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E xposure to microgravity during spaceflight is known to be associated with rapid and drastic bone loss in humans, which can increase the risks of fragility fracture and renal stone formation. Furthermore, the recovery of bone loss may require a relatively long time after returning to Earth. Therefore, bone loss has become a substantial obstacle to human exploration of outer space. Currently, the therapeutic effects of the countermeasures related to microgravity-induced bone loss, including exercise, pharmacological intervention, and supplementation, are not sufficient. Moreover, each class of pharmacological drugs has potential side effects. Hence, it is urgent to find safer and more effective drugs to alleviate microgravity-induced bone loss. Melatonin is a tryptophan-derived methoxyindole synthesized and released principally from the pineal gland. The secondary sources of melatonin are bone marrow, retina, gut, and skin. The production of melatonin occurs almost exclusively during the night, so exposure to light at night can reduce its production. Through receptor-mediated and receptor-independent actions, melatonin performs pleiotropic physiological functions in vertebrates. Due to its production and secretion being closely related to the environmental light/dark cycle, the key function of melatonin is to regulate the circadian rhythm. Moreover, there is credible evidence that melatonin possesses antioxidant, anti-aging, anti-inflammatory, and anticancer properties. Interestingly, melatonin is capable of chelating metals, such as iron, aluminum, cadmium, copper, lead, and zinc. It is worth noting that melatonin has a high safety profile and positive effects on osteoporosis, including microgravity-induced bone loss. As an attractive multitasking molecule, this review sheds light on the potential benefits of melatonin in the prevention and treatment of microgravity-induced bone loss.

Introduction
Space travel attracts individuals interested in space exploration. Although manned spaceflight has achieved exciting results, there are still some challenges. Ensuring the health and safety of space travelers is the main priority. Microgravity is well known to be a major threat to human health and safety during spaceflight. Exposure to microgravity in space causes numerous adverse changes in the physiological functions of the human body. Apart from cardiovascular dysfunction, immunodeficiency, and muscle atrophy, disorders of bone metabolism occur dramatically under microgravity conditions. These changes can influence the skeletal structure, subsequently resulting in rapid and vigorous bone loss. Astronauts lose 1.0%–1.6% of bone mass in the spine, femoral neck, trochanter, and pelvis per month, which is approximately 10 times the amount of bone loss observed in postmenopausal women. Additionally, the in-flight exercise program is insufficient to completely restore bone loss. So far, bone loss in response to microgravity in space has been identified as a stumbling block for human deep-space exploration unless effective countermeasures are established. Growing evidence has indicated that bone loss in response to microgravity is a consequence of imbalanced bone remodeling, which is manifested as decreased bone formation through osteoblasts and increased bone resorption by osteoclasts. However, the underlying mechanisms remain largely unknown. Therefore, further investigations that identify drugs or endogenous hormones that can effectively prevent bone loss associated with microgravity are needed.

Conventional antiosteoporosis drugs, mainly including antiresorptive and anabolic drugs, are successfully available for the clinical treatment of osteoporosis. However, each class of drugs usually has severe side effects. Therefore, it is most important to find safer and more effective drugs for mitigating microgravity-related bone loss. Melatonin, first isolated and identified from the bovine pineal gland in 1958 by Aaron Lerner, is an avirulent indoleamine produced in almost all living organisms from unicellular organisms to humans. In vertebrates, melatonin is mainly produced and secreted by a neuroendocrine organ termed the pineal gland. Endogenous melatonin is produced practically exclusively during the night, and light exposure in the nighttime results in the strongest melatonin inhibition. In addition, melatonin may be synthesized in several extrapineal organs, such as bone marrow, retina, gut, and skin. Since its production and secretion are directly dependent on the environmental light/dark cycle, the central function of melatonin is to modulate circadian and circannual rhythms, including seasonal reproduction. Additionally, melatonin is proficient in scavenging free radicals due to its remarkable antioxidant property. Moreover, the available evidence supports that melatonin can chelate metals, such as iron, aluminum, cadmium, copper, lead, and zinc. Recently, the positive effects of melatonin on bone homeostasis have been reported. However, research on its application for microgravity-induced bone loss is extremely lacking.

In this review, it is proposed that melatonin has potential therapeutic benefits for bone loss in response to microgravity. We first summarize the current knowledge of bone loss in response to microgravity. Then, the information about biosynthesis and physiological functions, as well as the safety and efficacy of melatonin, are discussed. Further, we introduce melatonin and bone remodeling, and then discuss the potential utility of melatonin for bone loss in response to microgravity. Finally, we provide some future research directions.

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