Osteoporosis International

, Volume 24, Issue 12, pp 2919–2927 | Cite as

Melatonin and the skeleton

  • A. K. Amstrup
  • T. Sikjaer
  • L. Mosekilde
  • L. Rejnmark
Review

Abstract

Melatonin may affect bone metabolism through bone anabolic as well as antiresorptive effects. An age-related decrease in peak melatonin levels at nighttime is well documented, which may increase bone resorption and bone loss in the elderly. In vitro, melatonin reduces oxidative stress on bone cells by acting as an antioxidant. Furthermore, melatonin improves bone formation by promoting differentiation of human mesenchymal stem cell (hMSC) into the osteoblastic cell linage. Bone resorption is reduced by increased synthesis of osteoprogeterin (OPG), a decoy receptor that prevents receptor activator of NK-κB ligand (RANKL) in binding to its receptor. Moreover, melatonin is believed to reduce the synthesis of RANKL preventing further bone resorption. In ovariectomized as well as nonovariectomized rodents, melatonin has shown beneficial effects on bone as assessed by biochemical bone turnover markers, DXA, and μCT scans. Furthermore, in pinealectomized animals, bone mineral density (BMD) is significantly decreased compared to controls, supporting the importance of sufficient melatonin levels. In humans, dysfunction of the melatonin signaling pathway may be involved in idiopathic scoliosis, and the increased fracture risk in nighttime workers may be related to changes in the circadian rhythm of melatonin. In the so-far only randomized study on melatonin treatment, no effects were, however, found on bone turnover markers. In conclusion, melatonin may have beneficial effects on the skeleton, but more studies on humans are warranted in order to find out whether supplementation with melatonin at bedtime may preserve bone mass and improve bone biomechanical competence.

Keywords

Melatonin Osteoblast Osteoclasts Osteoporosis Review Skeleton 

References

  1. 1.
    Stehle JH, Saade A, Rawashdeh O, Ackermann K, Jilg A, Sebesteny T, Maronde E (2011) A survey of molecular details in the human pineal gland in the light of phylogeny, structure, function and chronobiological diseases. J Pineal Res 51:17–43PubMedCrossRefGoogle Scholar
  2. 2.
    Dubocovich ML, Markowska M (2005) Functional MT1 and MT2 melatonin receptors in mammals. Endocrine 27:101–10PubMedCrossRefGoogle Scholar
  3. 3.
    Tan DX, Manchester LC, Reiter RJ, Qi WB, Zhang M, Weintraub ST, Cabrera J, Sainz RM, Mayo JC (1999) Identification of highly elevated levels of melatonin in bone marrow: Its origin and significance. Biochim Biophys Acta 1472:206–14PubMedCrossRefGoogle Scholar
  4. 4.
    Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni JM (2000) Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res 28:193–202PubMedCrossRefGoogle Scholar
  5. 5.
    Dijk DJ, Duffy JF, Riel E, Shanahan TL, Czeisler CA (1999) Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony of rest, melatonin and temperature rhythms. J Physiol 516(Pt 2):611–27PubMedCrossRefGoogle Scholar
  6. 6.
    Redman J, Armstrong S, Ng KT (1983) Free-running activity rhythms in the rat: Entrainment by melatonin. Science 219:1089–91PubMedCrossRefGoogle Scholar
  7. 7.
    Simonneaux V, Ouichou A, Pevet P (1990) Vasoactive intestinal peptide stimulates melatonin release from perifused pineal glands of rats. J Neural Transm Gen Sect 79:69–79PubMedCrossRefGoogle Scholar
  8. 8.
    Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT (2012) Melatonin membrane receptors in peripheral tissues: Distribution and functions. Mol Cell Endocrinol 351:152–66PubMedCrossRefGoogle Scholar
  9. 9.
    von Gall C, Stehle JH, Weaver DR (2002) Mammalian melatonin receptors: Molecular biology and signal transduction. Cell Tissue Res 309:151–62CrossRefGoogle Scholar
  10. 10.
    Sethi S, Radio NM, Kotlarczyk MP, Chen CT, Wei YH, Jockers R, Witt-Enderby PA (2010) Determination of the minimal melatonin exposure required to induce osteoblast differentiation from human mesenchymal stem cells and these effects on downstream signaling pathways. J Pineal Res 49:222–38PubMedCrossRefGoogle Scholar
  11. 11.
    Satomura K, Tobiume S, Tokuyama R, Yamasaki Y, Kudoh K, Maeda E, Nagayama M (2007) Melatonin at pharmacological doses enhances human osteoblastic differentiation in vitro and promotes mouse cortical bone formation in vivo. J Pineal Res 42:231–39PubMedCrossRefGoogle Scholar
  12. 12.
    Masana MI, Doolen S, Ersahin C, Al-Ghoul WM, Duckles SP, Dubocovich ML, Krause DN (2002) MT(2) melatonin receptors are present and functional in rat caudal artery. J Pharmacol Exp Ther 302:1295–302PubMedCrossRefGoogle Scholar
  13. 13.
    Krause DN, Barrios VE, Duckles SP (1995) Melatonin receptors mediate potentiation of contractile responses to adrenergic nerve stimulation in rat caudal artery. Eur J Pharmacol 276:207–13PubMedCrossRefGoogle Scholar
  14. 14.
    Cagnacci A, Elliott JA, Yen SS (1992) Melatonin: A major regulator of the circadian rhythm of core temperature in humans. J Clin Endocrinol Metab 75:447–52PubMedCrossRefGoogle Scholar
  15. 15.
    Grossman E, Laudon M, Zisapel N (2011) Effect of melatonin on nocturnal blood pressure: Meta-analysis of randomized controlled trials. Vasc Health Risk Manag 7:577–84PubMedGoogle Scholar
  16. 16.
    Esquifino AI, Villanua MA, Agrasal C (1987) Effect of neonatal melatonin administration on sexual development in the rat. J Steroid Biochem 27:1089–93PubMedCrossRefGoogle Scholar
  17. 17.
    Maestroni GJ, Conti A, Pierpaoli W (1986) Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates the antibody response and antagonizes the immunosuppressive effect of corticosterone. J Neuroimmunol 13:19–30PubMedCrossRefGoogle Scholar
  18. 18.
    Esteban S, Garau C, Aparicio S, Moranta D, Barcelo P, Fiol MA, Rial R (2010) Chronic melatonin treatment and its precursor l-tryptophan improve the monoaminergic neurotransmission and related behavior in the aged rat brain. J Pineal Res 48:170–177PubMedCrossRefGoogle Scholar
  19. 19.
    Martinez-Campa C, Gonzalez A, Mediavilla MD, Alonso-Gonzalez C, Alvarez-Garcia V, Sanchez-Barcelo EJ, Cos S (2009) Melatonin inhibits aromatase promoter expression by regulating cyclooxygenases expression and activity in breast cancer cells. Br J Cancer 101:1613–19PubMedCrossRefGoogle Scholar
  20. 20.
    Lynch HJ, Wurtman RJ, Moskowitz MA, Archer MC, Ho MH (1975) Daily rhythm in human urinary melatonin. Science 187:169–71PubMedCrossRefGoogle Scholar
  21. 21.
    Waldhauser F, Weiszenbacher G, Tatzer E, Gisinger B, Waldhauser M, Schemper M, Frisch H (1988) Alterations in nocturnal serum melatonin levels in humans with growth and aging. J Clin Endocrinol Metab 66:648–52PubMedCrossRefGoogle Scholar
  22. 22.
    Waldhauser F, Weiszenbacher G, Frisch H, Zeitlhuber U, Waldhauser M, Wurtman RJ (1984) Fall in nocturnal serum melatonin during prepuberty and pubescence. Lancet 1:362–65PubMedCrossRefGoogle Scholar
  23. 23.
    Zhdanova IV, Wurtman RJ, Balcioglu A, Kartashov AI, Lynch HJ (1998) Endogenous melatonin levels and the fate of exogenous melatonin: age effects. J Gerontol A Biol Sci Med Sci 53:B293–B298PubMedCrossRefGoogle Scholar
  24. 24.
    Sack RL, Lewy AJ, Erb DL, Vollmer WM, Singer CM (1986) Human melatonin production decreases with age. J Pineal Res 3:379–88PubMedCrossRefGoogle Scholar
  25. 25.
    Karasek M (2004) Melatonin, human aging, and age-related diseases. Exp Gerontol 39:1723–29PubMedCrossRefGoogle Scholar
  26. 26.
    Yocca FD, Friedman E (1984) Effect of immobilization stress on rat pineal beta-adrenergic receptor-mediated function. J Neurochem 42:1427–32PubMedCrossRefGoogle Scholar
  27. 27.
    Carr DB, Reppert SM, Bullen B, Skrinar G, Beitins I, Arnold M, Rosenblatt M, Martin JB, McArthur JW (1981) Plasma melatonin increases during exercise in women. J Clin Endocrinol Metab 53:224–25PubMedCrossRefGoogle Scholar
  28. 28.
    Ledger GA, Burritt MF, Kao PC, O'Fallon WM, Riggs BL, Khosla S (1995) Role of parathyroid hormone in mediating nocturnal and age-related increases in bone resorption. J Clin Endocrinol Metab 80:3304–10PubMedCrossRefGoogle Scholar
  29. 29.
    Greenspan SL, Dresner-Pollak R, Parker RA, London D, Ferguson L (1997) Diurnal variation of bone mineral turnover in elderly men and women. Calcif Tissue Int 60:419–23PubMedCrossRefGoogle Scholar
  30. 30.
    Sairanen S, Tahtela R, Laitinen K, Karonen SL, Valimaki MJ (1994) Nocturnal rise in markers of bone resorption is not abolished by bedtime calcium or calcitonin. Calcif Tissue Int 55:349–52PubMedCrossRefGoogle Scholar
  31. 31.
    Zhang L, Su P, Xu C, Chen C, Liang A, Du K, Peng Y, Huang D (2010) Melatonin inhibits adipogenesis and enhances osteogenesis of human mesenchymal stem cells by suppressing PPARgamma expression and enhancing Runx2 expression. J Pineal Res 49:364–72PubMedCrossRefGoogle Scholar
  32. 32.
    Nakade O, Koyama H, Ariji H, Yajima A, Kaku T (1999) Melatonin stimulates proliferation and type I collagen synthesis in human bone cells in vitro. J Pineal Res 27:106–10PubMedCrossRefGoogle Scholar
  33. 33.
    Park KH, Kang JW, Lee EM, Kim JS, Rhee YH, Kim M, Jeong SJ, Park YG, Kim SH (2011) Melatonin promotes osteoblastic differentiation through the BMP/ERK/Wnt signaling pathways. J Pineal Res 51:187–94PubMedCrossRefGoogle Scholar
  34. 34.
    Roth JA, Kim BG, Lin WL, Cho MI (1999) Melatonin promotes osteoblast differentiation and bone formation. J Biol Chem 274:22041–47PubMedCrossRefGoogle Scholar
  35. 35.
    Koyama H, Nakade O, Takada Y, Kaku T, Lau KH (2002) Melatonin at pharmacologic doses increases bone mass by suppressing resorption through down-regulation of the RANKL-mediated osteoclast formation and activation. J Bone Miner Res 17:1219–29PubMedCrossRefGoogle Scholar
  36. 36.
    Histing T, Anton C, Scheuer C, Garcia P, Holstein JH, Klein M, Matthys R, Pohlemann T, Menger MD (2012) Melatonin impairs fracture healing by suppressing RANKL-mediated bone remodeling. J Surg Res 173:83–90PubMedCrossRefGoogle Scholar
  37. 37.
    Chen YH, Xu DX, Wang JP, Wang H, Wei LZ, Sun MF, Wei W (2006) Melatonin protects against lipopolysaccharide-induced intra-uterine fetal death and growth retardation in mice. J Pineal Res 40:40–47PubMedCrossRefGoogle Scholar
  38. 38.
    Oktem G, Uslu S, Vatansever SH, Aktug H, Yurtseven ME, Uysal A (2006) Evaluation of the relationship between inducible nitric oxide synthase (iNOS) activity and effects of melatonin in experimental osteoporosis in the rat. Surg Radiol Anat 28:157–62PubMedCrossRefGoogle Scholar
  39. 39.
    Bai XC, Lu D, Bai J, Zheng H, Ke ZY, Li XM, Luo SQ (2004) Oxidative stress inhibits osteoblastic differentiation of bone cells by ERK and NF-kappaB. Biochem Biophys Res Commun 314:197–207PubMedCrossRefGoogle Scholar
  40. 40.
    Li M, Zhao L, Liu J, Liu AL, Zeng WS, Luo SQ, Bai XC (2009) Hydrogen peroxide induces G2 cell cycle arrest and inhibits cell proliferation in osteoblasts. Anat Rec (Hoboken ) 292:1107–13CrossRefGoogle Scholar
  41. 41.
    Mody N, Parhami F, Sarafian TA, Demer LL (2001) Oxidative stress modulates osteoblastic differentiation of vascular and bone cells. Free Radic Biol Med 31:509–19PubMedCrossRefGoogle Scholar
  42. 42.
    Radio NM, Doctor JS, Witt-Enderby PA (2006) Melatonin enhances alkaline phosphatase activity in differentiating human adult mesenchymal stem cells grown in osteogenic medium via MT2 melatonin receptors and the MEK/ERK (1/2) signaling cascade. J Pineal Res 40:332–42PubMedCrossRefGoogle Scholar
  43. 43.
    Sethi S, Radio NM, Kotlarczyk MP, Chen CT, Wei YH, Jockers R, Witt-Enderby PA (2010) Determination of the minimal melatonin exposure required to induce osteoblast differentiation from human mesenchymal stem cells and these effects on downstream signaling pathways. J Pineal Res 49:222–38PubMedCrossRefGoogle Scholar
  44. 44.
    Canalis E (2009) Growth factor control of bone mass. J Cell Biochem 108:769–77PubMedCrossRefGoogle Scholar
  45. 45.
    Picinato MC, Hirata AE, Cipolla-Neto J, Curi R, Carvalho CR, Anhe GF, Carpinelli AR (2008) Activation of insulin and IGF-1 signaling pathways by melatonin through MT1 receptor in isolated rat pancreatic islets. J Pineal Res 44:88–94PubMedGoogle Scholar
  46. 46.
    Ostrowska Z, Kos-Kudla B, Swietochowska E, Marek B, Kajdaniuk D, Ciesielska-Kopacz N (2001) Influence of pinealectomy and long-term melatonin administration on GH-IGF-I axis function in male rats. Neuro Endocrinol Lett 22:255–62PubMedGoogle Scholar
  47. 47.
    Bell NH (2001) Advances in the treatment of osteoporosis. Curr Drug Targets Immune Endocr Metabol Disord 1:93–102PubMedCrossRefGoogle Scholar
  48. 48.
    Blair HC, Athanasou NA (2004) Recent advances in osteoclast biology and pathological bone resorption. Histol Histopathol 19:189–99PubMedGoogle Scholar
  49. 49.
    Reiter RJ, Tan DX, Qi W, Manchester LC, Karbownik M, Calvo JR (2000) Pharmacology and physiology of melatonin in the reduction of oxidative stress in vivo. Biol Signals Recept 9:160–171PubMedCrossRefGoogle Scholar
  50. 50.
    Matuszak Z, Reszka K, Chignell CF (1997) Reaction of melatonin and related indoles with hydroxyl radicals: EPR and spin trapping investigations. Free Radic Biol Med 23:367–72PubMedCrossRefGoogle Scholar
  51. 51.
    Tan DX, Reiter RJ, Manchester LC, Yan MT, El-Sawi M, Sainz RM, Mayo JC, Kohen R, Allegra M, Hardeland R (2002) Chemical and physical properties and potential mechanisms: Melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2:181–97PubMedCrossRefGoogle Scholar
  52. 52.
    Baek KH, Oh KW, Lee WY, Lee SS, Kim MK, Kwon HS, Rhee EJ, Han JH, Song KH, Cha BY, Lee KW, Kang MI (2010) Association of oxidative stress with postmenopausal osteoporosis and the effects of hydrogen peroxide on osteoclast formation in human bone marrow cell cultures. Calcif Tissue Int 87:226–35PubMedCrossRefGoogle Scholar
  53. 53.
    Bax BE, Alam AS, Banerji B, Bax CM, Bevis PJ, Stevens CR, Moonga BS, Blake DR, Zaidi M (1992) Stimulation of osteoclastic bone resorption by hydrogen peroxide. Biochem Biophys Res Commun 183:1153–58PubMedCrossRefGoogle Scholar
  54. 54.
    Basu S, Michaelsson K, Olofsson H, Johansson S, Melhus H (2001) Association between oxidative stress and bone mineral density. Biochem Biophys Res Commun 288:275–79PubMedCrossRefGoogle Scholar
  55. 55.
    Lee NK, Choi YG, Baik JY, Han SY, Jeong DW, Bae YS, Kim N, Lee SY (2005) A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood 106:852–59PubMedCrossRefGoogle Scholar
  56. 56.
    Ozler M, Simsek K, Ozkan C, Akgul EO, Topal T, Oter S, Korkmaz A (2010) Comparison of the effect of topical and systemic melatonin administration on delayed wound healing in rats that underwent pinealectomy. Scand J Clin Lab Invest 70:447–52PubMedCrossRefGoogle Scholar
  57. 57.
    Sahna E, Parlakpinar H, Vardi N, Cigremis Y, Acet A (2004) Efficacy of melatonin as protectant against oxidative stress and structural changes in liver tissue in pinealectomized rats. Acta Histochem 106:331–36PubMedCrossRefGoogle Scholar
  58. 58.
    Gilad E, Wong HR, Zingarelli B, Virag L, O'Connor M, Salzman AL, Szabo C (1998) Melatonin inhibits expression of the inducible isoform of nitric oxide synthase in murine macrophages: Role of inhibition of NFkappaB activation. FASEB J 12:685–93PubMedGoogle Scholar
  59. 59.
    Crespo E, Macias M, Pozo D, Escames G, Martin M, Vives F, Guerrero JM, Acuna-Castroviejo D (1999) Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharide-induced multiple organ dysfunction syndrome in rats. FASEB J 13:1537–46PubMedGoogle Scholar
  60. 60.
    Cardinali DP, Ladizesky MG, Boggio V, Cutrera RA, Mautalen C (2003) Melatonin effects on bone: Experimental facts and clinical perspectives. J Pineal Res 34:81–87PubMedCrossRefGoogle Scholar
  61. 61.
    Altindag O, Erel O, Soran N, Celik H, Selek S (2008) Total oxidative/anti-oxidative status and relation to bone mineral density in osteoporosis. Rheumatol Int 28:317–21PubMedCrossRefGoogle Scholar
  62. 62.
    Sheweita SA, Khoshhal KI (2007) Calcium metabolism and oxidative stress in bone fractures: Role of antioxidants. Curr Drug Metab 8:519–25PubMedCrossRefGoogle Scholar
  63. 63.
    Melhus H, Michaelsson K, Holmberg L, Wolk A, Ljunghall S (1999) Smoking, antioxidant vitamins, and the risk of hip fracture. J Bone Miner Res 14:129–35PubMedCrossRefGoogle Scholar
  64. 64.
    Suzuki N, Hattori A (2002) Melatonin suppresses osteoclastic and osteoblastic activities in the scales of goldfish. J Pineal Res 33:253–58PubMedCrossRefGoogle Scholar
  65. 65.
    Ostrowska Z, Kos-Kudla B, Marek B, Kajdaniuk D, Ciesielska-Kopacz N (2002) The relationship between the daily profile of chosen biochemical markers of bone metabolism and melatonin and other hormone secretion in rats under physiological conditions. Neuro Endocrinol Lett 23:417–25PubMedGoogle Scholar
  66. 66.
    Ladizesky MG, Boggio V, Albornoz LE, Castrillon PO, Mautalen C, Cardinali DP (2003) Melatonin increases oestradiol-induced bone formation in ovariectomized rats. J Pineal Res 34:143–51PubMedCrossRefGoogle Scholar
  67. 67.
    Cos S, Gonzalez A, Martinez-Campa C, Mediavilla MD, Alonso-Gonzalez C, Sanchez-Barcelo EJ (2006) Estrogen-signaling pathway: A link between breast cancer and melatonin oncostatic actions. Cancer Detect Prev 30:118–28PubMedCrossRefGoogle Scholar
  68. 68.
    Ladizesky MG, Cutrera RA, Boggio V, Somoza J, Centrella JM, Mautalen C, Cardinali DP (2001) Effect of melatonin on bone metabolism in ovariectomized rats. Life Sci 70:557–65PubMedCrossRefGoogle Scholar
  69. 69.
    Ostrowska Z, Kos-Kudla B, Marek B, Kajdaniuk D, Staszewicz P, Szapska B, Strzelczyk J (2002) The influence of pinealectomy and melatonin administration on the dynamic pattern of biochemical markers of bone metabolism in experimental osteoporosis in the rat. Neuro Endocrinol Lett 23(Suppl 1):104–9PubMedGoogle Scholar
  70. 70.
    Uslu S, Uysal A, Oktem G, Yurtseven M, Tanyalcin T, Basdemir G (2007) Constructive effect of exogenous melatonin against osteoporosis after ovariectomy in rats. Anal Quant Cytol Histol 29:317–25PubMedGoogle Scholar
  71. 71.
    Witt-Enderby PA, Slater JP, Johnson NA, Bondi CD, Dodda BR, Kotlarczyk MP, Clafshenkel WP, Sethi S, Higginbotham S, Rutkowski JL, Gallagher KM, Davis VL (2012) Effects on bone by the light/dark cycle and chronic treatment with melatonin and/or hormone replacement therapy in intact female mice. J Pineal ResGoogle Scholar
  72. 72.
    Waldhauser F, Waldhauser M, Lieberman HR, Deng MH, Lynch HJ, Wurtman RJ (1984) Bioavailability of oral melatonin in humans. Neuroendocrinology 39:307–13PubMedCrossRefGoogle Scholar
  73. 73.
    Egermann M, Gerhardt C, Barth A, Maestroni GJ, Schneider E, Alini M (2011) Pinealectomy affects bone mineral density and structure—an experimental study in sheep. BMC Musculoskelet Disord 12:271PubMedCrossRefGoogle Scholar
  74. 74.
    Turgut M, Kaplan S, Turgut AT, Aslan H, Guvenc T, Cullu E, Erdogan S (2005) Morphological, stereological and radiological changes in pinealectomized chicken cervical vertebrae. J Pineal Res 39:392–99PubMedCrossRefGoogle Scholar
  75. 75.
    Feskanich D, Hankinson SE, Schernhammer ES (2009) Nightshift work and fracture risk: The Nurses' health study. Osteoporos Int 20:537–42PubMedCrossRefGoogle Scholar
  76. 76.
    Burch JB, Yost MG, Johnson W, Allen E (2005) Melatonin, sleep, and shift work adaptation. J Occup Environ Med 47:893–901PubMedCrossRefGoogle Scholar
  77. 77.
    Kotlarczyk MP, Lassila HC, O'Neil CK, D'Amico F, Enderby LT, Witt-Enderby PA, Balk JL (2012) Melatonin osteoporosis prevention study (MOPS): a randomized, double-blind, placebo-controlled study examining the effects of melatonin on bone health and quality of life in perimenopausal women. J Pineal Res 52:414–26PubMedCrossRefGoogle Scholar
  78. 78.
    Crepaldi G, Romanato G, Tonin P, Maggi S (2007) Osteoporosis and body composition. J Endocrinol Invest 30:42–47PubMedGoogle Scholar
  79. 79.
    Fideleff HL, Boquete H, Fideleff G, Albornoz L, Perez LS, Suarez M, Esquifino AI, Honfi M, Cardinali DP (2006) Gender-related differences in urinary 6-sulfatoxymelatonin levels in obese pubertal individuals. J Pineal Res 40:214–18PubMedCrossRefGoogle Scholar
  80. 80.
    Shafii M, MacMillan DR, Key MP, Kaufman N, Nahinsky ID (1997) Case study: Melatonin in severe obesity. J Am Acad Child Adolesc Psychiatry 36:412–16PubMedCrossRefGoogle Scholar
  81. 81.
    Blaicher W, Imhof MH, Gruber DM, Schneeberger C, Sator MO, Huber JC (1999) Endocrinological disorders. Focusing on melatonin's interactions. Gynecol Obstet Invest 48:179–82PubMedCrossRefGoogle Scholar
  82. 82.
    Blaicher W, Speck E, Imhof MH, Gruber DM, Schneeberger C, Sator MO, Huber JC (2000) Melatonin in postmenopausal females. Arch Gynecol Obstet 263:116–18PubMedCrossRefGoogle Scholar
  83. 83.
    Ostrowska Z, Ziora K, Kos-Kudla B, Swietochowska E, Oswiecimska J, Dyduch A, Wolkowska-Pokrywa K, Szapska B (2010) Melatonin, the RANKL/RANK/OPG system, and bone metabolism in girls with anorexia nervosa. Endokrynol Pol 61:117–23PubMedGoogle Scholar
  84. 84.
    Lam TP, Hung VW, Yeung HY, Tse YK, Chu WC, Ng BK, Lee KM, Qin L, Cheng JC (2011) Abnormal bone quality in adolescent idiopathic scoliosis: A case–control study on 635 subjects and 269 normal controls with bone densitometry and quantitative ultrasound. Spine (Phila Pa 1976) 36:1211–17CrossRefGoogle Scholar
  85. 85.
    Machida M, Dubousset J, Imamura Y, Iwaya T, Yamada T, Kimura J (1995) Role of melatonin deficiency in the development of scoliosis in pinealectomised chickens. J Bone Joint Surg Br 77:134–38PubMedGoogle Scholar
  86. 86.
    Turgut M, Yenisey C, Uysal A, Bozkurt M, Yurtseven ME (2003) The effects of pineal gland transplantation on the production of spinal deformity and serum melatonin level following pinealectomy in the chicken. Eur Spine J 12:487–94PubMedCrossRefGoogle Scholar
  87. 87.
    Machida M, Dubousset J, Yamada T, Kimura J (2009) Serum melatonin levels in adolescent idiopathic scoliosis prediction and prevention for curve progression—a prospective study. J Pineal Res 46:344–48PubMedCrossRefGoogle Scholar
  88. 88.
    Brodner W, Krepler P, Nicolakis M, Langer M, Kaider A, Lack W, Waldhauser F (2000) Melatonin and adolescent idiopathic scoliosis. J Bone Joint Surg Br 82:399–403PubMedCrossRefGoogle Scholar
  89. 89.
    Man GC, Wong JH, Wang WW, Sun GQ, Yeung BH, Ng TB, Lee SK, Ng BK, Qiu Y, Cheng JC (2011) Abnormal melatonin receptor 1B expression in osteoblasts from girls with adolescent idiopathic scoliosis. J Pineal Res 50:395–402PubMedCrossRefGoogle Scholar
  90. 90.
    Moreau A, Wang DS, Forget S, Azeddine B, Angeloni D, Fraschini F, Labelle H, Poitras B, Rivard CH, Grimard G (2004) Melatonin signaling dysfunction in adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 29:1772–81CrossRefGoogle Scholar
  91. 91.
    Azeddine B, Letellier K, Wang dS, Moldovan F, Moreau A (2007) Molecular determinants of melatonin signaling dysfunction in adolescent idiopathic scoliosis. Clin Orthop Relat Res 462:45–52PubMedCrossRefGoogle Scholar
  92. 92.
    Elsea SH, Girirajan S (2008) Smith–Magenis syndrome. Eur J Hum Genet 16:412–21PubMedCrossRefGoogle Scholar
  93. 93.
    Spilsbury J, Mohanty K (2003) The orthopaedic manifestations of Smith–Magenis syndrome. J Pediatr Orthop B 12:22–26PubMedGoogle Scholar
  94. 94.
    De LH, De Blois MC, Claustrat B, Romana S, Albrecht U, Von Kleist-Retzow JC, Delobel B, Viot G, Lyonnet S, Vekemans M, Munnich A (2001) Inversion of the circadian rhythm of melatonin in the Smith–Magenis syndrome. J Pediatr 139:111–16CrossRefGoogle Scholar
  95. 95.
    Boudreau EA, Johnson KP, Jackman AR, Blancato J, Huizing M, Bendavid C, Jones M, Chandrasekharappa SC, Lewy AJ, Smith AC, Magenis RE (2009) Review of disrupted sleep patterns in Smith–Magenis syndrome and normal melatonin secretion in a patient with an atypical interstitial 17p11.2 deletion. Am J Med Genet A 149A:1382–91PubMedCrossRefGoogle Scholar
  96. 96.
    Ferlin A, Schipilliti M, Foresta C (2011) Bone density and risk of osteoporosis in Klinefelter syndrome. Acta Paediatr 100:878–84PubMedCrossRefGoogle Scholar
  97. 97.
    Ferlin A, Schipilliti M, Vinanzi C, Garolla A, Di MA, Selice R, Lenzi A, Foresta C (2011) Bone mass in subjects with Klinefelter syndrome: Role of testosterone levels and androgen receptor gene CAG polymorphism. J Clin Endocrinol Metab 96:E739–E745PubMedCrossRefGoogle Scholar
  98. 98.
    Luboshitzky R, Wagner O, Lavi S, Herer P, Lavie P (1996) Abnormal melatonin secretion in male patients with hypogonadism. J Mol Neurosci 7:91–98PubMedCrossRefGoogle Scholar
  99. 99.
    Luboshitzky R, Wagner O, Lavi S, Herer P, Lavie P (1997) Abnormal melatonin secretion in hypogonadal men: The effect of testosterone treatment. Clin Endocrinol (Oxf) 47:463–69CrossRefGoogle Scholar
  100. 100.
    Mosekilde L (2008) Primary hyperparathyroidism and the skeleton. Clin Endocrinol (Oxf) 69:1–19CrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2013

Authors and Affiliations

  • A. K. Amstrup
    • 1
  • T. Sikjaer
    • 1
  • L. Mosekilde
    • 1
  • L. Rejnmark
    • 1
  1. 1.Department of Internal Medicine and Endocrinology (MEA)THG Tage-Hansens Gade 2, Aarhus University Hospital8000 AarhusDenmark

Personalised recommendations