title: Melatonin-micronutrients Osteopenia Treatment Study (MOTS): a translational study assessing melatonin, strontium (citrate), vitamin D3 and vitamin K2 (MK7) on bone density, bone marker turnover and health related quality of life in postmenopausal osteopenic women following a one-year double-blind RCT and on osteoblast-osteoclast co-cultures.
abstract: This one-year double blind randomized control trial assessed the effects of nightly melatonin, strontium (citrate), vitamin D3 and vitamin K2 (MK7; MSDK) on bone mineral density (BMD) and quality of life (QOL) in postmenopausal osteopenic women (ages 49-75). Compared to placebo, MSDK treatment increased BMD in lumbar spine (4.3%) and left femoral neck (2.2%), with an upward trend for total left hip (p=0.069). MSDK increased serum P1NP levels and reduced bone turnover (CTx:P1NP). Psychometric analyses indicated that mood and sleep quality improved for the MSDK group. MSDK-exposed human mesenchymal stem cells (hMSCs) and human peripheral blood monocytes (hPBMCs) plated in transwells or layered demonstrated increases in osteoblastogenesis, decreases in osteoclastogenesis, increases in OPG (TNFRSF11B) and decreases in RANKL (TNFSF11) levels. In transwell osteoblasts, MSDK increased pERK1/2 (MAPK1/MAPK3) and RUNX2 levels; decreased ERK5 (MAPK7); and did not affect the expression of NFκB (NFKB1) and β1integrin (ITGB1). In layered osteoblasts, MSDK also decreased expression of the metabolic proteins PPARγ (PPARG) and GLUT4 (SLC2A4). In adipose-derived human MSCs, MSDK induced osteoblastogenesis. These findings provide both clinical and mechanistic support for the use of MSDK for the prevention or treatment of osteopenia, osteoporosis or other bone-related diseases.
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University School of Pharmacy, Pittsburgh, PA 15282, USA.
authors.forename: Sifat
authors.initials: S
authors.lastname: Maria
authors.affiliation: Functional Medicine, Heart Preventics, LLC, Sequim, WA 98382, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Swanson
authors.affiliation: Enderby Healthcare/Legal Consulting, LLC, Pittsburgh, PA 15102, USA.
authors.forename: Larry T
authors.initials: LT
authors.lastname: Enderby
authors.affiliation: Department of Mathematics, Duquesne University School of Liberal Arts, Pittsburgh, PA 15282, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: D'Amico
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University School of Pharmacy, Pittsburgh, PA 15282, USA.
authors.forename: Brianna
authors.initials: B
authors.lastname: Enderby
authors.affiliation: Mayo Clinic, Department of Orthopedic Surgery, Rochester, MN 55905, USA.
authors.forename: Rebekah M
authors.initials: RM
authors.lastname: Samsonraj
authors.affiliation: Mayo Clinic, Department of Orthopedic Surgery, Rochester, MN 55905, USA.
authors.forename: Amel
authors.initials: A
authors.lastname: Dudakovic
authors.affiliation: Mayo Clinic, Department of Orthopedic Surgery, Rochester, MN 55905, USA.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.affiliation: Division of Pharmaceutical Sciences, Duquesne University School of Pharmacy, Pittsburgh, PA 15282, USA.
authors.forename: Paula A
authors.initials: PA
authors.lastname: Witt-Enderby
mesh_terms: D000368:Aged; D015519:Bone Density / Q000187:drug effects*; D001851:Bone Diseases, Metabolic / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D016723:Bone Remodeling; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects*; D002762:Cholecalciferol / Q000008:administration & dosage*; D018920:Coculture Techniques; D004311:Double-Blind Method; D005260:Female; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D006304:Health Status; D006801:Humans; D008550:Melatonin / Q000008:administration & dosage*; D018977:Micronutrients / Q000008:administration & dosage; D008875:Middle Aged; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053244:Osteoprotegerin / Q000097:blood; D047495:PPAR gamma / Q000378:metabolism; D017698:Postmenopause; D011788:Quality of Life; D053245:RANK Ligand / Q000097:blood; D013324:Strontium / Q000008:administration & dosage*; D024482:Vitamin K 2 / Q000008:administration & dosage*
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D018977:Micronutrients; D053244:Osteoprotegerin; D047495:PPAR gamma; D053245:RANK Ligand; D024482:Vitamin K 2; D002762:Cholecalciferol; D008550:Melatonin; D013324:Strontium
keywords: GLUT4; PPARγ; adipocytes; melatonin; osteoblasts; osteoclasts; osteopenia