H, Weitzman ED, et al. Anorexia nervosa. Immaturity of the 24-hour luteinizing hormone secretory pattern. N Engl J Med. 1974;291(17):861–5.  https://doi.org/10.1056/NEJM197410242911701.CrossRefPubMedGoogle Scholar
  67. 67.
    Riis BJ, Rodbro P, Christiansen C. The role of serum concentrations of sex steroids and bone turnover in the development and occurrence of postmenopausal osteoporosis. Calcif Tissue Int. 1986;38(6):318–22.CrossRefGoogle Scholar
  68. 68.
    Seeman E. Estrogen, androgen, and the pathogenesis of bone fragility in women and men. Curr Osteoporos Rep. 2004;2(3):90–6.CrossRefGoogle Scholar
  69. 69.
    Falahati-Nini A, Riggs BL, Atkinson EJ, O'Fallon WM, Eastell R, Khosla S. Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. J Clin Invest. 2000;106(12):1553–60.  https://doi.org/10.1172/JCI10942.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Finkelstein JS, Lee H, Leder BZ, Burnett-Bowie SA, Goldstein DW, Hahn CW, et al. Gonadal steroid-dependent effects on bone turnover and bone mineral density in men. J Clin Invest. 2016;126(3):1114–25.  https://doi.org/10.1172/JCI84137.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Klibanski A, Biller BM, Schoenfeld DA, Herzog DB, Saxe VC. The effects of estrogen administration on trabecular bone loss in young women with anorexia nervosa. J Clin Endocrinol Metab. 1995;80(3):898–904.PubMedGoogle Scholar
  72. 72.
    Golden NH, Lanzkowsky L, Schebendach J, Palestro CJ, Jacobson MS, Shenker IR. The effect of estrogen-progestin treatment on bone mineral density in anorexia nervosa. J Pediatr Adolesc Gynecol. 2002;15(3):135–43.CrossRefGoogle Scholar
  73. 73.
    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. 2002;87(6):2883–91.CrossRefGoogle Scholar
  74. 74.
    Misra M, Katzman D, Miller KK, Mendes N, Snelgrove D, Russell M, et al. Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa. J Bone Miner Res Off J Am Soc Bone Miner Res. 2011;26(10):2430–8.  https://doi.org/10.1002/jbmr.447.CrossRefGoogle Scholar
  75. 75.
    Counts DR, Gwirtsman H, Carlsson LM, Lesem M, Cutler GB 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;75(3):762–7.PubMedGoogle Scholar
  76. 76.
    Weissberger AJ, Ho KK, Lazarus L. Contrasting effects of oral and transdermal routes of estrogen replacement therapy on 24-hour growth hormone (GH) secretion, insulin-like growth factor I, and GH-binding protein in postmenopausal women. J Clin Endocrinol Metab. 1991;72(2):374–81.  https://doi.org/10.1210/jcem-72-2-374.CrossRefPubMedGoogle Scholar
  77. 77.
    Kam GY, Leung KC, Baxter RC, Ho KK. 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. 2000;85(5):1918–22.  https://doi.org/10.1210/jcem.85.5.6527.CrossRefPubMedGoogle Scholar
  78. 78.
    Saggese G, Bertelloni S, Baroncelli GI, 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;151(10):764–8.CrossRefGoogle Scholar
  79. 79.
    Heer M, Mika C, Grzella I, Heussen N, Herpertz-Dahlmann B. Bone turnover during inpatient nutritional therapy and outpatient follow-up in patients with anorexia nervosa compared with that in healthy control subjects. Am J Clin Nutr. 2004;80(3):774–81.  https://doi.org/10.1093/ajcn/80.3.774.CrossRefPubMedGoogle Scholar
  80. 80.
    Hotta M, Fukuda I, Sato K, Hizuka N, Shibasaki T, Takano K. 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. 2000;85(1):200–6.PubMedGoogle Scholar
  81. 81.
    Weinbrenner T, Zittermann A, Gouni-Berthold I, Stehle P, Berthold HK. Body mass index and disease duration are predictors of disturbed bone turnover in anorexia nervosa. A case-control study. Eur J Clin Nutr. 2003;57(10):1262–7.  https://doi.org/10.1038/sj.ejcn.1601683.CrossRefPubMedGoogle Scholar
  82. 82.
    Bolton JG, Patel S, Lacey JH, White S. A prospective study of changes in bone turnover and bone density associated with regaining weight in women with anorexia nervosa. Osteoporos Int. 2005;16(12):1955–62.  https://doi.org/10.1007/s00198-005-1972-7.CrossRefPubMedGoogle Scholar
  83. 83.
    Viapiana O, Gatti D, Dalle Grave R, Todesco T, Rossini M, Braga V, et al. Marked increases in bone mineral density and biochemical markers of bone turnover in patients with anorexia nervosa gaining weight. Bone. 2007;40(4):1073–7.  https://doi.org/10.1016/j.bone.2006.11.015.CrossRefPubMedGoogle Scholar
  84. 84.
    Hughes DE, Dai A, Tiffee JC, Li HH, Mundy GR, Boyce BF. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. Nat Med. 1996;2(10):1132–6.CrossRefGoogle Scholar
  85. 85.
    Miller KK, Meenaghan E, Lawson EA, Misra M, Gleysteen S, Schoenfeld D, 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. 2011;96(7):2081–8.  https://doi.org/10.1210/jc.2011-0380.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Golden NH, Iglesias EA, Jacobson MS, Carey D, Meyer W, Schebendach J, et al. Alendronate for the treatment of osteopenia in anorexia nervosa: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2005;90(6):3179–85.  https://doi.org/10.1210/jc.2004-1659.CrossRefPubMedGoogle Scholar
  87. 87.
    Seeman E. Reduced bone formation and increased bone resorption: rational targets for the treatment of osteoporosis. Osteoporos Int. 2003;14(Suppl 3):S2–8.  https://doi.org/10.1007/s00198-002-1340-9.CrossRefPubMedGoogle Scholar
  88. 88.
    van Binsbergen CJ, Coelingh Bennink HJ, Odink J, Haspels AA, Koppeschaar HP. A comparative and longitudinal study on endocrine changes related to ovarian function in patients with anorexia nervosa. J Clin Endocrinol Metab. 1990;71(3):705–11.CrossRefGoogle Scholar
  89. 89.
    Gahete MD, Cordoba-Chacon J, Luque RM, Kineman RD. The rise in growth hormone during starvation does not serve to maintain glucose levels or lean mass but is required for appropriate adipose tissue response in female mice. Endocrinology. 2013;154(1):263–9.  https://doi.org/10.1210/en.2012-1849.CrossRefPubMedGoogle Scholar
  90. 90.
    Zhao TJ, Liang G, Li RL, Xie X, Sleeman MW, Murphy AJ, et al. Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice. Proc Natl Acad Sci U S A. 2010;107(16):7467–72.  https://doi.org/10.1073/pnas.1002271107.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Garfinkel PE, Brown GM, Stancer HC, Moldofsky H. Hypothalamic-pituitary function in anorexia nervosa. Arch Gen Psychiatry. 1975;32(6):739–44.CrossRefGoogle Scholar
  92. 92.
    Scacchi M, Pincelli AI, Caumo A, Tomasi P, Delitala G, Baldi G, et al. Spontaneous nocturnal growth hormone secretion in anorexia nervosa. J Clin Endocrinol Metab. 1997;82(10):3225–9.CrossRefGoogle Scholar
  93. 93.
    Stoving RK, Veldhuis JD, Flyvbjerg A, Vinten J, Hangaard J, Koldkjaer OG, et al. Jointly amplified basal and pulsatile growth hormone (GH) secretion and increased process irregularity in women with anorexia nervosa: indirect evidence for disruption of feedback regulation within the GH-insulin-like growth factor I axis. J Clin Endocrinol Metab. 1999;84(6):2056–63.PubMedGoogle Scholar
  94. 94.
    Misra M, Miller KK, Bjornson J, Hackman A, Aggarwal A, Chung J, et al. Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab. 2003;88(12):5615–23.CrossRefGoogle Scholar
  95. 95.
    Grinspoon SK, Baum HB, Peterson S, Klibanski A. Effects of rhIGF-I administration on bone turnover during short-term fasting. J Clin Invest. 1995;96(2):900–6.  https://doi.org/10.1172/JCI118137.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Fazeli PK, Lawson EA, Prabhakaran R, Miller KK, Donoho DA, Clemmons DR, et al. Effects of recombinant human growth hormone in anorexia nervosa: a randomized, placebo-controlled study. J Clin Endocrinol Metab. 2010;95(11):4889–97.  https://doi.org/10.1210/jc.2010-0493.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Grinspoon S, Baum H, Lee K, Anderson E, Herzog D, Klibanski A. 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. 1996;81(11):3864–70.  https://doi.org/10.1210/jcem.81.11.8923830.CrossRefPubMedGoogle Scholar
  98. 98.
    Misra M, McGrane J, Miller KK, Goldstein MA, Ebrahimi S, Weigel T, et al. Effects of rhIGF-1 administration on surrogate markers of bone turnover in adolescents with anorexia nervosa. Bone. 2009;45(3):493–8.  https://doi.org/10.1016/j.bone.2009.06.002.CrossRefPubMedPubMedCentralGoogle Scholar
  99. 99.
    Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 2007;5(6):426–37.  https://doi.org/10.1016/j.cmet.2007.05.002.CrossRefPubMedGoogle Scholar
  100. 100.
    Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, et al. Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab. 2007;5(6):415–25.  https://doi.org/10.1016/j.cmet.2007.05.003.CrossRefPubMedGoogle Scholar
  101. 101.
    Fazeli PK, Lun M, Kim SM, Bredella MA, Wright S, Zhang Y, et al. FGF21 and the late adaptive response to starvation in humans. J Clin Invest. 2015;125(12):4601–11.  https://doi.org/10.1172/JCI83349.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Inagaki T, Lin VY, Goetz R, Mohammadi M, Mangelsdorf DJ, Kliewer SA. Inhibition of growth hormone signaling by the fasting-induced hormone FGF21. Cell Metab. 2008;8(1):77–83.  https://doi.org/10.1016/j.cmet.2008.05.006.CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Fazeli PK, Misra M, Goldstein M, Miller KK, Klibanski A. Fibroblast growth factor-21 may mediate growth hormone resistance in anorexia nervosa. J Clin Endocrinol Metab. 2010;95(1):369–74.  https://doi.org/10.1210/jc.2009-1730.CrossRefPubMedGoogle Scholar
  104. 104.
    Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, et al. FGF-21 as a novel metabolic regulator. J Clin Invest. 2005;115(6):1627–35.  https://doi.org/10.1172/JCI23606.CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Wei W, Dutchak PA, Wang X, Ding X, Wang X, Bookout AL, et al. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor gamma. Proc Natl Acad Sci U S A. 2012;109(8):3143–8.  https://doi.org/10.1073/pnas.1200797109.CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Morris HA, Need AG, O'Loughlin PD, Horowitz M, Bridges A, Nordin BE. Malabsorption of calcium in corticosteroid-induced osteoporosis. Calcif Tissue Int. 1990;46(5):305–8.CrossRefGoogle Scholar
  107. 107.
    Hansen JW, Gordan GS, Prussin SG. Direct measurement of osteolysis in man. J Clin Invest. 1973;52(2):304–15.  https://doi.org/10.1172/JCI107186.CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Canalis E. Clinical review 83: mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis. J Clin Endocrinol Metab. 1996;81(10):3441–7.PubMedGoogle Scholar
  109. 109.
    Rauch A, Seitz S, Baschant U, Schilling AF, Illing A, Stride B, et al. Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor. Cell Metab. 2010;11(6):517–31.  https://doi.org/10.1016/j.cmet.2010.05.005.CrossRefPubMedGoogle Scholar
  110. 110.
    Padmanabhan V, Keech C, Convey EM. Cortisol inhibits and adrenocorticotropin has no effect on luteinizing hormone-releasing hormone-induced release of luteinizing hormone from bovine pituitary cells in vitro. Endocrinology. 1983;112(5):1782–7.CrossRefGoogle Scholar
  111. 111.
    Walsh BT, Katz JL, Levin J, Kream J, Fukushima DK, Hellman LD, et al. Adrenal activity in anorexia nervosa. Psychosom Med. 1978;40(6):499–506.CrossRefGoogle Scholar
  112. 112.
    Boyar RM, Hellman LD, Roffwarg H, Katz J, Zumoff B, O'Connor J, et al. Cortisol secretion and metabolism in anorexia nervosa. N Engl J Med. 1977;296(4):190–3.  https://doi.org/10.1056/NEJM197701272960403.CrossRefPubMedGoogle Scholar
  113. 113.
    Misra M, Miller KK, Almazan C, Ramaswamy K, Lapcharoensap W, Worley M, et al. Alterations in cortisol secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab. 2004;89(10):4972–80.  https://doi.org/10.1210/jc.2004-0723.CrossRefPubMedGoogle Scholar
  114. 114.
    Zumoff B, Walsh BT, Katz JL, Levin J, Rosenfeld RS, Kream J, et al. Subnormal plasma dehydroisoandrosterone to cortisol ratio in anorexia nervosa: a second hormonal parameter of ontogenic regression. J Clin Endocrinol Metab. 1983;56(4):668–72.CrossRefGoogle Scholar
  115. 115.
    Winterer J, Gwirtsman HE, George DT, Kaye WH, Loriaux DL, Cutler GB Jr. Adrenocorticotropin-stimulated adrenal androgen secretion in anorexia nervosa: impaired secretion at low weight with normalization after long-term weight recovery. J Clin Endocrinol Metab. 1985;61(4):693–7.  https://doi.org/10.1210/jcem-61-4-693.CrossRefPubMedGoogle Scholar
  116. 116.
    Divasta AD, Feldman HA, Giancaterino C, Rosen CJ, Leboff MS, Gordon CM. The effect of gonadal and adrenal steroid therapy on skeletal health in adolescents and young women with anorexia nervosa. Metab Clin Exp. 2012;61(7):1010–20.  https://doi.org/10.1016/j.metabol.2011.11.016.CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    DiVasta AD, Feldman HA, Beck TJ, LeBoff MS, Gordon CM. Does hormone replacement normalize bone geometry in adolescents with anorexia nervosa? J Bone Miner Res Off J Am Soc Bone Miner Res. 2014;29(1):151–7.  https://doi.org/10.1002/jbmr.2005.CrossRefGoogle Scholar
  118. 118.
    Gordon CM, Grace E, Emans SJ, Feldman HA, Goodman E, Becker KA, et al. Effects of oral dehydroepiandrosterone on bone density in young women with anorexia nervosa: a randomized trial. J Clin Endocrinol Metab. 2002;87(11):4935–41.CrossRefGoogle Scholar
  119. 119.
    Bloch M, Ish-Shalom S, Greenman Y, Klein E, Latzer Y. Dehydroepiandrosterone treatment effects on weight, bone density, bone metabolism and mood in women suffering from anorexia nervosa-a pilot study. Psychiatry Res. 2012;200(2–3):544–9.  https://doi.org/10.1016/j.psychres.2012.07.012.CrossRefPubMedGoogle Scholar
  120. 120.
    Halmi KA, Sunday S, Puglisi A, Marchi P. Hunger and satiety in anorexia and bulimia nervosa. Ann N Y Acad Sci. 1989;575:431–44 discussion 44-5.CrossRefGoogle Scholar
  121. 121.
    Wong IP, Driessler F, Khor EC, Shi YC, Hormer B, Nguyen AD, et al. Peptide YY regulates bone remodeling in mice: a link between gut and skeletal biology. PLoS One. 2012;7(7):e40038.  https://doi.org/10.1371/journal.pone.0040038.CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, et al. Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol. 2001;145(5):669–73.CrossRefGoogle Scholar
  123. 123.
    Fukushima N, Hanada R, Teranishi H, Fukue Y, Tachibana T, Ishikawa H, et al. Ghrelin directly regulates bone formation. J Bone Miner Res Off J Am Soc Bone Miner Res. 2005;20(5):790–8.  https://doi.org/10.1359/JBMR.041237.CrossRefGoogle Scholar
  124. 124.
    Misra M, Miller KK, Stewart V, Hunter E, Kuo K, Herzog DB, et al. Ghrelin and bone metabolism in adolescent girls with anorexia nervosa and healthy adolescents. J Clin Endocrinol Metab. 2005;90(9):5082–7.  https://doi.org/10.1210/jc.2005-0512.CrossRefPubMedGoogle Scholar
  125. 125.
    Hotta M, Ohwada R, Katakami H, Shibasaki T, Hizuka N, Takano K. Plasma levels of intact and degraded ghrelin and their responses to glucose infusion in anorexia nervosa. J Clin Endocrinol Metab. 2004;89(11):5707–12.  https://doi.org/10.1210/jc.2004-0353.CrossRefPubMedGoogle Scholar
  126. 126.
    Fazeli PK, Lawson EA, Faje AT, Eddy KT, Lee H, Fiedorek FT, et al. Treatment with a ghrelin agonist in outpatient women with anorexia nervosa: a randomized clinical trial. J Clin Psychiatry. 2018; in press.Google Scholar
  127. 127.
    Fazeli PK, Klibanski A. The paradox of marrow adipose tissue in anorexia nervosa. Bone. 2019;118:47–52.  https://doi.org/10.1016/j.bone.2018.02.013.CrossRefPubMedGoogle Scholar
  128. 128.
    Tamma R, Colaianni G, Zhu LL, DiBenedetto A, Greco G, Montemurro G, et al. Oxytocin is an anabolic bone hormone. Proc Natl Acad Sci U S A. 2009;106(17):7149–54.  https://doi.org/10.1073/pnas.0901890106.CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Elabd C, Basillais A, Beaupied H, Breuil V, Wagner N, Scheideler M, et al. Oxytocin controls differentiation of human mesenchymal stem cells and reverses osteoporosis. Stem Cells. 2008;26(9):2399–407.  https://doi.org/10.1634/stemcells.2008-0127.CrossRefPubMedGoogle Scholar
  130. 130.
    Abdallah BM, Jensen CH, Gutierrez G, Leslie RG, Jensen TG, Kassem M. Regulation of human skeletal stem cells differentiation by Dlk1/Pref-1. J Bone Miner Res Off J Am Soc Bone Miner Res. 2004;19(5):841–52.  https://doi.org/10.1359/JBMR.040118.CrossRefGoogle Scholar
  131. 131.
    McClung MR, Grauer A, Boonen S, Bolognese MA, Brown JP, Diez-Perez A, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med. 2014;370(5):412–20.  https://doi.org/10.1056/NEJMoa1305224.CrossRefPubMedGoogle Scholar
  132. 132.
    Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375(16):1532–43.  https://doi.org/10.1056/NEJMoa1607948.CrossRefPubMedGoogle Scholar
  133. 133.
    Maimoun L, Guillaume S, Lefebvre P, Philibert P, Bertet H, Picot MC, et al. Role of sclerostin and Dickkopf-1 in the dramatic alteration in bone mass acquisition in adolescents and young women with recent anorexia nervosa. J Clin Endocrinol Metab. 2014:jc20132565.  https://doi.org/10.1210/jc.2013-2565.
  134. 134.
    Fazeli PK, Wang IS, Miller KK, Herzog DB, Misra M, Lee H, et al. Teriparatide increases bone formation and bone mineral density in adult women with anorexia nervosa. J Clin Endocrinol Metab. 2014:jc20134105.  https://doi.org/10.1210/jc.2013-4105.
  135. 135.
    Faje AT, Fazeli PK, Katzman DK, Miller KK, Breggia A, Rosen CJ, et al. Sclerostin levels and bone turnover markers in adolescents with anorexia nervosa and healthy adolescent girls. Bone. 2012;51(3):474–9.  https://doi.org/10.1016/j.bone.2012.06.006.CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Bachrach LK, Katzman DK, Litt IF, Guido D, Marcus R. Recovery from osteopenia in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab. 1991;72(3):602–6.  https://doi.org/10.1210/jcem-72-3-602.CrossRefPubMedGoogle Scholar
  137. 137.
    Vahle JL, Sato M, Long GG, Young JK, Francis PC, Engelhardt JA, et al. Skeletal changes in rats given daily subcutaneous injections of recombinant human parathyroid hormone (1-34) for 2 years and relevance to human safety. Toxicol Pathol. 2002;30(3):312–21.  https://doi.org/10.1080/01926230252929882.CrossRefPubMedGoogle Scholar
  138. 138.
    Schilcher J, Koeppen V, Aspenberg P, Michaelsson K. Risk of atypical femoral fracture during and after bisphosphonate use. N Engl J Med. 2014;371(10):974–6.  https://doi.org/10.1056/NEJMc1403799.CrossRefPubMedGoogle Scholar
  139. 139.
    Patlas N, Golomb G, Yaffe P, Pinto T, Breuer E, Ornoy A. Transplacental effects of bisphosphonates on fetal skeletal ossification and mineralization in rats. Teratology. 1999;60(2):68–73.  https://doi.org/10.1002/(SICI)1096-9926(199908)60:2<68::AID-TERA10>3.0.CO;2-H.CrossRefPubMedGoogle Scholar
  140. 140.
    Lin JH. Bisphosphonates: a review of their pharmacokinetic properties. Bone. 1996;18(2):75–85.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Neuroendocrine UnitMassachusetts General Hospital and Harvard Medical SchoolBostonUSA

Personalised recommendations