**6. Melatonin effects on bone metabolism**

At present a relation between melatonin and skeleton is known. Melatonin may produce an effect on bone tissue which manifests itself in bone tissue formation with osteoblasts and/or hindering bone resorption with osteoclasts. The study of K. Satomura et al. [31] confirms the melatonin (*Mel1*) receptor expression in human osteoblasts and tendency of its level reduction with aging. It is also demonstrated that melatonin can have a boosting effect on proliferation and differentiation of human osteoblasts [32]. Through a controlled randomized trial (2012), exogenous melatonin effect on bone tissue density was revealed. Bone tissue condition was controlled in two ways—bone tissue density estimation and bone marker determination. There was no considerable improvement noted in terms of bone tissue density in T points or as compared with placebo. An average change in the activity of bone resorption marker, N-telopeptide (NTX), in this study did not differ much inside and between the groups. Similarly, the average change in the activity of bone formation marker, osteocalcin, did not show any remarkable differences either inside a group or between groups. However, NTX to osteocalcin ratio followed a downward trend among the women who took melatonin as compared to placebo. It is quite important because among menopausal women, this ratio is known to increase so that osteoclasts activity outstrips osteoblast activity, which leads to a loss of bone mass. Probably, decreased level of nocturnal melatonin that occurs during a menopause causes hormonal unbalance and perimenopause symptoms, including the loss in bone mass. These data prove that melatonin intake may enable the balancing of bone resorption and formation processes, potentially preventing fast loss of bone mass attributed to a menopausal period [33].

Melatonin inhibits resorption activity by reducing RANKL-mediated osteoclastogenesis and therefore decreases bone resorption. Melatonin also protects from losing bone mass induced by free radicals, which occurs in the case of extreme bone resorption, due to its powerful antioxidative properties [34, 35]. In addition to its direct effect on the bone tissue, melatonin can produce an indirect influence on bone metabolism through the hypothalamus-pituitary axis, by suppressing levels of follicle-stimulating hormone and estrogen and increasing the level of progesterone. In contrast to the follicle-stimulating hormone, melatonin has positive correlation with progesterone level. Progesterone is known to influence on the mineral density of bone tissue, especially on osteoblast differentiation [36]. Reduced level of progesterone during a perimenopause may lead to the decreasing of bone tissue density because of osteoblasts loss.
