• cancer;
  • hormone replacement therapy;
  • melatonin;
  • melatonin receptors;
  • osteoporosis


  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References

Abstract:  Melatonin's therapeutic potential is grossly underestimated because its functional roles are diverse and its mechanism(s) of action are complex and varied. Melatonin produces cellular effects via a variety of mechanisms in a receptor independent and dependent manner. In addition, melatonin is a chronobiotic agent secreted from the pineal gland during the hours of darkness. This diurnal release of melatonin impacts the sensitivity of melatonin receptors throughout a 24-hr period. This changing sensitivity probably contributes to the narrow therapeutic window for use of melatonin in treating sleep disorders, that is, at the light-to-dark (dusk) or dark-to-light (dawn) transition states. In addition to the cyclic changes in melatonin receptors, many genes cycle over the 24-hr period, independent or dependent upon the light/dark cycle. Interestingly, many of these genes support a role for melatonin in modulating metabolic and cardiovascular physiology as well as bone metabolism and immune function and detoxification of chemical agents and cancer reduction. Melatonin also enhances the actions of a variety of drugs or hormones; however, the role of melatonin receptors in modulating these processes is not known. The goal of this review is to summarize the evidence related to the utility of melatonin as a therapeutic agent by focusing on its other potential uses besides sleep disorders. In particular, its use in cancer prevention, osteoporosis and, as an adjuvant to other therapies are discussed. Also, the role that melatonin and, particularly, its receptors play in these processes are highlighted.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References

Melatonin has been shown to play a role in many physiological systems, including those involved in sleep [1], gastrointestinal physiology [2–4], immune defense [5, 6], cardiovascular function [2, 3, 7–9], renal function [2], detoxification [10–12], reproduction [13–15], and retinal [16], as well as bone physiology [17]. Some of these systems regulate peripheral clocks, which, in turn, attempt to synchronize themselves against the master biological clock's pacemaker [18]. With the cloning of the receptors [19, 20] and microarray analyses of select tissues [21–23], it is obvious that melatonin impacts on multiple physiological systems, but how it does remains to be determined.

It is difficult to attribute a specific mechanism to an effect of melatonin on a particular physiological process or in treating disease as melatonin's actions are diverse. For example, as shown in Fig. 1, melatonin can produce effects through receptors [3, 24] or independent of receptors [10–12]. The receptors, once activated by melatonin, can signal through cAMP-dependent cascades, mitogen activated protein kinase cascades [24], and also through estrogen-dependent signaling cascades [8, 25]. The receptors (MT1, MT2) belong to the G-protein coupled receptor class while the MT3 binding site belongs to the quinone reductase 2 family of detoxifying enzymes [26]. Because of the overlap of some signaling cascades to produce the same effect [e.g. inhibition of estrogen receptor (ER) transactivation or detoxification], it is difficult to decipher whether or not these responses are mediated via receptors.


Figure 1.  The diverse mechanisms mediated by melatonin within a cell. Melatonin produces effects in a receptor-dependent or independent manner. Melatonin alone and independent of receptors, passes through cell membranes, accumulates within a cell, and inhibits calmodulin or acts in radical detoxification. Detoxification occurs through melatonin's free radical scavenging properties and due to its ability to up-regulate detoxifying enzymes including catalase, superoxide dismutase, and glutathione peroxidase. Melatonin effects via MT3 sites regulating quinone reductase 2 activity are still unclear but may be involved with oxidative/reductive mechanisms through unidentified mechanisms. Melatonin inhibits calmodulin activity by preventing calcium binding and/or by inducing its phosphorylation through PKC alpha. The consequence of calmodulin inhibition by melatonin may result in a reduction in cAMP accumulation through calmodulin-sensitive adenylyl cyclases. This may cause an attenuation of cAMP-dependent signaling cascades, including the activation of cAMP response element binding (CREB) protein and cAMP response element (CRE)-containing genes. Melatonin-mediated reductions in calmodulin activation decrease estrogen receptor (ER) binding to and activation of estrogen response element (ERE)-containing genes. Also, as depicted, melatonin can act via its G-protein coupled receptors, MT1 or MT2 to suppress CREB-induced and/or ER-induced activation of genes. Furthermore, through its activation of MT2 receptors, melatonin activates the mitogen activated protein kinase cascade (MEK/ERK 1/2) and promotes cellular differentiation and retards cellular proliferation. This may occur via autocrine actions of heparin-bound epidermal growth factor (HB-EGF) released following the activation of MT2 melatonin receptors, Gi proteins, matrix metalloproteinases (MMPs) and internalization processes.

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The fact that melatonin is a chronobiotic agent means that the timing of the release from the pineal gland or dose may dictate whether the response to melatonin is absent, weak or strong. Melatonin displays different periods of sensitivity as it relates to its effects on phase-shifting circadian rhythms [1, 27]. Perhaps other targets of melatonin (i.e. genes or proteins regulated by melatonin receptors) show similar rhythms. Many genes [22, 23, 28], disease-related entities such as tumors [29] and melatonin (MT1) receptor mRNA [24, 30] exhibit a circadian rhythm (Fig. 2) and some, including cancer cells, express the same clock genes found in the master biological clock [31]. A thorough understanding of the regulatory patterns of melatonin receptors and its targets in response to melatonin or throughout the 24-hr day should be examined. A better understanding of these targets and how melatonin and its receptors play in their physiology will hopefully lead to its regular use in the clinic. To further this stated objective, this review will focus on areas that show promise yet are still not used regularly in the clinical setting.


Figure 2.  Schematic showing the variables that may contribute to melatonin's efficacy as a therapeutic agent. For some functions, melatonin has different periods of sensitivity throughout the 24 hr light/dark cycle, that is, at dusk and at dawn as shown by the arrows. Also, in some organs, melatonin receptor density (depicted by the sun symbols), affinity and (perhaps) sensitivity fluctuate throughout a 24-hr period. When melatonin levels are low (during the day), melatonin receptor affinity and density are high. By contrast, when melatonin levels are high (during the night), melatonin receptor affinity and density are low. Thus, to maximize the therapeutic efficacy of melatonin when its actions are receptor-mediated, it may be important to administer melatonin during the period when receptor sensitivity is highest. Many genes fluctuate throughout the light/dark cycle or in a circadian manner as shown. These genes support a role for melatonin and its receptors in cancer prevention, metabolism, host defense, bone metabolism, and cellular differentiation.

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Melatonin as a therapy for the prevention of osteoporosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References

Osteoporosis, a disease predominantly associated with aging, occurs following prolonged structural deterioration of the skeletal system. Recent therapies include targeting bone-resorbing osteoclasts by use of bisphosphonates, estrogen, and calcitonin to prevent further bone breakdown. However, these therapies are limited because they do not form bone as is necessary in cases of individuals suffering from severe osteoporosis. One drug is available that stimulates bone-forming osteoblasts (e.g. teriparatide); however, its treatment is limited to 2 yr, it is expensive and has risks associated with its use. Melatonin as a therapy for the prevention and treatment of osteoporosis should be considered. The rationale for its use is described below.

Noctural plasma melatonin levels significantly decline after the age of 50 in both genders [1, 6, 32] perhaps due to neuroaxonal dystrophy of sympathetic innervation of the pineal gland [33]. A correlation between reduced plasma melatonin levels and an increased incidence of bone deterioration as seen in osteoporosis has been examined [17]. In fact, removal of the pineal gland in rats promotes the induction of bone metabolism biomarkers while melatonin exposure suppresses them [34]. Furthermore, light influences the oscillations of these bone markers where a short day induces the expression of these markers and a long day suppresses them [28]. Other associations between melatonin and bone have been observed in the clinic whereby melatonin-related patterned skin pigmentation is commonly seen in certain bone disorders [35].

Melatonin has been shown at the cellular and organismal level to promote osteogenesis and prevent bone deterioration [36–40]. In fact, elevated melatonin levels have been identified in the bone marrow of rats, with nighttime concentrations approximately twice as high as in the peripheral blood [41]. The enzymes involved in melatonin biosynthesis, N-acetyltransferase and hydroxyindole-o-methyltransferase are also expressed in bone marrow cells [17]. The presence of melatonin in bone marrow may be protective against oxidative damage in the proliferating hematopoietic cells or involved in bone development through osteoblast differentiation [42].

Several studies using various animal models show that melatonin prevents bone deterioration, including preventing idiopathic scoliosis in adolescents [40]. However, there was no correlation between gene variants and the phenotype for this particular disease [43]. Whether or not posture and gravity are determinants in these beneficial melatonin effects are still unclear. For example, pinealectomized Atlantic salmon show abnormal spinal curvature with a reduction in mechanical properties and vertebral mineral content reduction [39]. Pinealectomy in chickens induces histomorphometrical changes in the vertebral column. In particular, the loss of melatonin induces a scoliotic curvature and reduces mean weight and length of cervical vertebrae possibly due to a reduction in the total number of osteocytes. Melatonin, therefore, may act to enhance osteocyte proliferation in the cervical vertebrae [37]. In another study, it is shown that bipedal ambulation, in a mouse strain with genetically low levels of melatonin (C57BL/6J mice), induces scoliosis. Also, ambulation in C3H/HeJ mice, a mouse strain which displays normal melatonin rhythms, results in a scoliosis rate of 25% that increases to 70% when they are pinealectomized [44]. However, ambulation does not always induce scoliosis as demonstrated in rhesus monkeys. Here, it is found that pinealectomy in nonhuman primates does not produce idiopathic scoliosis [45].

The mechanism(s) by which melatonin protects bone may occur through its actions on both osteoclasts and osteoblasts and through an interaction with estrogen. As already known, the structural integrity of the skeletal system is dependent upon the continual remodeling process of bone-resorbing osteoclasts and bone-forming osteoblasts [46, 47]. Through this remodeling process, weakened bone is resorbed via activated osteoclasts and new bone is synthesized via activated osteoblasts. Melatonin may enhance bone formation by suppressing osteoclasts [48, 49] via its free radical scavenging properties and actions on RANKL and/or by enhancing osteoblast activity [42, 50] through specific melatonin receptors [40, 42].

Regarding its effects on osteoclasts, a study in goldfish scales indicates that melatonin enhances bone formation by inhibiting osteoclast activity. Tartrate-resistant acid phosphatase, a biomarker of osteoclast activity, significantly decreases after incubation with melatonin [48]. This study also shows that melatonin (1 nm) suppresses the activity of osteoblasts, possibly via a down-regulation of ER and insulin-like growth factor-1 mRNAs [48]. An interaction between melatonin and ERs is reported in other systems [8, 25] and is highlighted elsewhere in this review. The relationship between estrogen and melatonin is usually reciprocal in nature, however, in one study [51], melatonin actually enhanced its efficacy. Here, it is shown that melatonin administration (500 μg/day) prevents bone loss induced by ovariectomy in rats, but only if appropriate concentrations of estradiol are present. Also, in the study in question, melatonin enhanced the efficacy of estradiol in preventing bone loss [51].

Regarding the effect of melatonin on bone-forming osteoblasts, the data are conflicting. In the study using goldfish scales as their model, melatonin (1 nm) suppressed the activity of osteoblast cells [48]. Similar findings were also found in male Wistar rats whereby high endogenous levels of melatonin correlate with low levels of bone forming markers (i.e. alkaline phosphatase, carboxyterminal propeptide of type 1 procollagen, and carboxyterminal telopeptide of type 1 collagen) [28]. Also, pinealectomy results in induced levels of bone metabolism biomarkers and alters the phase and amplitude of their circadian oscillations [34].

By contrast, in other studies melatonin induced osteoblast activity either by enhancing their proliferation or differentiation. In preosteoblast MC3T3 cells, 50 nm melatonin stimulated bone mineralization and osteoblast differentiation, as assessed by bone marker proteins alkaline phosphatase, osteopontin and osteocalcin, via a transmembrane receptor that is pertusis toxin sensitive [50]. In human bone cells and human osteoblastic cells, melatonin increased the proliferation of both cell types in a dose-dependent manner [52] and, after a 2-day incubation, significantly increased the production of procollagen type I c-peptide. In human adult mesenchymal stem cells, melatonin (50 nm), acting through MT2 melatonin receptors, enhanced alkaline phosphatase activity by 50% relative to osteogenic media alone; this suggests that melatonin acts synergistically with the osteogenic medium to promote osteoblast development [42].

The signaling mechanisms underlying how melatonin enhances osteoblast cell formation are less well understood. In general, the promotion of osteoblast differentiation has been shown by numerous laboratories to be mediated via the mitogen activated protein kinase cascade [42, 53–57]; however, which ones (p38, MEK/ERK 1/2) remain unclear. The inputs leading to MAPK activation in osteoblastic cells may involve cAMP [57] and EGFR activation [42] (Fig. 1). Once activated, MAPK has been shown to phosphorylate osteoblast-specific proteins, including Cbfa-1 to control the expression of osteoblast-specific genes, including osteocalcin [56]. Clearly, the role of the MAPK pathway in melatonin-induced osteoblast differentiation is important and more studies are needed to further define these signaling cascades. In addition, the role of estrogen and melatonin in bone formation should be assessed as these combinational therapies may prove to be effective for the treatment of osteoporosis. Overall, the majority of the studies suggest a protective role of melatonin on bone, i.e. it prevents bone degradation and promotes bone formation most probably through an action that involves melatonin receptors. Furthermore, considering that bone-related genes are under a circadian rhythm [28, 34], determining the therapeutic window for melatonin's effects on bone marker proteins warrants further investigation as well.

Melatonin as a therapy for the prevention of cancer

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References

Decreased melatonin levels have been correlated with increased cancer risk, leading to suggestions of its potential as an antitumor or cancer preventative agent. The preponderance of the reports relate to melatonin's effects on breast cancer. Breast cancer risk is altered in instances that disrupt the normal cycling of melatonin levels, such as providing protection in blind women and an increased risk in women with reduced dark phases as a result of working in night shifts [58–61]. Studies in patients with breast cancer [62], lung cancer [63], and cervical cancer [64] have been found to have reduced nocturnal melatonin levels; whether these are a cause or consequence of the cancer is unknown. Disrupted circadian function in patients with advance non-small-cell lung cancer is also observed [65].

Melatonin is frequently concentrated in tissues, including the breast. Melatonin levels are higher in neoplastic breast tissues compared with serum levels, and higher concentrations are inversely correlated with nuclear grade or positively associated with ER status [66]. In clinical trials, on patients with different types of metastatic cancer, co-administration of melatonin and tamoxifen in untreatable metastatic cancer patients induced partial responses or stable disease in some patients and improved the survival time for some; this treatment also slowed cancer progression, and improved quality of life [67]. These data indicate that the anti-tumor properties of melatonin are relevant to cancer patients.

In a recent study that examined total melatonin produced over a 24-hr period, no correlation between melatonin levels and breast cancer was found [68]. However, from other studies it appears that the magnitude of the nocturnal rise in melatonin is more predictive of cancer risk rather than overall daily melatonin levels [10, 11, 69]. In studies examining nocturnal or first morning urine melatonin levels, an inverse correlation with breast cancer risk was noted [70]. Also, mutations in clock genes such as per-2 and per-3 results in an increase in spontaneous tumorigenesis in mice [71] or an increase in risk for premenopausal breast cancer [72], respectively.

Multiple mammary tumor studies on the effects of melatonin administration, constant light versus light/dark cycles, and pinealectomy to modify melatonin levels, demonstrate that melatonin has antitumor activities, including changes in cell proliferation, incidence of cancer, and latency to onset, in cultured cells and carcinogen-induced and spontaneous mammary cancer animal models [61, 62, 69, 73, 74]. Antimetastatic properties are also demonstrated using cultured MCF-7 cells [62]. Physiological levels of melatonin reduce the invasion of MCF-7 cells, and counteracts the increase in estrogen-induced invasiveness [75]. Melatonin also reduces the chemotactic response and increases the expression of cell surface adhesion molecules that have been inversely correlated with in vitro invasiveness [62]. Regarding telomerase activity, melatonin decreases its activity in the tumors of nude mice and the mRNA expression of the telomerase reverse transcriptase, the catalytic subunit of telomerase as well as the RNA telomerase subunit [76].

Mammary tumor studies in MMTV-neu mice with activated neu demonstrate that administration of melatonin during the darkness either with interrupted [77] or constant treatment [78] reduces the incidence of the primary and metastatic mammary tumors compared with untreated controls. In addition, the size of the mammary tumors are smaller after melatonin treatment suggesting an effect on tumor growth [77, 78]. Levels of neu expression in the tumors are also significantly decreased with melatonin treatment [77]. Higher doses of melatonin delay the onset, inhibit the growth, and reduce multiplicity and incidence of neu tumors [79].

Melatonin has multiple activities that could influence tumor initiation, promotion, and progression. The detoxifying properties of melatonin are potent, occur independent of its receptors and are protective against cancer [10–12]. The anti-proliferative and differentiating effects of melatonin may also occur through its receptors and thereafter through an inhibition of calmodulin [80] and/or a stimulation of [81] or inhibition of [61] the MEK/ERK 1/2 signaling cascades.

In humans, higher expression of MT1 receptors occur more frequently in breast tumors than normal breast epithelium and is associated with a high nuclear grade [82]. MT1 receptors are also expressed in tumors of the prostate [83]. Overexpression of MT1 receptors in MCF-7 cells renders the cells and xenografts more sensitive to melatonin therapy [84, 85]. Expression of MT1 receptors in S-91 murine melanoma cells (normally devoid of MT1 receptors), increases the anti-proliferative effects of melatonin [86]. Melatonin inhibits cell proliferation and transformation in MT1- or MT2-melatonin receptor expressing NIH 3T3 cells [87]. Also, in both rat hepatoma and human breast cancer xenografts, perfusion of these xenografts with melatonin-rich blood collected during the night from human subjects, significantly inhibits cAMP levels, MEK/ERK (1/2), linoleic acid uptake/metabolism and proliferative activity in these tumors. Additionally, these melatonin-induced effects are mediated by MT1/MT2 melatonin receptors as the addition of a nonselective melatonin receptor antagonist (S20928) blocks the effects [61]. Also, MT1 melatonin receptors, and MT3 receptors may be involved in the anti-proliferative effects of melatonin in human melanoma cells [88] and and MT2 melatonin receptors in the anti-proliferative effects of melatonin on an ER + human endometrial cancer cell line [89]. Also, the anti-proliferative effects of melatonin on tumor cells may be via its action on telomerase activity through melatonin receptors [76, 90].

Melatonin has additional activities that influence cancer, including modulation of the endocrine and immune systems [91] and stimulation of gap-junction intercellular communications [62, 73]. Reduced immune function resulting from lower melatonin levels may enhance tumor proliferation and reduce tumor surveillance [62]. Melatonin influences the levels of both estrogen and prolactin, which are also important in the promotion and proliferation of mammary tumors [25, 73]. In addition, melatonin downregulates ER levels in breast cancer cells and blocks ER DNA binding and transactivation functions [25, 77, 92–94]. Inhibition of estrogen results in the decrease in estrogen regulated factors such as cyclin D1 through its actions on c-jun and ATF-2, transcription factors known to bind to minimal estrogen-sensitive cyclin D1 promoter elements [95]. In addition, melatonin decreases EGF action via cross talk mechanisms with the ER [75]. Cumulatively, these data suggest melatonin should inhibit factors important in carcinogenesis and, thus, may have a role in cancer protection.

Melatonin as an adjuvant therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References

In numerous studies, the addition of melatonin with other treatments improves therapeutic outcomes because of its protective mechanisms and its ability to enhance the efficacy of these drugs [96, 97]. Clearly, melatonin enhances the actions of many different classes of drugs probably because of its diverse pharmacological actions at the cellular level. If the drug exhibits toxicity, as seen with many chemotherapeutic agents [98], then melatonin use as an adjuvant to current, clinically-accepted therapies may prove to be beneficial [99, 100]. Due to melatonin's ability to enhance the efficacy of some drugs, doses of these drugs could be adjusted to either reduce toxicities or enhance therapeutic effects. In addition, because of melatonin's ability to accumulate within a cell and function in detoxification, its use as an adjuvant is protective [99]. Furthermore, by virtue of its ability to activate multiple targets within the cell, melatonin may be useful in enhancing the therapeutic efficacy of other drugs class with similar functions. For example, melatonin, given in combination with tamoxifen, enhances the chemopreventative actions of tamoxifen by acting on a site other than the ER, e.g. calmodulin. In this scenario, tamoxifen acts to antagonize ERs in the breast whereas melatonin acts on calmodulin to inhibit ER binding to ERE-containing genes [25].

As melatonin is a chronobiotic agent and that many of its targets may exhibit circadian rhythms (Fig. 2), the timing of the administration to ensure maximum therapeutic efficacy may be a consideration. This idea is supported by recent findings showing that some tumors display circadian rhythms [29, 101, 102]. Many other genes also are rhythmic [11, 22, 23] (Fig. 2); however, whether they are targets for melatonin remain unanswered. Finally, the timing of melatonin could be used to reset circadian clocks in an attempt to reduce cancer risks associated with altered circadian rhythms [103].

In addition to its use as an adjuvant in treating cancer, the co-administration of melatonin with other therapies such as hormone replacement therapy (HRT) to decrease the risk factors associated with menopause, i.e. breast cancer, osteoporosis and stroke [8] should be considered. A negative correlation between the amplitude of the melatonin rhythm and circadian indicators of collagen metabolism exists [28, 34]. Therefore, a reduction in circulating melatonin levels may be a risk factor associated with the loss of bone in postmenopausal women. As reductions in melatonin occur during aging and also after HRT [104], restoring melatonin levels before the onset of menopause and maintaining this therapy during HRT, if needed, may help prevent bone loss and ultimately prevent osteoporosis.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References

In general, the mechanisms of action of melatonin remain poorly defined at the molecular level. Studies aimed to determine how melatonin produces its effects in its models should be determined so that proteins, other than melatonin receptors, can be targets for future drug development. Many current therapies for treating diseases such as cancer, osteoporosis and diabetes, use multiple drugs that act at different sites. This strategy is used to enhance the effectiveness of the therapy so as to improve the outcome of the treatment. Understanding whether the effects of melatonin in a given situation are being mediated via receptors or are receptor independent would aid in determining the efficacy of melatonin as a therapeutic agent. In addition, being that melatonin is a chronobiotic agent, and that many of its targets, including some tumors, contain clock genes [31] indicates that the timing of melatonin administration may determine its therapeutic efficacy (Fig. 2). As clock gene disruption increases spontaneous tumor formation in mice [71] and increases breast cancer risk in premenopausal women [72], then consideration should be given to those factors that desynchronize the internal timekeeping parameters to minimize these risks.

Although three areas were the focus of this review, this by no means negates or downplays the importance of melatonin use in other therapies, including its use as an anxiolytic or as an anti-hypertensive agent.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References

This review is dedicated to our dear friend, John S. Doctor, one of the authors of this review, who died suddenly. Even though he will be missed greatly, his memories will be cherished and his ideas put forward.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Melatonin as a therapy for the prevention of osteoporosis
  5. Melatonin as a therapy for the prevention of cancer
  6. Melatonin as an adjuvant therapy
  7. Conclusion
  8. Acknowledgments
  9. References
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