Melatonin improves bone mineral density at the femoral neck in postmenopausal women with osteopenia: a randomized controlled trial

Melatonin is known for its regulation of circadian rhythm. Recently, studies have shown that melatonin may have a positive effect on the skeleton. By increasing age, the melatonin levels decrease, which may lead to a further imbalanced bone remodeling. We aimed to investigate whether treatment with...

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Published inJournal of pineal research Vol. 59; no. 2; pp. 221 - 229
Main Authors Amstrup, Anne Kristine, Sikjaer, Tanja, Heickendorff, Lene, Mosekilde, Leif, Rejnmark, Lars
Format Journal Article
LanguageEnglish
Published England Blackwell Publishing Ltd 01.09.2015
Subjects
Absorptiometry, Photon
Aged
Bone Density - drug effects
Bone Diseases, Metabolic - diagnostic imaging
Bone Diseases, Metabolic - drug therapy
Bone Diseases, Metabolic - metabolism
bone mineral density
clinical trial
Dose-Response Relationship, Drug
Double-Blind Method
Female
Femur Neck - diagnostic imaging
Femur Neck - metabolism
Humans
melatonin
Middle Aged
osteoporosis
postmenopausal women
Postmenopause - metabolism
clinical trial
bone mineral density
postmenopausal women
melatonin
osteoporosis
Online AccessGet full text
ISSN0742-3098
1600-079X
1600-079X
DOI10.1111/jpi.12252

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Abstract Melatonin is known for its regulation of circadian rhythm. Recently, studies have shown that melatonin may have a positive effect on the skeleton. By increasing age, the melatonin levels decrease, which may lead to a further imbalanced bone remodeling. We aimed to investigate whether treatment with melatonin could improve bone mass and integrity in humans. In a double‐blind RCT, we randomized 81 postmenopausal osteopenic women to 1‐yr nightly treatment with melatonin 1 mg (N = 20), 3 mg (N = 20), or placebo (N = 41). At baseline and after 1‐yr treatment, we measured bone mineral density (BMD) by dual X‐ray absorptiometry, quantitative computed tomography (QCT), and high‐resolution peripheral QCT (HR‐pQCT) and determined calciotropic hormones and bone markers. Mean age of the study subjects was 63 (range 56–73) yr. Compared to placebo, femoral neck BMD increased by 1.4% in response to melatonin (P < 0.05) in a dose‐dependent manner (P < 0.01), as BMD increased by 0.5% in the 1 mg/day group (P = 0.55) and by 2.3% (P < 0.01) in the 3 mg/day group. In the melatonin group, trabecular thickness in tibia increased by 2.2% (P = 0.04), and volumetric bone mineral density (vBMD) in the spine, by 3.6% (P = 0.04) in the 3 mg/day. Treatment did not significantly affect BMD at other sites or levels of bone turnover markers; however, 24‐hr urinary calcium was decreased in response to melatonin by 12.2% (P = 0.02). In conclusion, 1‐yr treatment with melatonin increased BMD at femoral neck in a dose‐dependent manner, while high‐dose melatonin increased vBMD in the spine. Further studies are needed to assess the mechanisms of action and whether the positive effect of nighttime melatonin will protect against fractures.
AbstractList Melatonin is known for its regulation of circadian rhythm. Recently, studies have shown that melatonin may have a positive effect on the skeleton. By increasing age, the melatonin levels decrease, which may lead to a further imbalanced bone remodeling. We aimed to investigate whether treatment with melatonin could improve bone mass and integrity in humans. In a double‐blind RCT, we randomized 81 postmenopausal osteopenic women to 1‐yr nightly treatment with melatonin 1 mg (N = 20), 3 mg (N = 20), or placebo (N = 41). At baseline and after 1‐yr treatment, we measured bone mineral density (BMD) by dual X‐ray absorptiometry, quantitative computed tomography (QCT), and high‐resolution peripheral QCT (HR‐pQCT) and determined calciotropic hormones and bone markers. Mean age of the study subjects was 63 (range 56–73) yr. Compared to placebo, femoral neck BMD increased by 1.4% in response to melatonin ( P  < 0.05) in a dose‐dependent manner ( P  < 0.01), as BMD increased by 0.5% in the 1 mg/day group ( P  = 0.55) and by 2.3% ( P  < 0.01) in the 3 mg/day group. In the melatonin group, trabecular thickness in tibia increased by 2.2% ( P  = 0.04), and volumetric bone mineral density (vBMD) in the spine, by 3.6% ( P  = 0.04) in the 3 mg/day. Treatment did not significantly affect BMD at other sites or levels of bone turnover markers; however, 24‐hr urinary calcium was decreased in response to melatonin by 12.2% ( P  = 0.02). In conclusion, 1‐yr treatment with melatonin increased BMD at femoral neck in a dose‐dependent manner, while high‐dose melatonin increased vBMD in the spine. Further studies are needed to assess the mechanisms of action and whether the positive effect of nighttime melatonin will protect against fractures.
Melatonin is known for its regulation of circadian rhythm. Recently, studies have shown that melatonin may have a positive effect on the skeleton. By increasing age, the melatonin levels decrease, which may lead to a further imbalanced bone remodeling. We aimed to investigate whether treatment with melatonin could improve bone mass and integrity in humans. In a double‐blind RCT, we randomized 81 postmenopausal osteopenic women to 1‐yr nightly treatment with melatonin 1 mg (N = 20), 3 mg (N = 20), or placebo (N = 41). At baseline and after 1‐yr treatment, we measured bone mineral density (BMD) by dual X‐ray absorptiometry, quantitative computed tomography (QCT), and high‐resolution peripheral QCT (HR‐pQCT) and determined calciotropic hormones and bone markers. Mean age of the study subjects was 63 (range 56–73) yr. Compared to placebo, femoral neck BMD increased by 1.4% in response to melatonin (P < 0.05) in a dose‐dependent manner (P < 0.01), as BMD increased by 0.5% in the 1 mg/day group (P = 0.55) and by 2.3% (P < 0.01) in the 3 mg/day group. In the melatonin group, trabecular thickness in tibia increased by 2.2% (P = 0.04), and volumetric bone mineral density (vBMD) in the spine, by 3.6% (P = 0.04) in the 3 mg/day. Treatment did not significantly affect BMD at other sites or levels of bone turnover markers; however, 24‐hr urinary calcium was decreased in response to melatonin by 12.2% (P = 0.02). In conclusion, 1‐yr treatment with melatonin increased BMD at femoral neck in a dose‐dependent manner, while high‐dose melatonin increased vBMD in the spine. Further studies are needed to assess the mechanisms of action and whether the positive effect of nighttime melatonin will protect against fractures.
Melatonin is known for its regulation of circadian rhythm. Recently, studies have shown that melatonin may have a positive effect on the skeleton. By increasing age, the melatonin levels decrease, which may lead to a further imbalanced bone remodeling. We aimed to investigate whether treatment with melatonin could improve bone mass and integrity in humans. In a double-blind RCT, we randomized 81 postmenopausal osteopenic women to 1-yr nightly treatment with melatonin 1 mg (N = 20), 3 mg (N = 20), or placebo (N = 41). At baseline and after 1-yr treatment, we measured bone mineral density (BMD) by dual X-ray absorptiometry, quantitative computed tomography (QCT), and high-resolution peripheral QCT (HR-pQCT) and determined calciotropic hormones and bone markers. Mean age of the study subjects was 63 (range 56-73) yr. Compared to placebo, femoral neck BMD increased by 1.4% in response to melatonin (P < 0.05) in a dose-dependent manner (P < 0.01), as BMD increased by 0.5% in the 1 mg/day group (P = 0.55) and by 2.3% (P < 0.01) in the 3 mg/day group. In the melatonin group, trabecular thickness in tibia increased by 2.2% (P = 0.04), and volumetric bone mineral density (vBMD) in the spine, by 3.6% (P = 0.04) in the 3 mg/day. Treatment did not significantly affect BMD at other sites or levels of bone turnover markers; however, 24-hr urinary calcium was decreased in response to melatonin by 12.2% (P = 0.02). In conclusion, 1-yr treatment with melatonin increased BMD at femoral neck in a dose-dependent manner, while high-dose melatonin increased vBMD in the spine. Further studies are needed to assess the mechanisms of action and whether the positive effect of nighttime melatonin will protect against fractures.
Melatonin is known for its regulation of circadian rhythm. Recently, studies have shown that melatonin may have a positive effect on the skeleton. By increasing age, the melatonin levels decrease, which may lead to a further imbalanced bone remodeling. We aimed to investigate whether treatment with melatonin could improve bone mass and integrity in humans. In a double-blind RCT, we randomized 81 postmenopausal osteopenic women to 1-yr nightly treatment with melatonin 1 mg (N = 20), 3 mg (N = 20), or placebo (N = 41). At baseline and after 1-yr treatment, we measured bone mineral density (BMD) by dual X-ray absorptiometry, quantitative computed tomography (QCT), and high-resolution peripheral QCT (HR-pQCT) and determined calciotropic hormones and bone markers. Mean age of the study subjects was 63 (range 56-73) yr. Compared to placebo, femoral neck BMD increased by 1.4% in response to melatonin (P < 0.05) in a dose-dependent manner (P < 0.01), as BMD increased by 0.5% in the 1 mg/day group (P = 0.55) and by 2.3% (P < 0.01) in the 3 mg/day group. In the melatonin group, trabecular thickness in tibia increased by 2.2% (P = 0.04), and volumetric bone mineral density (vBMD) in the spine, by 3.6% (P = 0.04) in the 3 mg/day. Treatment did not significantly affect BMD at other sites or levels of bone turnover markers; however, 24-hr urinary calcium was decreased in response to melatonin by 12.2% (P = 0.02). In conclusion, 1-yr treatment with melatonin increased BMD at femoral neck in a dose-dependent manner, while high-dose melatonin increased vBMD in the spine. Further studies are needed to assess the mechanisms of action and whether the positive effect of nighttime melatonin will protect against fractures.Melatonin is known for its regulation of circadian rhythm. Recently, studies have shown that melatonin may have a positive effect on the skeleton. By increasing age, the melatonin levels decrease, which may lead to a further imbalanced bone remodeling. We aimed to investigate whether treatment with melatonin could improve bone mass and integrity in humans. In a double-blind RCT, we randomized 81 postmenopausal osteopenic women to 1-yr nightly treatment with melatonin 1 mg (N = 20), 3 mg (N = 20), or placebo (N = 41). At baseline and after 1-yr treatment, we measured bone mineral density (BMD) by dual X-ray absorptiometry, quantitative computed tomography (QCT), and high-resolution peripheral QCT (HR-pQCT) and determined calciotropic hormones and bone markers. Mean age of the study subjects was 63 (range 56-73) yr. Compared to placebo, femoral neck BMD increased by 1.4% in response to melatonin (P < 0.05) in a dose-dependent manner (P < 0.01), as BMD increased by 0.5% in the 1 mg/day group (P = 0.55) and by 2.3% (P < 0.01) in the 3 mg/day group. In the melatonin group, trabecular thickness in tibia increased by 2.2% (P = 0.04), and volumetric bone mineral density (vBMD) in the spine, by 3.6% (P = 0.04) in the 3 mg/day. Treatment did not significantly affect BMD at other sites or levels of bone turnover markers; however, 24-hr urinary calcium was decreased in response to melatonin by 12.2% (P = 0.02). In conclusion, 1-yr treatment with melatonin increased BMD at femoral neck in a dose-dependent manner, while high-dose melatonin increased vBMD in the spine. Further studies are needed to assess the mechanisms of action and whether the positive effect of nighttime melatonin will protect against fractures.
Author Rejnmark, Lars
Mosekilde, Leif
Heickendorff, Lene
Amstrup, Anne Kristine
Sikjaer, Tanja
Author_xml – sequence: 1
  givenname: Anne Kristine
  surname: Amstrup
  fullname: Amstrup, Anne Kristine
  email: Address reprint requests to Anne Kristine Amstrup, Osteoporosis Clinic, Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital, Tage-Hansens Gade 2, 8000 DK-Aarhus C, Denmark., anne_kristine_am@hotmail.com
  organization: Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital, THG, Aarhus, Denmark
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  givenname: Tanja
  surname: Sikjaer
  fullname: Sikjaer, Tanja
  organization: Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital, THG, Aarhus, Denmark
– sequence: 3
  givenname: Lene
  surname: Heickendorff
  fullname: Heickendorff, Lene
  organization: Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
– sequence: 4
  givenname: Leif
  surname: Mosekilde
  fullname: Mosekilde, Leif
  organization: Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital, THG, Aarhus, Denmark
– sequence: 5
  givenname: Lars
  surname: Rejnmark
  fullname: Rejnmark, Lars
  organization: Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital, THG, Aarhus, Denmark
BackLink https://www.ncbi.nlm.nih.gov/pubmed/26036434$$D View this record in MEDLINE/PubMed
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Issue 2
Keywords clinical trial
bone mineral density
postmenopausal women
melatonin
osteoporosis
Language English
License http://onlinelibrary.wiley.com/termsAndConditions#vor
2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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Central Denmark Region
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Danish Osteoporosis Patient Union and Toyota Foundation, Denmark
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Karen Elise Jensens Foundation
A.P. Møller og hustru Chastine MC-Kinney Møllers Foundation
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PublicationTitle Journal of pineal research
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References Hansen S, Brixen K, Gravholt CH. Compromised trabecular microarchitecture and lower finite element estimates of radius and tibia bone strength in adults with turner syndrome: a cross-sectional study using high-resolution-pQCT. J Bone Miner Res 2012; 27:1794-1803.
Karagas MR, Lu-Yao GL, Barrett JA et al. Heterogeneity of hip fracture: age, race, sex, and geographic patterns of femoral neck and trochanteric fractures among the US elderly. Am J Epidemiol 1996; 143:677-682.
Laib A, Ruegsegger P. Calibration of trabecular bone structure measurements of in vivo three-dimensional peripheral quantitative computed tomography with 28-microm-resolution microcomputed tomography. Bone 1999; 24:35-39.
Histing T, Anton C, Scheuer C et al. Melatonin impairs fracture healing by suppressing RANKL-mediated bone remodeling. J Surg Res 2012; 173:83-90.
Wehren LE, Magaziner J. Hip fracture: risk factors and outcomes. Curr Osteoporos Rep 2003; 1:78-85.
Hermann AP, Thomasen J, Vestergaard P et al. Assessment of calcium intake. A quick method compared to a 7 days food diary. Calcif Tissue Int 2009; 64(Suppl 1):S82.
Baek KH, Oh KW, Lee WY et al. 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 2010; 87:226-235.
Zhang L, Su P, Xu C et al. Melatonin inhibits adipogenesis and enhances osteogenesis of human mesenchymal stem cells by suppressing PPARgamma expression and enhancing Runx2 expression. J Pineal Res 2010; 49:364-372.
Zhang HM, Zhang Y. Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J Pineal Res 2014; 57:131-146.
Ostrowska Z, Kos-Kudla B, Marek B et al. 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 2002; 23:417-425.
Zhang L, Zhang J, Ling Y et al. Sustained release of melatonin from poly (lactic-co-glycolic acid) (PLGA) microspheres to induce osteogenesis of human mesenchymal stem cells in vitro. J Pineal Res 2013; 54:24-32.
Ostrowska Z, Kos-Kudla B, Nowak M et al. The relationship between bone metabolism, melatonin and other hormones in sham-operated and pinealectomized rats. Endocr Regul 2003; 37:211-224.
Kotlarczyk MP, Lassila HC, O'Neil CK et al. 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 2012; 52:414-426.
Zhdanova IV, Wurtman RJ, Balcioglu A et al. Endogenous melatonin levels and the fate of exogenous melatonin: age effects. J Gerontol A Biol Sci Med Sci 1998; 53:B293-B298.
Marks R. Hip fracture epidemiological trends, outcomes, and risk factors, 1970-2009. Int J Gen Med 2010; 3:1-17.
Khoo BC, Brown K, Cann C et al. Comparison of QCT-derived and DXA-derived areal bone mineral density and T scores. Osteoporos Int 2009; 20:1539-1545.
Hojskov CS, Heickendorff L, Moller HJ. High-throughput liquid-liquid extraction and LCMSMS assay for determination of circulating 25(OH) vitamin D3 and D2 in the routine clinical laboratory. Clin Chim Acta 2010; 411:114-116.
Son JH, Cho YC, Sung IY et al. Melatonin promotes osteoblast differentiation and mineralization of MC3T3-E1 cells under hypoxic conditions through activation of PKD/p38 pathways. J Pineal Res 2014; 57:385-392.
Wade AG, Ford I, Crawford G et al. Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety. BMC Med 2010; 8:51.
Galano A, Tan DX, Reiter RJ. On the free radical scavenging activities of melatonin's metabolites, AFMK and AMK. J Pineal Res 2013; 54:245-257.
Stehle JH, Saade A, Rawashdeh O et al. A survey of molecular details in the human pineal gland in the light of phylogeny, structure, function and chronobiological diseases. J Pineal Res 2011; 51:17-43.
Satomura K, Tobiume S, Tokuyama R et al. Melatonin at pharmacological doses enhances human osteoblastic differentiation in vitro and promotes mouse cortical bone formation in vivo. J Pineal Res 2007; 42:231-239.
Mody N, Parhami F, Sarafian TA et al. Oxidative stress modulates osteoblastic differentiation of vascular and bone cells. Free Radic Biol Med 2001; 31:509-519.
Tresguerres IF, Tamimi F, Eimar H et al. Melatonin dietary supplement as an anti-aging therapy for age-related bone loss. Rejuvenation Res 2014; 17:341-346.
Pistoia W, Van RB, Lochmuller EM et al. Estimation of distal radius failure load with micro-finite element analysis models based on three-dimensional peripheral quantitative computed tomography images. Bone 2002; 30:842-848.
Nakade O, Koyama H, Ariji H et al. Melatonin stimulates proliferation and type I collagen synthesis in human bone cells in vitro. J Pineal Res 1999; 27:106-110.
Koyama H, Nakade O, Takada Y et al. 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 2002; 17:1219-1229.
Chan CW, Song Y, Ailenberg M et al. Studies of melatonin effects on epithelia using the human embryonic kidney-293 (HEK-293) cell line. Endocrinology 1997; 138:4732-4739.
Radio NM, Doctor JS, Witt-Enderby PA. 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 2006; 40:332-342.
Song Y, Tam PC, Poon AM et al. 2-[125I]iodomelatonin-binding sites in the human kidney and the effect of guanosine 5′-O-(3-thiotriphosphate). J Clin Endocrinol Metab 1995; 80:1560-1565.
Uslu S, Uysal A, Oktem G et al. Constructive effect of exogenous melatonin against osteoporosis after ovariectomy in rats. Anal Quant Cytol Histol 2007; 29:317-325.
Buscemi N, Vandermeer B, Hooton N et al. The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med 2005; 20:1151-1158.
Turgut M, Kaplan S, Turgut AT et al. Morphological, stereological and radiological changes in pinealectomized chicken cervical vertebrae. J Pineal Res 2005; 39:392-399.
Egermann M, Gerhardt C, Barth A et al. Pinealectomy affects bone mineral density and structure-an experimental study in sheep. BMC Musculoskelet Disord 2011; 12:271.
Genant HK, Block JE, Steiger P et al. Quantitative computed tomography in assessment of osteoporosis. Semin Nucl Med 1987; 17:316-333.
Sethi S, Radio NM, Kotlarczyk MP et al. 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 2010; 49:222-238.
Witt-Enderby PA, Slater JP, Johnson NA et al. 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 2012; 53:374-384.
Bondi CD, Khairnar R, Kamal K et al. An early development budget impact model for the use of melatonin in the treatment and prevention of osteoporosis. Clin Pharmacol Biopharm 2015; 4:132.
Park KH, Kang JW, Lee EM et al. Melatonin promotes osteoblastic differentiation through the BMP/ERK/Wnt signaling pathways. J Pineal Res 2011; 51:187-194.
Bai XC, Lu D, Bai J et al. Oxidative stress inhibits osteoblastic differentiation of bone cells by ERK and NF-kappaB. Biochem Biophys Res Commun 2004; 314:197-207.
Li M, Zhao L, Liu J et al. Hydrogen peroxide induces G2 cell cycle arrest and inhibits cell proliferation in osteoblasts. Anat Rec (Hoboken) 2009; 292:1107-1113.
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References_xml – reference: Zhang HM, Zhang Y. Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J Pineal Res 2014; 57:131-146.
– reference: Zhang L, Su P, Xu C et al. Melatonin inhibits adipogenesis and enhances osteogenesis of human mesenchymal stem cells by suppressing PPARgamma expression and enhancing Runx2 expression. J Pineal Res 2010; 49:364-372.
– reference: Park KH, Kang JW, Lee EM et al. Melatonin promotes osteoblastic differentiation through the BMP/ERK/Wnt signaling pathways. J Pineal Res 2011; 51:187-194.
– reference: Wehren LE, Magaziner J. Hip fracture: risk factors and outcomes. Curr Osteoporos Rep 2003; 1:78-85.
– reference: Pistoia W, Van RB, Lochmuller EM et al. Estimation of distal radius failure load with micro-finite element analysis models based on three-dimensional peripheral quantitative computed tomography images. Bone 2002; 30:842-848.
– reference: Zhdanova IV, Wurtman RJ, Balcioglu A et al. Endogenous melatonin levels and the fate of exogenous melatonin: age effects. J Gerontol A Biol Sci Med Sci 1998; 53:B293-B298.
– reference: Stehle JH, Saade A, Rawashdeh O et al. A survey of molecular details in the human pineal gland in the light of phylogeny, structure, function and chronobiological diseases. J Pineal Res 2011; 51:17-43.
– reference: Bai XC, Lu D, Bai J et al. Oxidative stress inhibits osteoblastic differentiation of bone cells by ERK and NF-kappaB. Biochem Biophys Res Commun 2004; 314:197-207.
– reference: Son JH, Cho YC, Sung IY et al. Melatonin promotes osteoblast differentiation and mineralization of MC3T3-E1 cells under hypoxic conditions through activation of PKD/p38 pathways. J Pineal Res 2014; 57:385-392.
– reference: Koyama H, Nakade O, Takada Y et al. 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 2002; 17:1219-1229.
– reference: Ostrowska Z, Kos-Kudla B, Nowak M et al. The relationship between bone metabolism, melatonin and other hormones in sham-operated and pinealectomized rats. Endocr Regul 2003; 37:211-224.
– reference: Li M, Zhao L, Liu J et al. Hydrogen peroxide induces G2 cell cycle arrest and inhibits cell proliferation in osteoblasts. Anat Rec (Hoboken) 2009; 292:1107-1113.
– reference: Nakade O, Koyama H, Ariji H et al. Melatonin stimulates proliferation and type I collagen synthesis in human bone cells in vitro. J Pineal Res 1999; 27:106-110.
– reference: Genant HK, Block JE, Steiger P et al. Quantitative computed tomography in assessment of osteoporosis. Semin Nucl Med 1987; 17:316-333.
– reference: Histing T, Anton C, Scheuer C et al. Melatonin impairs fracture healing by suppressing RANKL-mediated bone remodeling. J Surg Res 2012; 173:83-90.
– reference: Sethi S, Radio NM, Kotlarczyk MP et al. 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 2010; 49:222-238.
– reference: Wade AG, Ford I, Crawford G et al. Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety. BMC Med 2010; 8:51.
– reference: Karagas MR, Lu-Yao GL, Barrett JA et al. Heterogeneity of hip fracture: age, race, sex, and geographic patterns of femoral neck and trochanteric fractures among the US elderly. Am J Epidemiol 1996; 143:677-682.
– reference: Baek KH, Oh KW, Lee WY et al. 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 2010; 87:226-235.
– reference: Chan CW, Song Y, Ailenberg M et al. Studies of melatonin effects on epithelia using the human embryonic kidney-293 (HEK-293) cell line. Endocrinology 1997; 138:4732-4739.
– reference: Bondi CD, Khairnar R, Kamal K et al. An early development budget impact model for the use of melatonin in the treatment and prevention of osteoporosis. Clin Pharmacol Biopharm 2015; 4:132.
– reference: Marks R. Hip fracture epidemiological trends, outcomes, and risk factors, 1970-2009. Int J Gen Med 2010; 3:1-17.
– reference: Hermann AP, Thomasen J, Vestergaard P et al. Assessment of calcium intake. A quick method compared to a 7 days food diary. Calcif Tissue Int 2009; 64(Suppl 1):S82.
– reference: Satomura K, Tobiume S, Tokuyama R et al. Melatonin at pharmacological doses enhances human osteoblastic differentiation in vitro and promotes mouse cortical bone formation in vivo. J Pineal Res 2007; 42:231-239.
– reference: Radio NM, Doctor JS, Witt-Enderby PA. 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 2006; 40:332-342.
– reference: Hansen S, Brixen K, Gravholt CH. Compromised trabecular microarchitecture and lower finite element estimates of radius and tibia bone strength in adults with turner syndrome: a cross-sectional study using high-resolution-pQCT. J Bone Miner Res 2012; 27:1794-1803.
– reference: Mody N, Parhami F, Sarafian TA et al. Oxidative stress modulates osteoblastic differentiation of vascular and bone cells. Free Radic Biol Med 2001; 31:509-519.
– reference: Egermann M, Gerhardt C, Barth A et al. Pinealectomy affects bone mineral density and structure-an experimental study in sheep. BMC Musculoskelet Disord 2011; 12:271.
– reference: Uslu S, Uysal A, Oktem G et al. Constructive effect of exogenous melatonin against osteoporosis after ovariectomy in rats. Anal Quant Cytol Histol 2007; 29:317-325.
– reference: Zhang L, Zhang J, Ling Y et al. Sustained release of melatonin from poly (lactic-co-glycolic acid) (PLGA) microspheres to induce osteogenesis of human mesenchymal stem cells in vitro. J Pineal Res 2013; 54:24-32.
– reference: Hojskov CS, Heickendorff L, Moller HJ. High-throughput liquid-liquid extraction and LCMSMS assay for determination of circulating 25(OH) vitamin D3 and D2 in the routine clinical laboratory. Clin Chim Acta 2010; 411:114-116.
– reference: Galano A, Tan DX, Reiter RJ. On the free radical scavenging activities of melatonin's metabolites, AFMK and AMK. J Pineal Res 2013; 54:245-257.
– reference: Song Y, Tam PC, Poon AM et al. 2-[125I]iodomelatonin-binding sites in the human kidney and the effect of guanosine 5′-O-(3-thiotriphosphate). J Clin Endocrinol Metab 1995; 80:1560-1565.
– reference: Buscemi N, Vandermeer B, Hooton N et al. The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. J Gen Intern Med 2005; 20:1151-1158.
– reference: Tresguerres IF, Tamimi F, Eimar H et al. Melatonin dietary supplement as an anti-aging therapy for age-related bone loss. Rejuvenation Res 2014; 17:341-346.
– reference: Ostrowska Z, Kos-Kudla B, Marek B et al. 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 2002; 23:417-425.
– reference: Witt-Enderby PA, Slater JP, Johnson NA et al. 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 2012; 53:374-384.
– reference: Khoo BC, Brown K, Cann C et al. Comparison of QCT-derived and DXA-derived areal bone mineral density and T scores. Osteoporos Int 2009; 20:1539-1545.
– reference: Laib A, Ruegsegger P. Calibration of trabecular bone structure measurements of in vivo three-dimensional peripheral quantitative computed tomography with 28-microm-resolution microcomputed tomography. Bone 1999; 24:35-39.
– reference: Kotlarczyk MP, Lassila HC, O'Neil CK et al. 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 2012; 52:414-426.
– reference: Turgut M, Kaplan S, Turgut AT et al. Morphological, stereological and radiological changes in pinealectomized chicken cervical vertebrae. J Pineal Res 2005; 39:392-399.
– volume: 20
  start-page: 1151
  year: 2005
  end-page: 1158
  article-title: The efficacy and safety of exogenous melatonin for primary sleep disorders. A meta‐analysis
  publication-title: J Gen Intern Med
– volume: 51
  start-page: 187
  year: 2011
  end-page: 194
  article-title: Melatonin promotes osteoblastic differentiation through the BMP/ERK/Wnt signaling pathways
  publication-title: J Pineal Res
– volume: 80
  start-page: 1560
  year: 1995
  end-page: 1565
  article-title: 2‐[125I]iodomelatonin‐binding sites in the human kidney and the effect of guanosine 5′‐O‐(3‐thiotriphosphate)
  publication-title: J Clin Endocrinol Metab
– volume: 57
  start-page: 131
  year: 2014
  end-page: 146
  article-title: Melatonin: a well‐documented antioxidant with conditional pro‐oxidant actions
  publication-title: J Pineal Res
– volume: 57
  start-page: 385
  year: 2014
  end-page: 392
  article-title: Melatonin promotes osteoblast differentiation and mineralization of MC3T3‐E1 cells under hypoxic conditions through activation of PKD/p38 pathways
  publication-title: J Pineal Res
– volume: 53
  start-page: B293
  year: 1998
  end-page: B298
  article-title: Endogenous melatonin levels and the fate of exogenous melatonin: age effects
  publication-title: J Gerontol A Biol Sci Med Sci
– volume: 49
  start-page: 222
  year: 2010
  end-page: 238
  article-title: Determination of the minimal melatonin exposure required to induce osteoblast differentiation from human mesenchymal stem cells and these effects on downstream signaling pathways
  publication-title: J Pineal Res
– volume: 3
  start-page: 1
  year: 2010
  end-page: 17
  article-title: Hip fracture epidemiological trends, outcomes, and risk factors, 1970–2009
  publication-title: Int J Gen Med
– volume: 87
  start-page: 226
  year: 2010
  end-page: 235
  article-title: Association of oxidative stress with postmenopausal osteoporosis and the effects of hydrogen peroxide on osteoclast formation in human bone marrow cell cultures
  publication-title: Calcif Tissue Int
– volume: 17
  start-page: 341
  year: 2014
  end-page: 346
  article-title: Melatonin dietary supplement as an anti‐aging therapy for age‐related bone loss
  publication-title: Rejuvenation Res
– volume: 17
  start-page: 316
  year: 1987
  end-page: 333
  article-title: Quantitative computed tomography in assessment of osteoporosis
  publication-title: Semin Nucl Med
– volume: 12
  start-page: 271
  year: 2011
  article-title: Pinealectomy affects bone mineral density and structure–an experimental study in sheep
  publication-title: BMC Musculoskelet Disord
– volume: 52
  start-page: 414
  year: 2012
  end-page: 426
  article-title: 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
  publication-title: J Pineal Res
– volume: 49
  start-page: 364
  year: 2010
  end-page: 372
  article-title: Melatonin inhibits adipogenesis and enhances osteogenesis of human mesenchymal stem cells by suppressing PPARgamma expression and enhancing Runx2 expression
  publication-title: J Pineal Res
– volume: 42
  start-page: 231
  year: 2007
  end-page: 239
  article-title: Melatonin at pharmacological doses enhances human osteoblastic differentiation in vitro and promotes mouse cortical bone formation in vivo
  publication-title: J Pineal Res
– volume: 138
  start-page: 4732
  year: 1997
  end-page: 4739
  article-title: Studies of melatonin effects on epithelia using the human embryonic kidney‐293 (HEK‐293) cell line
  publication-title: Endocrinology
– volume: 54
  start-page: 24
  year: 2013
  end-page: 32
  article-title: Sustained release of melatonin from poly (lactic‐co‐glycolic acid) (PLGA) microspheres to induce osteogenesis of human mesenchymal stem cells in vitro
  publication-title: J Pineal Res
– volume: 1
  start-page: 78
  year: 2003
  end-page: 85
  article-title: Hip fracture: risk factors and outcomes
  publication-title: Curr Osteoporos Rep
– volume: 27
  start-page: 1794
  year: 2012
  end-page: 1803
  article-title: Compromised trabecular microarchitecture and lower finite element estimates of radius and tibia bone strength in adults with turner syndrome: a cross‐sectional study using high‐resolution‐pQCT
  publication-title: J Bone Miner Res
– volume: 39
  start-page: 392
  year: 2005
  end-page: 399
  article-title: Morphological, stereological and radiological changes in pinealectomized chicken cervical vertebrae
  publication-title: J Pineal Res
– volume: 53
  start-page: 374
  year: 2012
  end-page: 384
  article-title: Effects on bone by the light/dark cycle and chronic treatment with melatonin and/or hormone replacement therapy in intact female mice
  publication-title: J Pineal Res
– volume: 314
  start-page: 197
  year: 2004
  end-page: 207
  article-title: Oxidative stress inhibits osteoblastic differentiation of bone cells by ERK and NF‐kappaB
  publication-title: Biochem Biophys Res Commun
– volume: 292
  start-page: 1107
  year: 2009
  end-page: 1113
  article-title: Hydrogen peroxide induces G2 cell cycle arrest and inhibits cell proliferation in osteoblasts
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Snippet Melatonin is known for its regulation of circadian rhythm. Recently, studies have shown that melatonin may have a positive effect on the skeleton. By...
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SubjectTerms Absorptiometry, Photon
Aged
Bone Density - drug effects
Bone Diseases, Metabolic - diagnostic imaging
Bone Diseases, Metabolic - drug therapy
Bone Diseases, Metabolic - metabolism
bone mineral density
clinical trial
Dose-Response Relationship, Drug
Double-Blind Method
Female
Femur Neck - diagnostic imaging
Femur Neck - metabolism
Humans
melatonin
Middle Aged
osteoporosis
postmenopausal women
Postmenopause - metabolism
Title Melatonin improves bone mineral density at the femoral neck in postmenopausal women with osteopenia: a randomized controlled trial
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https://onlinelibrary.wiley.com/doi/abs/10.1111%2Fjpi.12252
https://www.ncbi.nlm.nih.gov/pubmed/26036434
https://www.proquest.com/docview/1701300582
Volume 59
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