Melatonin as a chronobiotic/cytoprotective agent in bone. Doses involved

Abstract

Because the chronobiotic and cytoprotective molecule melatonin diminishes with age, its involvement in postmenopausal and senescence pathology has been considered since long. One relevant melatonin target site in aging individuals is bone where melatonin chronobiotic effects mediated by MT1 and MT2 receptors are demonstrable. Precursors of bone cells located in bone marrow are exposed to high quantities of melatonin and the possibility arises that melatonin acts a cytoprotective compound via an autacoid effect. Proteins that are incorporated into the bone matrix, like procollagen type I c‐peptide, augment after melatonin exposure. Melatonin augments osteoprotegerin, an osteoblastic protein that inhibits the differentiation of osteoclasts. Osteoclasts are target cells for melatonin as they degrade bone partly by generating free radicals. Osteoclast activity and bone resorption are impaired via the free radical scavenger properties of melatonin. The administration of melatonin in chronobiotic doses (less than 10 mg daily) is commonly used in clinical studies on melatonin effect on bone. However, human equivalent doses allometrically derived from animal studies are in the 1–1.5 mg/kg/day range for a 75 kg human adult, a dose rarely used clinically. In view of the absence of toxicity of melatonin in phase 1 pharmacological studies with doses up to 100 mg in normal volunteers, further investigation is needed to determine whether high melatonin doses have higher therapeutic efficacy in preventing bone loss.

Melatonin Decreases Alveolar Bone Loss in Rats with Experimental Periodontitis and Osteoporosis: A Morphometric and Histopathologic Study

“…In studies focusing on the chronobiotic effect, lower doses of melatonin were found to be effective. However, the impact of melatonin on bone occurs through a distinct pathway from that of the receptors involved in its chronobiotic effect [ 16 , 22 , 61 ]. It has been observed that higher doses of melatonin are required to have an impact on bone remodelling [ 62 ].…”

“…One of the strongest known antioxidants [ 13 ], melatonin, is a hormone synthesised in the pineal gland [ 15 ]. It can be demonstrated that it has both chronobiotic and cytoprotective functions [ 16 ]. Melatonin is crucial in regulating the daily biorhythm, [ 14 ] immunity, and sleep [ 15 ]; it also has antioxidant [ 13 ] and anti-inflammatory [ 17 ] effects.…”

“…Melatonin is crucial in regulating the daily biorhythm, [ 14 ] immunity, and sleep [ 15 ]; it also has antioxidant [ 13 ] and anti-inflammatory [ 17 ] effects. Numerous studies indicate that melatonin promotes healthy aging and slows the aging process [ 16 ]. High doses of melatonin have anti-inflammatory effects by reducing free radicals and proinflammatory cytokines [ 16 , 18 ].…”

“…Numerous studies indicate that melatonin promotes healthy aging and slows the aging process [ 16 ]. High doses of melatonin have anti-inflammatory effects by reducing free radicals and proinflammatory cytokines [ 16 , 18 ]. Melatonin acts directly as an antioxidant by scavenging free radicals and increasing its antioxidant activity to high levels [ 19 ].…”

“…Kotlarcyzk et al reported that melatonin improves physical symptoms associated with perimenopause, possibly by restoring the balance in bone remodelling [ 26 ]. Studies have shown that melatonin is well tolerated and does not cause any known toxicity [ 16 ]. In all studies conducted with rats and mice, it has been stated that melatonin between 0.5 and 100 mg of calcium enhance bone remodelling by reducing bone resorption and that it positively affects the BMD without significant side effects [ 21 , 22 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].…”