Advertisement

Journal of Bone and Mineral Metabolism

, Volume 37, Issue 1, pp 60–71 | Cite as

Relationship between melatonin and bone resorption rhythms in premenopausal women

  • Melissa A. St HilaireEmail author
  • Shadab A. Rahman
  • Joshua J. Gooley
  • Paula A. Witt-Enderby
  • Steven W. Lockley
Original Article

Abstract

Although evidence exists for a daily rhythm in bone metabolism, the contribution of factors such as melatonin levels, the light–dark cycle, and the sleep–wake cycle is difficult to differentiate given their highly correlated time courses. To examine these influences on bone resorption, we collected 48-h sequential urine samples under both ambulatory (8-h sleep:16-h wake) and constant routine (CR) (constant wake, posture, nutrition and dim light) conditions from 20 healthy premenopausal women. Urinary 6-sulphatoxymelatonin (aMT6s; ng/h) and the bone resorption marker amino-terminal cross-linked collagen I telopeptide (NTx; bone collagen equivalents nM/h) were assayed and fit by cosinor models to determine significant 24-h rhythms and acrophase. Most participants had significant 24-h aMT6s rhythms during both ambulatory and CR conditions (95 and 85%, respectively), but fewer had significant 24-h NTx rhythms (70 and 70%, respectively). Among individuals with significant rhythms, mean (± SD) aMT6s acrophase times were 3:57 ± 1:50 and 3:43 ± 1:25 h under ambulatory and CR conditions, respectively, and 23:44 ± 5:55 and 3:06 ± 5:15 h, respectively, for NTx. Mean 24-h levels of both aMT6s and NTx were significantly higher during CR compared with ambulatory conditions (p < 0.0001 and p = 0.03, respectively). Menstrual phase (follicular versus luteal) had no impact on aMT6s or NTx timing or 24-h levels. This study confirms an endogenous circadian rhythm in NTx with a night-time peak when measured under CR conditions, but also confirms that environmental factors such as the sleep–wake or light–dark cycles, posture or meal timing affects overall concentrations and peak timing under ambulatory conditions, the significance of which remains unclear.

Keywords

Melatonin Circadian rhythm Bone metabolism Light Sleep 

Notes

Acknowledgements

MAStH and SAR were supported by a National Heart, Lung and Blood Institute fellowship in the program of training in Sleep, Circadian and Respiratory Neurobiology at Brigham and Women’s Hospital (T32 HL079010). PWE was supported by the Resident Fellow Translational Research Program in the Division of Clinical, Social and Administrative Sciences at the Duquesne University School of Pharmacy.

Compliance with ethical standards

Conflict of interest

In the last 24 months, MAStH has provided consulting services to The MathWorks Inc., MentalWorkout, and the Cooperative Research Centre for Alertness, Safety and Productivity, Australia. None of these commercial interests are related to the research or topic reported in this article. SAR, JJG, and PWE report no conflicts of interest. SWL has had a number of commercial interests in the last 24 months. None of them are directly related to the research or topic reported in this article; however, in the interests of full disclosure, are outlined below. In the past 2 years (2014–2016), SWL has received consulting fees from the Atlanta Falcons, Atlanta Hawks, Carbon Limiting Technologies Ltd on behalf of PhotonStar LED, Perceptive Advisors, and Serrado Capital; has current consulting contracts with Akili Interactive, Delos Living LLC, Environmental Light Sciences LLC, Focal Point LLC, Headwaters Inc., Hintsa Performance AG, Light Cognitive, OpTerra Energy Services Inc., Pegasus Capital Advisors LP, PlanLED, and Wyle Integrated Science and Engineering; owns equity in iSleep pty, Australia; has received unrestricted equipment gifts from Bioilluminations LLC, Bionetics Corporation, and F. Lux Software LLC; has received royalties from Oxford University Press; has received honoraria plus travel, accommodation or meals for invited seminars, conference presentations or teaching from Estee Lauder, Informa Exhibitions (USGBC), and Lightfair; travel, accommodation and/or meals only (no honoraria) for invited seminars, conference presentations or teaching from FASEB, Lightfair and USGBC. Through Brigham and Women’s Hospital, SWL has ongoing investigator-initiated research Grants from Biological Illuminations LLC and F. Lux Software LLC; has completed service agreements with Rio Tinto Iron Ore and Vanda Pharmaceuticals Inc; and had completed three sponsor-initiated clinical research contracts with Vanda Pharmaceuticals Inc. SWL holds process patents for the use of short-wavelength light for resetting the human circadian pacemaker and improving alertness and performance, and for a novel method to measure sleep, which are assigned to the Brigham and Women’s Hospital per Hospital policy. SWL has also served as a paid expert in arbitrations related to sleep, circadian rhythms and work hours and legal proceedings related to light, sleep and health. SWL is also a Program Leader for the Cooperative Research Centre for Alertness, Safety and Productivity, Australia.

Supplementary material

774_2017_896_MOESM1_ESM.tif (29.4 mb)
Supplementary material 1 (TIFF 30113 kb)
774_2017_896_MOESM2_ESM.tif (29.4 mb)
Supplementary material 2 (TIFF 30113 kb)

References

  1. 1.
    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 27:106–110CrossRefGoogle Scholar
  2. 2.
    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 70:557–565CrossRefGoogle Scholar
  3. 3.
    Cardinali DP, Ladizesky MG, Boggio V, Cutrera RA, Mautalen C (2003) Melatonin effects on bone: experimental facts and clinical perspectives. J Pineal Res 34:81–87CrossRefGoogle Scholar
  4. 4.
    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 42:231–239CrossRefGoogle Scholar
  5. 5.
    Sanchez-Barcelo EJ, Mediavilla MD, Tan DX, Reiter RJ (2010) Scientific basis for the potential use of melatonin in bone diseases: osteoporosis and adolescent idiopathic scoliosis. J Osteoporos 2010:830231CrossRefGoogle Scholar
  6. 6.
    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 Res 53:374–384CrossRefGoogle Scholar
  7. 7.
    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 40:332–342CrossRefGoogle Scholar
  8. 8.
    Roth JA, Kim BG, Lin WL, Cho MI (1999) Melatonin promotes osteoblast differentiation and bone formation. J Biol Chem 274:22041–22047CrossRefGoogle Scholar
  9. 9.
    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 49:222–238CrossRefGoogle Scholar
  10. 10.
    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 17:1219–1229CrossRefGoogle Scholar
  11. 11.
    Suzuki N, Hattori A (2002) Melatonin suppresses osteoclastic and osteoblastic activities in the scales of goldfish. J Pineal Res 33:253–258CrossRefGoogle Scholar
  12. 12.
    Ostrowska Z, Kos-Kudla B, Marek B, Kajdaniuk D (2003) Influence of lighting conditions on daily rhythm of bone metabolism in rats and possible involvement of melatonin and other hormones in this process. Endocr Regul 37:163–174Google Scholar
  13. 13.
    Ostrowska Z, Kos-Kudla B, Nowak M, Swietochowska E, Marek B, Gorski J, Kajdaniuk D, Wolkowska K (2003) The relationship between bone metabolism, melatonin and other hormones in sham-operated and pinealectomized rats. Endocr Regul 37:211–224Google Scholar
  14. 14.
    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 52:414–426CrossRefGoogle Scholar
  15. 15.
    Amstrup AK, Sikjaer T, Heickendorff L, Mosekilde L, Rejnmark L (2015) Melatonin improves bone mineral density at the femoral neck in postmenopausal women with osteopenia: a randomized controlled trial. J Pineal Res 59:221–229CrossRefGoogle Scholar
  16. 16.
    Joseph F, Chan BY, Durham BH, Ahmad AM, Vinjamuri S, Gallagher JA, Vora JP, Fraser WD (2007) The circadian rhythm of osteoprotegerin and its association with parathyroid hormone secretion. J Clin Endocrinol Metab 92:3230–3238CrossRefGoogle Scholar
  17. 17.
    Eastell R, Calvo MS, Burritt MF, Offord KP, Russell RG, Riggs BL (1992) Abnormalities in circadian patterns of bone resorption and renal calcium conservation in type I osteoporosis. J Clin Endocrinol Metab 74:487–494Google Scholar
  18. 18.
    Berruti A, Dogliotti L, Gorzegno G, Torta M, Tampellini M, Tucci M, Cerutti S, Frezet MM, Stivanello M, Sacchetto G, Angeli A (1999) Differential patterns of bone turnover in relation to bone pain and disease extent in bone in cancer patients with skeletal metastases. Clin Chem 45:1240–1247Google Scholar
  19. 19.
    Fraser WD, Anderson M, Chesters C, Durham B, Ahmad A, Chattington P, Vora J, Squire C, Diver M (2001) Circadian rhythm studies of serum bone resorption markers: implications for optimal sample timing and clinical utility. In: Eastell R, Baumann M, Hoyle NR, Wieczorek L (eds) Bone markers: biochemical and clinical perspectives. Martin Dunitz, London, pp 107–118Google Scholar
  20. 20.
    Rejnmark L, Vestergaard P, Heickendorff L, Andreasen F, Mosekilde L (2001) Loop diuretics alter the diurnal rhythm of endogenous parathyroid hormone secretion. A randomized-controlled study on the effects of loop- and thiazide-diuretics on the diurnal rhythms of calcitropic hormones and biochemical bone markers in postmenopausal women. Eur J Clin Invest 31:764–772CrossRefGoogle Scholar
  21. 21.
    Qvist P, Christgau S, Pedersen BJ, Schlemmer A, Christiansen C (2002) Circadian variation in the serum concentration of C-terminal telopeptide of type I collagen (serum CTx): effects of gender, age, menopausal status, posture, daylight, serum cortisol, and fasting. Bone 31:57–61CrossRefGoogle Scholar
  22. 22.
    Hassager C, Risteli J, Risteli L, Jensen SB, Christiansen C (1992) Diurnal variation in serum markers of type I collagen synthesis and degradation in healthy premenopausal women. J Bone Miner Res 7:1307–1311CrossRefGoogle Scholar
  23. 23.
    Heshmati HM, Riggs BL, Burritt MF, McAlister CA, Wollan PC, Khosla S (1998) Effects of the circadian variation in serum cortisol on markers of bone turnover and calcium homeostasis in normal postmenopausal women. J Clin Endocrinol Metab 83:751–756Google Scholar
  24. 24.
    Generali D, Berruti A, Tampellini M, Dovio A, Tedoldi S, Bonardi S, Tucci M, Allevi G, Aguggini S, Milani M, Bottini A, Dogliotti L, Angeli A (2007) The circadian rhythm of biochemical markers of bone resorption is normally synchronized in breast cancer patients with bone lytic metastases independently of tumor load. Bone 40:182–188CrossRefGoogle Scholar
  25. 25.
    Pellegrini GG, Gonzales Chaves MM, Fajardo MA, Ponce GM, Toyos GI, Lifshitz F, Friedman SM, Zeni SN (2012) Salivary bone turnover markers in healthy pre- and postmenopausal women: daily and seasonal rhythm. Clin Oral Investig 16:651–657CrossRefGoogle Scholar
  26. 26.
    Duffy JF, Dijk DJ (2002) Getting through to circadian oscillators: why use constant routines? J Biol Rhythms 17:4–13CrossRefGoogle Scholar
  27. 27.
    Gooley JJ, Rajaratnam SMW, Brainard GC, Kronauer RE, Czeisler CA, Lockley SW (2010) Spectral responses of the human circadian system depend on the irradiance and duration of exposure to light. Sci Transl Med 2:31ra3CrossRefGoogle Scholar
  28. 28.
    Aldhous ME, Arendt J (1988) Radioimmunoassay for 6-sulphatoxymelatonin in urine using an iodinated tracer. Ann Clin Biochem 25:298–303CrossRefGoogle Scholar
  29. 29.
    Lockley SW, Skene DJ, Arendt J, Tabandeh H, Bird AC, Defrance R (1997) Relationship between melatonin rhythms and visual loss in the blind. J Clin Endocrinol Metab 82:3763–3770Google Scholar
  30. 30.
    Skene DJ, Lockley SW, James K, Arendt J (1999) Correlation between urinary cortisol and 6-sulphatoxymelatonin rhythms in field studies of blind subjects. Clin Endocrinol (Oxf) 50:715–719CrossRefGoogle Scholar
  31. 31.
    Gunn PJ, Middleton B, Davies SK, Revell VL, Skene DJ (2016) Sex differences in the circadian profiles of melatonin and cortisol in plasma and urine matrices under constant routine conditions. Chronobiol Int 33:39–50CrossRefGoogle Scholar
  32. 32.
    Ostrowska Z, Kos-Kudla B, Marek B, Swietochowska E, Gorski J (2001) Assessment of the relationship between circadian variations of salivary melatonin levels and type I collagen metabolism in postmenopausal obese women. Neuro Endocrinol Lett 22:121–127Google Scholar
  33. 33.
    Fuleihan E-H, Klerman EB, Brown E, Czeisler CA (1997) N-Tx diurnal rhythm is truly endogenous. ASBMR Annual MeetingGoogle Scholar
  34. 34.
    Buehlmeier J, Frings-Meuthen P, Mohorko N, Lau P, Mazzucco S, Ferretti JL, Biolo G, Pisot R, Simunic B, Rittweger J (2017) Markers of bone metabolism during 14 days of bed rest in young and older men. J Musculoskelet Neuronal Interact 17:399–408Google Scholar
  35. 35.
    Morgan JL, Zwart SR, Heer M, Ploutz-Snyder R, Ericson K, Smith SM (2012) Bone metabolism and nutritional status during 30-day head-down-tilt bed rest. J Appl Physiol 1985 113:1519–1529CrossRefGoogle Scholar
  36. 36.
    LeBlanc A, Shackelford L, Schneider V (1998) Future human bone research in space. Bone 22:113S–116SCrossRefGoogle Scholar
  37. 37.
    Chua EC, Shui G, Lee IT, Lau P, Tan LC, Yeo SC, Lam BD, Bulchand S, Summers SA, Puvanendran K, Rozen SG, Wenk MR, Gooley JJ (2013) Extensive diversity in circadian regulation of plasma lipids and evidence for different circadian metabolic phenotypes in humans. Proc Natl Acad Sci USA 110:14468–14473CrossRefGoogle Scholar
  38. 38.
    Rahman SA, Castanon-Cervantes O, Scheer FA, Shea SA, Czeisler CA, Davidson AJ, Lockley SW (2015) Endogenous circadian regulation of pro-inflammatory cytokines and chemokines in the presence of bacterial lipopolysaccharide in humans. Brain Behav Immun 47:4–13CrossRefGoogle Scholar
  39. 39.
    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 60:419–423CrossRefGoogle Scholar
  40. 40.
    Lucassen EA, Coomans CP, van Putten M, de Kreij SR, van Genugten JH, Sutorius RP, de Rooij KE, van der Velde M, Verhoeve SL, Smit JW, Löwik CW, Smits HH, Guigas B, Aartsma-Rus AM, Meijer JH (2016) Environmental 24-hr cycles are essential for health. Curr Biol 26:1843–1853CrossRefGoogle Scholar
  41. 41.
    Quevedo I, Zuniga AM (2010) Low bone mineral density in rotating-shift workers. J Clin Densitom 13:467–469CrossRefGoogle Scholar
  42. 42.
    Kim BK, Choi YJ, Chung YS (2013) Other than daytime working is associated with lower bone mineral density: the Korea National Health and Nutrition Examination Survey 2009. Calcif Tissue Int 93:495–501CrossRefGoogle Scholar
  43. 43.
    Feskanich D, Hankinson SE, Schernhammer ES (2009) Nightshift work and fracture risk: the Nurses’ Health Study. Osteoporos Int 20:537–542CrossRefGoogle Scholar
  44. 44.
    Dijk DJ, Neri DF, Wyatt JK, Ronda JM, Riel E, Ritz-De Cecco A, Hughes RJ, Elliott AR, Prisk GK, West JB, Czeisler CA (2001) Sleep, performance, circadian rhythms, and light-dark cycles during two space shuttle flights. Am J Physiol Regul Integr Comp Physiol 281:R1647–R1664CrossRefGoogle Scholar
  45. 45.
    Barger LK, Flynn-Evans EE, Kubey A, Walsh L, Ronda JM, Wang W, Wright KP Jr, Czeisler CA (2014) Prevalence of sleep deficiency and use of hypnotic drugs in astronauts before, during, and after spaceflight: an observational study. Lancet Neurol 13:904–912CrossRefGoogle Scholar
  46. 46.
    Sibonga JD, Spector ER, Johnston SL, Tarver WJ (2015) Evaluating bone loss in ISS astronauts. Aerosp Med Hum Perform 86:A38–A44CrossRefGoogle Scholar
  47. 47.
    Cappellesso R, Nicole L, Guido A, Pizzol D (2015) Spaceflight osteoporosis: current state and future perspective. Endocr Regul 49:231–239CrossRefGoogle Scholar
  48. 48.
    Duffy JF, Zitting KM, Chinoy ED (2015) Aging and circadian rhythms. Sleep Med Clin 10:423–434CrossRefGoogle Scholar
  49. 49.
    Wang K, Wu Y, Yang Y, Chen J, Zhang D, Hu Y, Liu Z, Xu J, Shen Q, Zhang N, Mao X, Liu C (2015) The associations of bedtime, nocturnal, and daytime sleep duration with bone mineral density in pre- and post-menopausal women. Endocrine 49:538–548CrossRefGoogle Scholar
  50. 50.
    Nishizawa Y, Ohta H, Miura M, Inaba M, Ichimura S, Shiraki M, Takada J, Chaki O, Hagino H, Fujiwara S, Fukunaga M, Miki T, Yoshimura N (2013) Guidelines for the use of bone metabolic markers in the diagnosis and treatment of osteoporosis (2012 edition). J Bone Miner Metab 31:1–15CrossRefGoogle Scholar
  51. 51.
    Wright KP Jr, Gronfier C, Duffy JF, Czeisler CA (2005) Intrinsic period and light intensity determine the phase relationship between melatonin and sleep in humans. J Biol Rhythms 20:168–177CrossRefGoogle Scholar
  52. 52.
    Sletten TL, Vincenzi S, Redman JR, Lockley SW, Rajaratnam SMW (2010) Timing in sleep and its relationship with the endogenous melatonin rhythm. Front Neurol 1:137CrossRefGoogle Scholar
  53. 53.
    Gooley JJ, Chamberlain K, Smith KA, Khalsa SB, Rajaratnam SM, Van Reen E, Zeitzer JM, Czeisler CA, Lockley SW (2011) Exposure to room light before bedtime suppresses melatonin onset and shortens melatonin duration in humans. J Clin Endocrinol Metab 96:E463–E472CrossRefGoogle Scholar
  54. 54.
    Singh R, Singh RK, Mahdi AA, Saxena SP, Cornélissen G, Halberg F (2000) Circadian periodicity of urinary volume, creatinine and 5-hydroxyindole acetic acid excretion in healthy indians. Life Sci 66:209–214CrossRefGoogle Scholar
  55. 55.
    Wisser H, Breuer H (1981) Circadian changes of clinical chemical and endocrinological parameters. J Clin Chem Clin Biochem 19:323–337Google Scholar
  56. 56.
    Kanabrocki EL, Sothern RB, Sackett-Lundeen L, Ryan MD, Johnson M, Foley S, Dawson S, Ocasio T, McCormick JB, Haus E, Kaplan E, Nemchausky B (2008) Creatinine clearance and blood pressure: a 34-year circadian study. Clin Ter 159:409–417Google Scholar
  57. 57.
    Kamperis K, Hagstroem S, Radvanska E, Rittig S, Djurhuus JC (2010) Excess diuresis and natriuresis during acute sleep deprivation in healthy adults. Am J Physiol Renal Physiol 299:F404–F411CrossRefGoogle Scholar
  58. 58.
    Arendt J (1995) Melatonin and the mammalian pineal gland. Chapman and Hall, LondonGoogle Scholar
  59. 59.
    Uebelhart D, Schlemmer A, Johansen JS, Gineyts E, Christiansen C, Delmas PD (1991) Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium cross-links. J Clin Endocrinol Metab 72:367–373CrossRefGoogle Scholar
  60. 60.
    Schlemmer A, Hassager C, Jensen SB, Christiansen C (1992) Marked diurnal variation in urinary excretion of pyridinium cross-links in premenopausal women. J Clin Endocrinol Metab 74:476–480Google Scholar
  61. 61.
    de la Piedra C, Traba ML, Dominguez Cabrera C, Sosa Henriquez M (1997) New biochemical markers of bone resorption in the study of postmenopausal osteoporosis. Clin Chim Acta 265:225–234CrossRefGoogle Scholar
  62. 62.
    Flynn-Evans EE, Tabandeh H, Skene DJ, Lockley SW (2014) Circadian rhythm disorders and melatonin production in 127 blind women with and without light perception. J Biol Rhythms 29:215–224CrossRefGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Sleep and Circadian Disorders, Departments of Medicine and NeurologyBrigham and Women’s HospitalBostonUSA
  2. 2.Division of Sleep MedicineHarvard Medical SchoolBostonUSA
  3. 3.Programme in Neuroscience and Behavioural DisordersDuke-National University of Singapore Medical SchoolSingaporeSingapore
  4. 4.Division of Pharmaceutical, Administrative and Social SciencesDuquesne University School of PharmacyPittsburghUSA

Personalised recommendations