Monthly Archives: October 2013

Nightshift Work Associated with Fractures


Nightshift work and fracture risk: the Nurses’ Health Study.

Nightshift work suppresses melatonin production and has been associated with an increased risk of major diseases including hormonally related tumors. Experimental evidence suggests that light at night acts through endocrine disruption likely mediated by melatonin. To date, no observational study has addressed the effect of night work on osteoporotic fractures, another condition highly sensitive to sex steroid exposure. Our study, to our knowledge, the first to address this question, supports the hypothesis that nightshift work may negatively affect bone health, adding to the growing list of ailments that have been associated with shift work.
We evaluated the association between nightshift work and fractures at the hip and wrist in postmenopausal nurses.
The study population was drawn from Nurses’ Health Study participants who were working full or part time in nursing in 1988 and had reported their total number of years of rotating nightshift work. Through 2000, 1,223 incident wrist and hip fractures involving low or moderate trauma were identified among 38,062 postmenopausal women. We calculated multivariate relative risks (RR) of fracture over varying lengths of follow-up in relation to years of nightshift work.
Compared with women who never worked night shifts, 20+ years of nightshift work was associated with a significantly increased risk of wrist and hip fractures over 8 years of follow-up [RR = 1.37, 95% confidence interval (CI), 1.04-1.80]. This risk was strongest among women with a lower body mass index (<24) who never used hormone replacement therapy (RR = 2.36; 95% CI, 1.33-4.20). The elevated risk was no longer apparent with 12 years of follow-up after the baseline single assessment of nightshift work.
Long durations of rotating nightshift work may contribute to risk of hip and wrist fractures, although the potential for unexplained confounding cannot be ruled out.

Feskanich D, Hankinson SE, Schernhammer ES
Osteoporos Int Apr 2009
PMID: 18766292

Melatonin May Protect Against Bone Loss in Postmenopausal Women


Assessment of the relationship between circadian variations of salivary melatonin levels and type I collagen metabolism in postmenopausal obese women.

Few experimental and clinical studies show that melatonin (MEL) can play a significant part to modulate circadian bone metabolism. On this basis it was suggested that MEL secretion which altered during 24-h in obese women could be of importance to regulate bony mass defect after menopause.
The aim of the study was to prove if there were any connection between changes in 24-h profile of serum MEL levels and circadian metabolism of type I collagen in postmenopausal women with visceral obesity.
The relationship of 24-h profile of salivary MEL and circadian metabolism of type I collagen (as assessed by measuring saliva concentrations of carboxyterminal propeptide of type I procollagen–PICP and cross-linked carboxyterminal telopeptide of type I collagen–ICTP) was investigated in 26 women with visceral obesity (33.5 < BMI < 42.1 kg/m(2)) and 18 healthy volunteers with correct body mass (21 < BMI < 24.5 kg/m(2); 0.73 < WHR < 0.76). The specimens were collected at subjects’ home at 3 h intervals during a 24 h span. The age range of all subjects was 52-60 years.
In all the obese women studied a tendency to suppress circadian levels of tested biochemical markers of bone metabolism was observed (especially regarding ICTP); those alterations were accompanied by substantial increment in MEL concentrations during the day. Significant and negative correlation was found between values of acrophase MEL and PICP rhythms and both amplitude and acrophase of MEL and ICTP rhythms.
Our results confirm hypothesis that alterations in MEL concentrations might have a protective effect against postmenopausal loss of bone mass.

Ostrowska Z, Kos-Kudla B, Marek B, Swietochowska E…
Neuro Endocrinol. Lett. Apr 2001
PMID: 11335888

Review: Melatonin Effects on Bone – 2003


Melatonin effects on bone: experimental facts and clinical perspectives.

Bone formation proceeds through a remodeling process that runs continuously, involving the resorption of old bone by osteoclasts, and the subsequent formation of new bone by osteoblasts. This is controlled by growth factors and cytokines produced in bone marrow microenvironment and by the action of systemic hormones, like parathyroid hormone, estradiol or growth hormone (GH). One candidate for hormonal modulation of osteoblast and osteoclast formation is melatonin. Because circulating melatonin declines with age, its possible involvement in post-menopausal and senescence osteoporosis is considered. This review article discusses early studies on melatonin-bone relationships and recent data that suggest a direct effect of melatonin on bone. Melatonin could act as an autacoid in bone cells as it is present in high quantities in bone marrow, where precursors of bone cells are located. Melatonin dose-dependently augmented proteins that are incorporated into the bone matrix, like procollagen type I c-peptide. Osteoprotegerin, an osteoblastic protein that inhibits the differentiation of osteoclasts is also augmented by melatonin in vitro. Another possible target cell for melatonin is the osteoclast, which degrades bone partly by generating free radicals. Melatonin through its free radical scavenger and antioxidant properties may impair osteoclast activity and bone resorption. At least in one study melatonin was both inhibitory to osteoclastic and osteoblastic cells. Therefore, the documented bone-protecting effect of melatonin in ovariectomized rats can depend in part on the free radical scavenging properties of melatonin. Additionally, melatonin may impair development of osteopenia associated with senescence by improving non-rapid eye movement sleep and restoring GH secretion. Whether melatonin can be used as a novel mode of therapy for augmenting bone mass in diseases deserves to be studied.

Cardinali DP, Ladizesky MG, Boggio V, Cutrera RA…
J. Pineal Res. Mar 2003
PMID: 12562498

Review: Melatonin Effects on Bones and Teeth


Melatonin effects on hard tissues: bone and tooth.

Melatonin is an endogenous hormone rhythmically produced in the pineal gland under the control of the suprachiasmatic nucleus (SCN) and the light/dark cycle. This indole plays an important role in many physiological processes including circadian entrainment, blood pressure regulation, seasonal reproduction, ovarian physiology, immune function, etc. Recently, the investigation and applications of melatonin in the hard tissues bone and tooth have received great attention. Melatonin has been investigated relative to bone remolding, osteoporosis, osseointegration of dental implants and dentine formation. In the present review, we discuss the large body of published evidence and review data of melatonin effects on hard tissues, specifically, bone and tooth.

Liu J, Huang F, He HW
Int J Mol Sci 2013
PMID: 23665905 | Free Full Text

From the full text:

Bone remolding processes are mediated by hormones, cytokines, growth factors and other molecules [22]. One of the hormones modulating bone formation and resorption is melatonin. It is hypothesized that melatonin, perhaps through three principle actions, modulates bone metabolism. Firstly, melatonin directly affects the actions of osteoblast and osteoclast. Numerous studies documented that melatonin increases pre-osteoblast/osteoblast/osteoblast-like cell proliferation, promotes the expression of type I collagen and bone marker proteins (e.g., alkaline phosphatase, osteopontin, bone sialoprotein and osteocalcin), and stimulates the formation of a mineralized matrix in these cells [23–27]. Besides, melatonin inhibits the differentiation of osteoclasts via decreases in the expression of RANK mRNA and increases in both the mRNA and protein levels of osteo-protegerin [28,29]. Secondly, melatonin indirectly regulates bone metabolism through the interaction with systemic hormones (e.g., PTH, calcitonin, and estrogen) or other moleculars. Ladizesky et al. [15] revealed that estradiol treatment could prolong the effect of melatonin to augment bone remodeling in ovariectomized rats; it indicates that appropriate circulating estradiol levels might be needed for melatonin effects on bone. Thirdly, osteoclasts generate high levels of superoxide anions during bone resorption that contribute to the degradative process. Melatonin is a significant free-radical scavenger and antioxidant. It can clear up the free radicals generated by osteoclast during the bone resorption process and protect bone cells from oxidative attacks [18,30,31].


Some studies revealed the possible etiologic role of melatonin in osteoporosis. Nocturnal plasma melatonin levels decline with age. It has also been reported that melatonin secretion decreases sharply during menopause, which is associated with post-menopausal osteoporosis [46,47]. A correlation between decreased plasma melatonin levels and an increased incidence of bone deterioration as seen in post-menopausal women has been examined [48]. Furthermore, Ostrowska et al. [49] found that a pinealectomy in rats promotes the induction of bone metabolism biomarkers. In addition, Feskanich et al. [50] reported that twenty or more years of nightshift work significantly increased the risk of wrist and hip fractures in post-menopausal women. Nightshift work leads to disturbances of melatonin secretion as well as severe circadian rhythm disruption. These observations taken together suggest that melatonin may be involved in the pathogenesis of osteoporosis.

Melatonin Increases Bone Density in Blind Mice


Effects on bone by the light/dark cycle and chronic treatment with melatonin and/or hormone replacement therapy in intact female mice.

In this study, the effects of the light/dark cycle, hormone replacement therapy (HRT), and nocturnal melatonin supplementation on osteogenic markers and serum melatonin levels were examined in a blind mouse model (MMTV-Neu transgenic mice). Melatonin levels in this mouse strain (FVB/N) with retinal degeneration (rd-/-) fluctuate in a diurnal manner, suggesting that these mice, although blind, still perceive light. Real-time RT-PCR analyses demonstrated that Runx2, Bmp2, Bmp6, Bglap, and Per2 mRNA levels coincide with melatonin levels. The effect of chronic HRT (0.5 mg 17β-estradiol + 50 mg progesterone in 1800 kcal of diet) alone and in combination with melatonin (15 mg/L drinking water) on bone quality and density was also assessed by histomorphometry and microcomputed tomography, respectively. Bone density was significantly increased (P < 0.05) after 1 yr of treatment with the individual therapies, HRT (22% increase) and nocturnal melatonin (20% increase) compared to control. Hormone replacement therapy alone also increased surface bone, decreased trabecular space, and decreased the number of osteoclasts without affecting osteoblast numbers compared to the control group (P < 0.05). Chronic HRT + melatonin therapy did not significantly increase bone density, even though this combination significantly increased Bglap mRNA levels. These data suggest that the endogenous melatonin rhythm modulates markers important to bone physiology. Hormone replacement therapy with or without nocturnal melatonin in cycling mice produces unique effects on bone markers and bone density. The effects of these therapies alone and combined may improve bone health in women in perimenopause and with low nocturnal melatonin levels from too little sleep, too much light, or age.

Witt-Enderby PA, Slater JP, Johnson NA, Bondi CD…
J. Pineal Res. Nov 2012
PMID: 22639972

Hypothesis: Melatonin for Facial Bone Loss


Could the Fountain of Youth Be All in Your Bones?

Melatonin, a molecule released from the pineal gland in response to darkness, has long been known to keep one’s sleep-wake cycles entrained to the light-dark cycle; however, there has been a surge in publications showing that melatonin has protective effects on bone. Disruption of nocturnal melatonin levels by light exposure at night, and through the natural aging process, produces adverse effects on bone. Use of melatonin to prevent bone loss or enhance bone formation has great clinical utility, including preventing maxillofacial bone loss and/or enhancing bone regeneration in maxillofacial bone reconstructive surgeries. This brief editorial comment sheds some “light” into a novel use for melatonin in preventing facial bone loss.

Witt-Enderby P
J Oral Implantol Apr 2012
PMID: 22506832

Review: Melatonin and the Skeleton


Melatonin and the skeleton.

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.

Amstrup AK, Sikjaer T, Mosekilde L, Rejnmark L
Osteoporos Int May 2013
PMID: 23716040

Melatonin Improves Formation:Resorption Ratio in Women


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.

The purpose of this double-blind study was to assess the effects of nightly melatonin supplementation on bone health and quality of life in perimenopausal women. A total of 18 women (ages 45-54) were randomized to receive melatonin (3mg, p.o., n=13) or placebo (n=5) nightly for 6 months. Bone density was measured by calcaneal ultrasound. Bone turnover marker (osteocalcin, OC for bone formation and NTX for bone resorption) levels were measured bimonthly in serum. Participants completed Menopause-Specific Quality of Life-Intervention (MENQOL) and Pittsburgh Sleep Quality Index (PSQI) questionnaires before and after treatment. Subjects also kept daily diaries recording menstrual cycling, well-being, and sleep patterns. The results from this study showed no significant change (6-month-baseline) in bone density, NTX, or OC between groups; however, the ratio of NTX:OC trended downward over time toward a ratio of 1:1 in the melatonin group. Melatonin had no effect on vasomotor, psychosocial, or sexual MENQOL domain scores; however, it did improve physical domain scores compared to placebo (mean change melatonin: -0.6 versus placebo: 0.1, P<0.05). Menstrual cycling was reduced in women taking melatonin (mean cycles melatonin: 4.3 versus placebo: 6.5, P<0.05), and days between cycles were longer (mean days melatonin: 51.2 versus placebo: 24.1, P<0.05). No differences in duration of menses occurred between groups. The overall PSQI score and average number of hours slept were similar between groups. These findings show that melatonin supplementation was well tolerated, improved physical symptoms associated with perimenopause, and may restore imbalances in bone remodeling to prevent bone loss. Further investigation is warranted.

Kotlarczyk MP, Lassila HC, O’Neil CK, D’Amico F…
J. Pineal Res. May 2012
PMID: 22220591

Melatonin Promotes Osteoblasts in Mouse Cells


Melatonin promotes osteoblastic differentiation through the BMP/ERK/Wnt signaling pathways.

Although melatonin has a variety of biological actions such as antitumor, antiangiogenic, and antioxidant activities, the osteogenic mechanism of melatonin still remains unclear.Thus, in the present study, the molecular mechanism of melatonin was elucidated in the differentiation of mouse osteoblastic MC3T3-E1 cells. Melatonin enhanced osteoblastic differentiation and mineralization compared to untreated controls in preosteoblastic MC3T3-E1 cells. Also, melatonin increased wound healing and dose-dependently activated osteogenesis markers such as runt-related transcription factor 2 (Runx2), osteocalcin (OCN), bone morphogenic protein (BMP)-2 and -4 in MC3T3-E1 cells. Of note, melatonin activated Wnt 5 α/β, β-catenin and the phosphorylation of c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) in a time-dependent manner while it attenuated phosphorylation of glycogen synthase kinase 3 beta (GSK-3β) in MC3T3-E1 cells. Consistently, confocal microscope observation revealed that BMP inhibitor Noggin blocked melatonin-induced nuclear localization of β-catenin. Furthermore, Western blotting showed that Noggin reversed activation of β-catenin and Wnt5 α/β and suppression of GSK-3β induced by melatonin in MC3T3-E1 cells, which was similarly induced by ERK inhibitor PD98059. Overall, these findings demonstrate that melatonin promotes osteoblastic differentiation and mineralization in MC3T3-E1 cells via the BMP/ERK/Wnt pathways.

Park KH, Kang JW, Lee EM, Kim JS…
J. Pineal Res. Sep 2011
PMID: 21470302p

Melatonin+Estrogen Increases Bone Formation in Ovariectomized Rats


Melatonin increases oestradiol-induced bone formation in ovariectomized rats.

To assess the effect of melatonin on bone metabolism in ovariectomized rats, receiving oestradiol therapy or not, melatonin was administered in the drinking water (25 microg/mL water) and oestradiol (10 microg/kg body weight) or vehicle was given subcutaneously 5 days/week for up to 60 days after surgery. Urinary deoxypyridinoline (a marker of bone resorption) and circulating levels of bone alkaline phosphatase activity (a marker of bone formation), as well as serum calcium and phosphorus levels, were measured every 15 days. Bone area (BA), bone mineral content (BMC), bone mineral density (BMD) and total body fat (expressed as 100 g body weight) were measured by dual-energy X-ray absorptiometry at the end of the experiment. Body weight and total body fat were augmented after ovariectomy, and decreased after melatonin or oestradiol treatment. The effect of melatonin on body weight was seen in sham-operated rats only. Ovariectomy augmented, and melatonin or oestradiol lowered, urinary deoxypyridinoline excretion. This effect of melatonin and oestradiol was seen mainly in ovariectomized rats. The efficacy of oestradiol to counteract ovariectomy-induced bone resorption was increased by melatonin. Melatonin or oestradiol lowered serum bone alkaline phosphatase activity. Melatonin inhibition was seen mainly on the increase of bone alkaline phosphatase activity that followed ovariectomy. Serum phosphorus levels decreased after melatonin administration and were augmented after oestradiol injection; overall, melatonin impaired the increase of serum phosphorus caused by oestradiol. Ovariectomy decreased, and oestradiol increased, serum calcium levels while melatonin augmented serum calcium in sham-operated rats only. On day 60 after surgery, BMD and content decreased after ovariectomy and were increased after oestradiol injection. Melatonin augmented BA of spine and BMC of whole of the skeleton and tibia. The highest values observed were those of rats treated concurrently with oestradiol and melatonin. The present results indicate that: (i) melatonin treatment restrained bone remodelling after ovariectomy; (ii) the effect of melatonin required adequate concentrations of oestradiol; (iii) melatonin augmented oestradiol effects on bone in ovariectomized rats; (iv) a counter-regulation by melatonin of the increase in body fat caused by ovariectomy was uncovered. The melatonin doses employed were pharmacological in terms of circulating melatonin levels but not necessarily for some other fluids or tissues.

Ladizesky MG, Boggio V, Albornoz LE, Castrillón PO…
J. Pineal Res. Mar 2003
PMID: 12562506