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The Link between Sleep and Osteoporosis
A typical example of sleep deprivation is insomnia. In recent decades, there have been an increasing number of patients who are claiming insomnia regardless of age, and the causes are not limited, however, daily influencing life environments such as smartphone use, light noise, overwork, and the presence of absence of diseases can be cited.12 Chronic sleep loss is associated with deficits in attention, cognition, immune function, metabolism, mood, and cardiovascular function and hormonal disturbances.23 In addition, it is not easily to say which symptom is first, but it is known that sleep deprivation and depression are also closely related.45 Even depression is recognized as a kind of disability in the United States, and some studies report that depression is an important risk factor for osteoporosis.56 Therefore, sleep quality is a very important factor for physical and mental health in human. In particular, postmenopausal women are under the influence of multiparity and prolonged lactation, severe hormonal changes by estrogen deficient condition, and osteoporosis is a major disease that occurs.7 Interestingly, osteoporosis is increasingly prevalent in men as well as women in recent years with hormonal disturbances.89 In male, eating behavior, appetite related hormone changes such as leptin, insulin and ghrelin, body mass index, sex hormone, and chronic consumptive disease such as pulmonary diseases are the major causes of osteoporosis.1011121314 Thus, the cause of osteoporosis in women may be slightly different with in men, however, the quality of sleep is an important factor in the development of osteoporosis.1516 Certainly, it is expected that there are hidden important links between sleep and osteoporosis, and there are effective mechanisms that can break the vicious cycle between the 2.
Possible Causative Factors of Bone Mass Deficit in Subjects with Insomnia
1. Hypothalamo-pituitary-adrenal (HPA) axis regulation
Stressors are imminent or perceived challenges to homeostasis in human. Our body is trying to restore the non-stressed homeostatic set point from any specific stress factors. Monoamine, cytokines, glutamate, γ-aminobutyric acid (GABA) and other central mediators have main roles in the normal stress response. In this context, corticotropin-releasing factor (CRF)/HPA axis and the sympathomedullary systems play a very important role in the regulation of the physical and psychological balance in body. Since HPA axis regulation is based on the principle of negative feedback system, it reacts by stress condition like insomnia, it secretes adrenal hormone to relieve this stress and reduces the secretion again when the cause is removed. However, if insomnia persists and stress factors are not removed, the secretion of adrenal hormone persists and body homeostasis is greatly affected. A research study demonstrated that sleep deprivation could increase cortisol concentration, which might decrease bone formation and bone mineral density (BMD).17 Moreover, there have reported that short sleep or long regulated in elevated pro-inflammatory cytokines, which subsequently increased osteoclast activity that insomnia is related to osteoporosis.1819202122
2. Sympathetic system
Stress is the disturbance of the complex dynamic equilibrium that all organisms must maintain, and is associated with activation of the stress system comprising of the HPA axis and the arousal/sympathetic nervous systems.23 As mentioned earlier, the stress system functions on a baseline circadian fashion and interacts with other systems in the organism to regulate diverse behaviors, endocrine, metabolic, immune and cardiovascular functions, and this chronic stress condition may lead to several psychopathologic conditions, metabolic syndrome, and osteoporosis.23 In mice experiment, mice were exposed to various severe stressors for 2 weeks, and the mice showed bone loss mediated by catecholaminergic system, as it could be improved by β-blocker.24
Thus, chronic tension conditions lead to abnormal cortisol secretion, which can have an additional impact on cognitive and emotional development, puberty and timing of the final key even in children and adolescence. To prevent distraction during stressful situations, the capacity to seek and experience pleasure is reduced, food intake is diminished and sexual activity and sleep are held in abeyance.25 Monoamines, cytokines, glutamate, GABA and other central mediators have key roles in the normal stress response. Many central loci are involved. The subgenual prefrontal cortex restrains the amygdala, the CRF/HPA axis and the sympathomedullary system.42526 The function of the subgenual prefrontal cortex is moderately diminished during general stress to disinhibit these loci. This disinhibition enhances anxiety and physiological hyperarousal, while diminishing appetite and sleep.2527 In addition, Kuriyama et al.28 have directly confirmed that short sleep was closely associated with a decline in cortical bone thickness by enhanced bone resorption and sympathetic nervous system hyperactivity in the middle-aged group.
3. Sleep and hormones
(1) Orexin
Orexin-A and -B (also known as hypocretin-1 and -2) are neuropeptides secreted in the lateral hypothalamus that stimulate wakefulness, feeding, thermogenesis, and reward behaviors.2930 Orexin deficiency in humans causes behavior abnormalities including sleep and mood disorders.31 Orexin deficiency and sleep disorders are also frequently related with major mood disorders such as depression.3233 They function through 2 receptors: Orexin-1R and Orexin-2R. It has known orexin deficiency in human and mice leads to narcolepsy, hypophagia, and obesity.343536 Thus, there is tremendous pharmacological interest in developing orexin-targeting small molecules for the medications of sleep and metabolic disorders such as insomnia,37 obesity, and diabetes,363839 some of which has completed phase III clinical trials.31
(2) Ghrelin
It has known that ghrelin is a recently discovered brain-gut peptide with 2 main physiological actions such as growth hormone secretagogue activity and food intake inducer. In addition, ghrelin also plays the role of control of energy metabolism, regulation of gastric and pancreatic activity, and cardiovascular and hemodynamic activities, modulation of bone homeostasis, sleep and behavioral influences.40 In same context, ghrelin and estrogen levels in plasma in women were significantly associated with according to Nouh et al.'s report41.
It has reported that Orexin-1R inhibits osteoblast differentiation by reducing osseous ghrelin expression without changing circulating ghrelin levels, suggesting that distinct mechanisms may account for the regulation of ghrelin expression in bone and stomach.31 Ghrelin siRNA knockdown experiments and previous pharmacological experiments show that ghrelin promotes osteoblastogenesis.424344 Although ghrelin has yet to be clarified more clearly about the relationship between ghrelin and sleep and bone metabolism, various functions of ghrelin need to pay attention to the relationship between sleep and bone for a therapeutic approach.
(3) Leptin
Although many observations of leptin's cyclical pattern over the 24-hour day, relatively few studies have examined how the circadian rhythm of leptin may be essential to leptin signaling and health yet.45 A circadian misalignment between behavior and circadian timing is known to lead to lower overall leptin levels suggesting that leptin responds to the endogenous circadian clock independently of some behaviors like feeding.4546 It is also reported bone density, fertility and body weight regulation by leptin level. As described in the sympathetic system section, leptin may influence the interactions between central and peripheral signals. In case of hypoleptinemia disturbed control of appetite and hormonal dysfunction as well as has implications for the hypothalamo-pituitary-gonadal axis, BMD and physical hyperactivity. Since leptin and orexin are very associated with sleep, eating, and bone density,3147 it is necessary to further study about the sharing signaling to medicate the symptoms.
(4) Serotonin
The amino acid tryptophan is the precursor of several important product such as serotonin and melatonin. The relationship between serotonin and melatonin has been actively studied for understanding mechanisms for insomnia, particularly, in aged sleep-wake cycle function.48 Serotonin metabolized to melatonin through the enzymes like aromatic L-amino acid decarboxylase and hydroxyindole-O-methyltransferase. This way can explain the reason why impaired the biosynthesis of serotonin led to states of total insomnia.48
(5) Melatonin
Melatonin has widely known to have beneficial actions through anti-inflammatory, anti-oxidative stress, and bone-preserving effects. In addition, melatonin is known to be relatively safe than other sleeping aids and is widely used in patients with insomnia.49 Melatonin treatment enhanced mesenchymal stem cells by upregulation of AMPK, FOXO3a, and RUNX2 responsible for the mechanistic link between oxidative stress and osteogenic phenotype.50 Also, melatonin promoted osteoblast differentiation in primary bone marrow mesenchymal stem cells from ovariectomized (OVX) mice. It also reduced activation of NLRP3 inflammasome in femoral bone protein and in induced osteoblasts stimulated by OVX.51 The intake of anti-inflammatory and antioxidant melatonin is thought to be beneficial not only for induction of sleep but for bone metabolism, and should be studied for more mechanisms.
4. Alternative medicines for sleep and osteoporosis
Although the markets for sleeping pills and anti-osteoporosis drugs are enormous, many patients suffer additional pain due to various side effects of drugs, abnormal behaviors, and high irritability to gastrointestinal tract.52 According to Jung's report53, zolpidem overdose and patient suicide with benefits and disadvantages of pharmacotherapy. Adverse effects concerning the central nervous system, including delirium and hallucination, as well as abnormal behavior during sleep, are commonly reported among patients who have taken zolpidem for more than 1 year. Therefore, long-term prescriptions to medication of these chemical drugs for sleep induction can be serious problems in cardiovascular system, cognitive, unrecognizing abnormal behaviors. Benzodiazepines and other sedative-hypnotic drugs are frequently claimed with adverse outcomes includes their anti-cholinergic effects and increased risks of falls and hip fractures in the old patients.54 In recent, oriental herbal pharmacy has been got attention as alternative medications for treating insomnia that can help relieved hypertension, cognitive function and improve sleep induction for seeking to increase safety and efficiency. Passiflora incarnate L., Rosmarinus officinalis L., Violet oil from Viola odrata, Ziziphus spinose, Poria cocos, Gycyrrhiza uralensis are recently introduced for sedative effect for well sleep.5556 These herbal medicine is known to act through GABA or GABA-A receptor.56 Since the mechanisms of these herbal medicines are thought to activate expression of Orexin-A, Orexin receptor, Leptin and Leptin receptor, therefore, we can confirm that all the mechanisms and principles of sleep therapy and bone metabolism mentioned earlier at “Possible causative factors of bone mass deficit in subjects with insomnia” also apply to herbal medicines. In particular, effect of Passiflora spp. extract recently reported they have possibility to use as sleep inducer and anti-osteoporosis substance.5557 In recent, Passiflora incarnate L. has been introduced safe and promising effects on sedative, inducing sleep and anti-anxiety functions.55585960 This serotonin and melatonin driving effects have been expected to have anabolic effect in bone. Compared to the side effects and risks of synthetic medicines, the ability to treat sleep and bone health using traditional plant-derived medicinal herbs, which are safe, offers benefits to many people, while providing opportunities for a sizable pharmacy market.
Conclusion
For modern people, the dream of longevity through quality of sleep and bone health is very tempting. However, due to the increasing differentiation rate and various stresses of modern society, people live with chronic insomnia as well as the problem of bone health. These metabolic causes are closely related to various diseases such as obesity, hypertension, chronic consumptive disease, abnormal behaviors and diverse depressions, so prevention and management of such diseases will be critical. As noted above, sudden changes in hormones after postmenopausal in female can be a major cause in many cases, however, it has been found that the inability to treat stressors is a very important reason for sleep and osteoporosis. Even in the case of currently prescribed synthetic drugs, there is a risk of various side effects that cannot be predicted, so more attention is required when physicians treat them. For this reason, it seems necessary to have a very effective adjuvant to alleviate the stress on the human body, such as the control of autonomic nervous system, hormonal control, and the effect on the appetite center. These stress factors are not only the stresses of everyday life but various inflammatory factors.
It is anticipated that the number of patients experiencing sleep deprivation and osteoporosis at a time should be tremendous, and herbal medicine originated from plant-derived herbal medicine, which has been proven safe for treatment, will play an alternative medical role. It is being actively introduced into the market as a supplementary nutritional food preparation. Concentrating and encouraging the review and management of these products at the national agency with a supervisory obligation would open the way for a comfortable treatment for patients with sleep and osteoporosis who rely on synthetic drug prescriptions now.
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