The Melatonin Osteoporosis Prevention Study (MOPS) demonstrated that nightly melatonin resulted in a time-dependent decrease in equilibrium ratios of serum osteoclasts and osteoblasts in perimenopausal women. This study examines mechanisms related to the ratios of osteoblasts and osteoclasts using coculture models (transwell or layered) of human mesenchymal stem cell (MSC) and human peripheral blood monocytes (PBMCs). Human MSC/PBMC cocultures exposed to melatonin in osteogenic (OS+) medium for 21 days induced osteoblast differentiation and mineralization; however, only in layered cocultures did melatonin inhibit osteoclastogenesis. Melatonin effects were mediated through MT2 melatonin receptors, MEK1/2, and MEK5. In layered but not transwell cocultures, melatonin increased OPG:RANKL ratios by inhibiting RANKL, suggesting that contact with osteoclasts during osteoblastogenesis inhibits RANKL secretion. Melatonin modulated expression of ERK1/2, ERK5, β1 integrin, GLUT4, and IRβ that was dependent upon the type of coculture; however, in both cultures, melatonin increased RUNX2 and decreased PPARγ expression, indicating a role for metabolic processes that control osteogenic vs adipogenic cell fates of MSCs. Furthermore, melatonin also has osteoblast-inducing effects on human adipose-derived MSCs. In vivo, one-year nightly melatonin (15 mg/L) given to neu female mice in their drinking water increased pErk1/2, pErk5, Runx2, and Opg and Rankl levels in bone consistent with melatonin's already reported bone-enhancing effects. Finally, analysis of daily logs from the MOPS demonstrated a significant improvement in mood and perhaps sleep quality in women receiving melatonin vs placebo. The osteoblast-inducing, bone-enhancing effects of melatonin and improvement in quality of life suggest that melatonin is a safe and effective bone loss therapy.

An important role for melatonin in bone formation and restructuring has emerged, and studies demonstrate the multiple mechanisms for these beneficial actions. Statistical analysis shows that even with existing osteoporotic therapies, bone-related disease, and mortality are on the rise, creating a huge financial burden for societies worldwide. These findings suggest that novel alternatives need to be developed to either prevent or reverse bone loss to combat osteoporosis-related fractures. The focus of this review describes melatonin's role in bone physiology and discusses how disruption of melatonin rhythms by light exposure at night, shift work, and disease can adversely impact on bone. The signal transduction mechanisms underlying osteoblast and osteoclast differentiation and coupling with one another are discussed with a focus on how melatonin, through the regulation of RANKL and osteoprotegerin synthesis and release from osteoblasts, can induce osteoblastogenesis while inhibiting osteoclastogenesis. Also, melatonin's free-radical scavenging and antioxidant properties of this indoleamine are discussed as yet an additional mechanism by which melatonin can maintain one's bone health, especially oral health. The clinical use for melatonin in bone-grafting procedures, in reversing bone loss due to osteopenia and osteoporosis, and in managing periodontal disease is discussed. ; the female-to-male ratio for fracture is 1.6 [1]. In the European Union, approximately 22 million women and 5.5 million men (between 50 and 84 yr) are projected to have osteoporosis; this number will rise by 23% by 2025 [3]. In the United States, nearly 57 million adults over age 50 are affected by bone disease, 48 million adults have osteopenia, and 9 million adults have osteoporosis, which places these individuals at risk for developing bone fracture. If left unchanged, by 2030, the prevalence of osteoporosis will increase to 11.9 million and 64.3 million with osteopenia [4].In the United States, the annual fracture rate is 1.5 million per year (300,000 hip and 700,000 vertebral fractures), which is expected to increase by 3 million by 2025 [5,6]. In the United Kingdom, although it was expected that the 12-month survival rate after hip fracture would be 90-91%, the actual numbers were less than expected with 63.3% of men and 74.9% of women surviving [7]. In the United States, hip fracture is responsible for approximately 31,000 excess deaths within 6 months, which can start as early as age 50; this is significant, considering that one in every three women and one in five men in the United States will experience an osteoporosis-related fracture in their lifetime [6]. In addition to increasing morbidity and mortality rates, osteoporosis-related fractures are also creating huge economical burdens to societies worldwide. For example, osteoporosis treatment and related fracture cost in the United States (per year) is $19 billion, which is expected to increase to $25.3 billion by 2025 [6]. In 2010, osteoporosis-related costs amounted ...

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.

This retrospective case series study, using data obtained through questionnaires and histopathological diagnoses from 656 patients enrolled in the Department of Defense (DoD) Clinical Breast Care Project (CBCP), evaluated associations between hormonal contraceptive use and breast cancer pathology including benign breast pathologies. Three combination hormonal contraceptive agents (COCs) Lo Ovral (LO), Ortho Novum (ON), and Ortho Tri-Cyclen (OTC) were evaluated as they represented the most commonly used hormonal contraceptives in our cohort. The results of this study suggest that the ever use of LO + ON + OTC does not influence the overall incidence of benign breast condition or malignant disease compared to other COCs; however, patients that have used OTC had an association with a diagnosis of benign or luminal A pathologies whereas ON was associated with a diagnosis of benign and DCIS; LO showed no association with any diagnosis-benign or malignant. Patients that have used LO or ON were more likely to be diagnosed with breast cancer at age ≥ 40 years whereas patients that had ever used OTC were likely to be diagnosed before the age of 40. Caucasians were less likely to have used OTC and more likely to have used ON; however, use of either hormonal agent positively correlated with premenopausal status at diagnosis and having a benign condition. Age at diagnosis, ethnicity, BMI, family history, menstruation status, and duration of use were all independent predictors of different histopathological subtypes. We conclude that patient-specific variables should be considered when deciding on which type of hormonal contraceptive to use to minimize the risk of developing breast cancer or a breast-related pathology.

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