Abstract
Anorexia nervosa (AN) and obesity are two major eating disorders present nowadays in Western countries. They are both characterized by striking body composition variations and hormonal alterations, which impact on skeletal metabolism, inducing bone tissue modifications and, thus, often cause an increased risk for fractures. AN and obesity are characterized by a severe reduction in fat mass and a high expression of it, respectively, and in both conditions hormones secreted or modulated by body fat content are important determinants of low bone density, impaired bone structure and reduced bone strength. In addition, in both AN and obesity, increased marrow adiposity, which correlates with low bone density, has been observed. This review will discuss the pathophysiological basis of bone alterations associated with AN and obesity, conditions of extreme energy deficiency and excess, respectively.
Introduction
Anorexia nervosa (AN) and obesity are the two major eating disorders, and are both characterized by marked body composition modifications and hormonal alterations which, in turn, influence bone metabolism causing an increased risk for fractures [1], [2], [3], [4], [5].
In particular, AN is characterized by a severe reduction in fat mass and obesity by a high expression of it. The importance of body composition alterations is based on observations that suggest several potential mechanisms to explain the complex relationship between adipose tissue and bone: fat has long been viewed as a passive energy reservoir, but after the discovery of leptin and the identification of other adipose tissue-derived hormones and serum mediators [6], [7], [8], it has come to be considered an active endocrine organ involved in the modulation of other tissues homeostasis. Adipose tissue, in fact, secretes various inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which are believed to have adverse metabolic, skeletal and cardiovascular consequences [9]. Moreover, as IL-6 other fat-derived mediators, which include leptin, adiponectin, and resistin affect human energy homeostasis and are involved in bone metabolism, contributing to the complex relationship between adipose and bone tissue [10]. Finally, fat tissue is one of the major sources of aromatase, an enzyme also expressed in the gonads, which synthesizes estrogens from androgen precursors. Estrogens are steroid hormones, which play a pivotal role in the maintenance of skeletal homeostasis, protecting against osteoporosis by reducing bone resorption and stimulating bone formation [11]. Thus, the pathophysiological role of adipose tissue in skeletal homeostasis lies in the production of several adipokines and hormones, which modulate bone remodeling via their effects on either bone formation or resorption.
As the demonstration that bone cells express several specific hormone receptors, the skeleton has come to be considered an endocrine target organ [12], [13], [14], [15], and as recent observations have shown that bone-derived factors, such as osteocalcin and osteopontin (OPN), affect body weight control and glucose homeostasis [16], [17], [18], the bone has come to be considered an endocrine organ itself [19]. These considerations suggest a potential role of bone as a player of a potential feedback mechanism between the skeleton and other endocrine organs [19]. Thus, the cross-talk between fat and bone likely constitutes a homoeostatic feedback system in which adipokines and bone-derived molecules represent the link of an active bone-adipose axis.
Finally, adipocytes and osteoblasts originate from a common progenitor, a pluripotential mesenchymal stem cell [20], which has an equal propensity for differentiation into adipocytes or osteoblasts (or other lines) under the influence of several cell-derived transcription factors. This process is complex, suggesting significant plasticity and multifaceted mechanism(s) of regulation within different cell lineages, among which are adipocytes and osteoblasts [21], [22]. Several human and animal studies have examined the function of adipocytes in bone marrow. Mesenchymal stem cells isolated from bone marrow in postmenopausal osteoporotic patients express more adipose differentiation markers than those from subjects with normal bone mass [23], and noticeable fatty infiltration in the bone marrow of rats following oophorectomy has been observed, suggesting a pivotal role of estrogens in regulating adipocyte and osteoblast recruitment [24].
This review will discuss the pathophysiological basis of bone alterations associated to AN and obesity, conditions of extreme energy deficiency and excess, respectively.
Anorexia nervosa and bone metabolism: energy homeostasis, hormone, body composition and bone marrow alterations
AN is a psychiatric disorder characterized by high morbidity and mortality, with the highest mortality rates among mental disorders. The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) has revised the diagnostic criteria for the disease, which now include caloric restriction leading to severe underweight, intense fear of gaining weight and distorted body image (Table 1). Amenorrhea has not been included among the criteria in DSM-V [25].
Academic purposes has classified AN patients into three different categories: | |
1. | low weight |
2. | short-term recovered |
3. | long-term recovered |
The American Psychiatric Association has subdivided AN into two distinct categories: | |
1. | Restrictive type (RAN), patients exhibit “restricted food intake without binge eating or purging” |
2. | Binge-eating/purging type (BPAN), involving both “binge eating/purging episodes during anorexia and bulimia phases” |
Modified from Faye WH et al. (1996); DSM-V, 2013.
The lifetime prevalence of AN in the general population is estimated between 0.3% and 0.9% in women, while it is <0.3% in men. AN primarily affects adolescent girls and young women, although it has occasionally been described in pediatric patients as well as in elderly women [26].
In the evolution of AN, energy homeostasis and hormone alterations occur, with most of them likely reflecting an adaptive response to malnutrition in an attempt to retain energy reserves. Patients with AN are characterized by a typical body composition phenotype with an extremely low percentage of body fat, when compared with healthy women with similar body mass index (BMI) [27], that, in association with the hormone adaptive condition, likely induces negative effects on bone metabolism. In fact, subjects affected by AN frequently present bone diseases, which include impairment of linear growth and reduced bone mineral density (BMD), associated with changes in bone turnover and structural and microarchitectural alterations, leading to increased fracture risk, as observed in postmenopausal osteoporosis [28]. In fact AN can significantly lead to impairment of peak bone mass, which plays a pivotal role in skeletal homeostasis (Figure 1).
The mechanisms involved in bone tissue alterations in AN are very complex and not, as yet, fully clarified. For instance, in patients with AN, leptin levels, which reflect energy stores, are very low, while adiponectin, which plays a pivotal role in energy homeostasis and insulin sensitivity, have been found higher than in matched controls [28].
Leptin stimulates the differentiation of stromal cells to osteoblasts, increases proliferation of osteoblasts and inhibits osteoclastogenesis. Moreover, systemic administration of leptin to adult mice results in reduced bone fragility [28], while leptin-deficient and leptin receptor-deficient mice, despite an obese and hypogonadal phenotype, are characterized by high bone mass due to increased bone formation [28]. Data in humans are contradictory: with regard to leptin’s action on bone physiology, either a beneficial role [29], [30], a detrimental one [31], [32], and a central inhibitory or a peripheral stimulatory effect of leptin on bone metabolism have been described. In women with AN, low leptin levels have been correlated with lower lumbar spine and hip BMD [33], as well as with microarchitecture alterations [34].
Interestingly, in vitro studies have demonstrated the expression of both adiponectin and its receptors in osteoblasts, as well as in osteoclasts; in addition, adiponectin affects osteoblastogenesis either positively or negatively, while suppressing osteoclastogenesis [28]. The locally produced adiponectin likely exerts more important effects on bone than circulating adiponectin. Indeed, although data regarding the effects of adiponectin on BMD in humans are largely inconsistent, there is enough evidence to hypothesize a negative correlation between circulating adiponectin levels and BMD [35]. Moreover, a negative association between adiponectin levels and BMD was observed in patients affected by AN [36].
In subjects affected by AN the plasma levels of ghrelin, an orexigenic peptide which also act as growth hormone (GH)-segretagogue and secreted primarily by the oxyntic cells of the stomach, are high when compared to normal controls. Remarkably, the refeeding of these patients does not lead to normality [28]. In addition, patients with AN show high fasting levels of peptide YY (PYY), an anorexigenic, gut-derived peptide secreted in response to food ingestion, which remain elevated even after an increase in body weight. Conversely, fasting levels of gastric inhibitory polypeptide (GIP), secreted from K-cells in the duodenum in response to food ingestion are low as compared to those of healthy controls [28].
Ghrelin, apart from stimulating GH release, modulates osteoblasts activity, increasing their proliferation and differentiation [37], [38]. Further, ghrelin infusion in experimental animal model determines an increase of BMD [38], but ghrelin knockout animal models show normal skeletal metabolism [39]. Healthy adolescent girls show a correlation between ghrelin secretion and BMD independently from body composition, circumstance not observed in adolescent girls with AN [40], suggesting that ghrelin probably does not play a major role in the skeletal status of these patients.
The system of neuropeptide Y (NPY), PYY and Y receptors, is a major regulator of energy homeostasis, and there are growing evidences that it is also important in bone metabolism. In particular Y2 knockout mice (Y2-/-) are characterized by increased cancellous bone volume, with increased trabecular number and thickness as well as neuropeptide Y knockout mice (NPY-/-) [41]. In contrast, NPY over-expression in the arcuate nucleus leads to weight gain and tibial BMC reductions through a decrease in osteoblastic activity [42]. Leptin constitutes an important regulator of NPY activity and low levels of leptin lead to enhanced hypothalamic NPY expression [43].
Finally, GIP enhances osteoblasts function [44], nevertheless no association between GIP levels and BMD values has been observed in subjects with AN [45].
Sex steroid hormones modulate the integrated metabolic interaction among major organs crucial for metabolically demanding activities such as reproduction and metabolic functions. Adipose tissue accumulation is sexually dysmorphic and females have a higher percentage of body fat than males. Adipose tissue distribution is also different, with females accumulating more subcutaneous fat and males accumulating more visceral fat [46]. Sex steroids are required to regulate adipocyte metabolism and they influence the sex-specific remodeling of particular adipose depots, thus strongly influencing body fat distribution and adipocyte differentiation and physiology.
Patients affected by AN show a characteristic body composition phenotype with an extremely low amount of body fat, and female subjects affected by AN typically have amenorrhea, which was a diagnostic criterion for AN until the latest revision of DSM. Amenorrhea in AN patients has a hypothalamic origin and it is due to a regression of the LH secretory pattern to prepubertal or pubertal standards [28]. Leptin is probably the mediator between low energy stores and impaired hypothalamic function, although there is evidence that ghrelin might have an independent impact on LH pulsatility [28]. Hypogonadotropic hypogonadism has also been described in male subjects affected by AN, with both low testosterone levels and relatively low gonadotropin levels [28], and females with AN likewise show low testosterone levels, with dehydroepiandrosterone sulfate (DHEAS) levels either normal or low [28].
It is well known that estrogens play a pivotal role in bone metabolism, improving bone formation and inhibiting bone resorption [47], [48], [49]. Indeed, estrogens inhibit receptor activator of nuclear factor kappa-B ligand (RANKL) and stimulate osteoprotegerin (OPG) secretion by osteoblasts [50] and they might also increase bone formation by inhibiting secretion of sclerostin, a transcription factor expressed by osteocytes that otherwise inhibits wnt signaling and therefore osteoblastic activity [50]. Postmenopausal osteoporosis is mainly the consequence of an imbalance between bone formation and resorption with an increase in bone resorption due to the reduction of estrogen levels, and hypogonadism constitutes a major cause of secondary osteoporosis also in young male individuals [51]. Nevertheless, amenorrhea is not the only mechanism of bone loss in AN, in fact women with AN have lower BMD values as well as women with hypothalamic amenorrhea, but with normal BMI, indicating that other factors contribute to bone disease [52]. These factors are represented by androgens, which apart from being aromatized to estrogens, have direct effects on osteoblast differentiation and proliferation [53]. In women with AN, a correlation between androgen (testosterone and DHEAS) levels and BMD, as well as in adolescent boys, has been observed [54], [55].
Hypercortisolemia affects bone metabolism, and both endogenous hypercortisolism, as Cushing syndrome, and the use of oral glucocorticoids have been associated with a significant increase in fracture risk [56], [57]. In fact, cortisol acts directly on osteoblasts and osteocytes, enhancing their apoptosis [58], [59], [60], [61], [62], and reduces both osteoblast and osteoclast formation [59]. However, it increases the lifespan of osteoclasts leading to a temporary increase in bone resorption [60]. AN is a condition in which a relative hypercortisolemia exists for an adaptive mechanism to maintain euglycemia in a state of low energy availability [50]. In subjects affected by AN higher cortisol concentrations are associated with lower BMI and fat mass, and are related to an increased frequency of cortisol secretory bursts and a longer cortisol half-life [50]. Weight gain leads to a significant decrease in cortisol burst frequency [50]. Individuals with AN show a negative correlation between hypercortisolemia and bone formation markers, whereas there is no association between cortisol levels and bone formation in healthy controls [61], and 12-h overnight mean serum cortisol levels correlate negatively with lumbar spine and hip BMD [62].
Insulin growth factors I and II (IGF-I and IGF-II) also appear to significantly affect bone metabolism in AN patients. IGF-I enhances bone formation through its action on mature osteoblasts [63] and normal circulating levels of IGF-I are of primary importance for the preservation of cortical bone mass [64]. In subjects with AN low levels of GH binding protein suggest decreased expression of the GH receptor and a state of GH resistance [65]. This is confirmed by the observation of lower levels of IGF-I despite higher concentrations of GH than in controls [66]. Higher GH concentrations are consequent to an increase in secretory burst amplitude and frequency, and higher basal GH secretion [66]. The increase in GH is likely an adaptive response to maintain euglycemia in a state of starvation by increasing availability of gluconeogenic substrates through increased lipolysis. GH concentrations are inversely associated with BMI and fat mass in AN patients, and are likely driven by lower levels of IGF-I and higher levels of ghrelin [66], [67]. Lower IGF-I levels are associated with lower levels of bone formation markers, lower bone density, and impaired bone microarchitecture [34], [68]. Whereas normal-weight girls with higher GH concentrations have higher levels of bone turnover markers, this association is not observed in girls with AN, suggestive of skeletal GH resistance [66]. This is further confirmed by lack of a significant increase in levels of IGF-I and bone turnover markers following administration of supraphysiologic doses of rhGH to adult women with AN over a 3-month period, indicative of hepatic and bone resistance to GH [69]. Instead, the administration of recombinant human IGF-I (rhIGF-I) in replacement doses causes an increase in markers of bone formation in adolescent girls and adult women with AN [70], [71].
Triiodothyronine (T3) acts on osteoblasts regulating their differentiation, proliferation and apoptosis by direct and indirect mechanisms [72], [73], [74]. Hypothyroidism is associated with prolonged bone turnover and with increased fracture risk [75], [76], [77]. T3 levels are low in patients with AN with a simultaneous increase in reverse T3 levels, while thyroid-stimulating hormone (TSH) usually remains within normal limits, creating a hormonal profile resembling the sick euthyroid syndrome. Thyroxine (T4) may also be decreased, and delayed patterns of TSH response to thyrotropin-releasing hormone (TRH) stimulation have also been described [28]. However, the contribution of thyroid axis alterations to AN bone disease is currently unclear.
BMI and lean mass are independent predictors of bone density in males and females with AN [55], [68], [78]. Although lower fat mass is associated with lower bone density, lean mass is a stronger determinant of bone density measures than fat mass, consistent with mechanical loading having a protective effect on bone. In adult women with AN, weight gain is associated with a preferential increase in bone density at the total hip, whereas menstrual recovery is associated with an increase in bone density at the spine [55]. In adolescent girls with AN, increases in lean body mass during weight recovery predict increases in bone density [79]. Finally, in adolescents with AN, recovery of weight and menses is associated with an improvement in bone accrual rates, although residual deficits persist, concerning for suboptimal peak bone mass acquisition despite recovery [80].
In healthy children and adults, a reciprocal relationship has been described between marrow adiposity and bone parameters at both axial and appendicular skeleton [81], [82], [83], [84]. Misra and colleagues have shown, using magnetic resonance spectroscopy techniques, that adults with AN have increased marrow fat compared to normal-weight controls, and that marrow fat is inversely associated with areal bone density measures [85]. Additionally, preadipocyte factor-1 (Pref-1), a member of the epidermal growth factor-like family of proteins, that reduces differentiation within the osteoblast lineage, is higher in women with AN than controls, and higher Pref-1 levels are associated with higher marrow fat and lower areal BMD [86]. Both marrow fat and Pref-1 levels decrease with recovery from AN [87].
Finally, inducible brown adipose tissue (BAT), or beige fat, seems to have anabolic effects on the skeleton in animal models [88], and positive associations of cold activated BAT with bone density measures in healthy adults and with cross-sectional dimensions on bone in healthy children have also been reported [89], [90]. Women with AN have lower cold-induced BAT than controls [91], likely an adaptive response to reduce cold-induced thermogenesis and energy expenditure, and lower BAT content is associated with lower bone density. In addition, IGF binding protein-2 is an inverse predictor of cold-induced BAT and BMD, possibly subsequent to increased binding to IGF-1, a crucial regulator of brown fat adipogenesis [92].
Obesity and bone metabolism: energy homeostasis, hormone, body composition and bone marrow alterations
Obesity, which is due to an imbalance where energy intake exceeds energy expenditure over a prolonged period, has always been known and recognized as a risk factor for metabolic and cardiovascular diseases [93], and considered a protective factor for bone loss and osteoporosis. In fact postmenopausal women, who often present weight gain and obesity, have an increased risk of developing hypertension, dyslipidemia, diabetes mellitus, cardiovascular disease, and some specific types of cancers, have always been considered protected against osteoporosis [11], [93], [94].
Even though body fat and lean mass are correlated with BMD, with obesity apparently exerting protection against bone loss, especially after menopause, during the last decades numerous evidences have described an opposite event, suggesting an inverse relationship between obesity and osteoporosis. In particular, recent studies have shown that an increased abdominal fat tissue could be considered a risk factor for bone loss and osteoporosis [95], [96], [97]. Interestingly, in men obesity correlates with hypogonadism, changes in body composition, glucose tolerance alteration, increased cardiovascular risk factors, and osteoporosis [46], strongly suggesting the lack of gender-specific events.
The mechanism whereby increased central adiposity leads to metabolic alterations, cardiovascular morbidity and bone loss has been largely based on the demonstration that adipose tissue secretes a number of cytokines and bioactive compounds, the adipokines.
The adipokines, which include a variety of pro-inflammatory peptides, are involved in many physiological or pathological processes, including inflammation, endothelial damage, atherosclerosis, impaired insulin signaling, hypertension and bone remodeling. Adipokine disregulation is a strong determinant of the low-grade inflammatory state of obesity, which promotes a cascade of metabolic alterations leading to cardiovascular complications, insulin resistance or diabetes mellitus and bone loss [6], [8].
Leptin, the first identified adipose tissue-derived factor, as mentioned above, is an anorexigenic hormone secreted by adipocytes in proportion to body fat content. Leptin levels are typically elevated in obesity, considered a leptin-resistant state [98]. In obese individuals hyperleptinemia has been widely recognized as an independent cardiovascular risk factor associated with hyperinsulimenia and insulin resistance [99] while its effect on bone is complex, as both negative and positive actions have been reported on the skeleton and on BMD, particularly [29], [30], [31], [32]. In vivo studies indicate that the effect of leptin might depend on its site and mode of action [100], and it has been proposed that peripheral administration of leptin could increase bone mass by inhibiting bone resorption and increasing bone formation, while it appears to inhibit bone formation through a central nervous system effect [101]. In vitro studies also found that leptin modulates directly bone marrow-derived mesenchimal stem cells (BMSCs) enhancing their differentiation into osteoblasts and inhibiingt their differentiation into adipocytes [102]. Finally, leptin also inhibits the expression of NPY, a hypothalamus-derived peptide, essential for the regulation of food consumption, energy homeostasis, and bone remodeling [41]. In particular, NPY seems to promote osteoblast proliferation and activiy in vitro [103].
Adiponectin exerts a protective role on cardiovascular system and glucose metabolism, and in contrast with leptin, serum adiponectin levels are reduced in obese and diabetic subjects and increase after weight loss [104]. Low levels of adiponectin are a common feature of obesity and correlate with insulin resistance [105]. Adiponectin levels are inversely related to the circulating levels of C reactive protein (CRP), TNF-α and IL-6, which are, especially the latter two, powerful inhibitors of adiponectin expression and secretion in cultured human adipose cells [106]. Human osteoblasts express adiponectin and its receptors, and in vivo and in vitro studies show that adiponectin increases bone mass by suppressing osteoclastogenesis and activating osteoblastogenesis [107], likely indicating that a rise in adiponectin levels, caused by fat reduction, could have a beneficial effect on BMD.
Resistin is produced by macrophages and visceral adipocytes, it is elevated in obesity, regulates insulin sensitivity in skeletal muscle and liver and is positively associated with insulin resistance and glucose tolerance in both human and animal models [108]. Resistin might also play a role in bone remodeling as it is expressed in mesenchimal stem cells, osteoblasts, and osteoclasts, and appears to increase osteoblast proliferation, cytokine release and osteoclast differentiation [109].
TNF-α is a pro-inflammatory cytokine which plays important regulatory effects on lipid metabolism, adipocyte function, insulin signaling and bone remodeling [110]. Its expression has been shown to correlate with percent body fat and insulin resistance in humans [111], and it was further recognized that inflammatory processes predispose to bone loss, giving rise to speculation that inflammatory cytokines, such as IL-6 and TNF-α, may play critical roles in osteoclast activity [112]. It has also become clear that TNF-α promotes RANKL production by BMSC and mature osteoblasts, reduces OPG production, and up-regulates the receptor receptor activator of nuclear factor kappa-B ligand (RANK) on osteoclast precursors, increasing their sensitivity to prevailing RANKL concentrations [113]. Additionally, TNF-α turns out to have another property that is relatively unique among the inflammatory cytokines, it has potent effects on osteoclastogenesis as it not only promotes RANKL production but synergizes with RANKL to amplify osteoclastogenesis, and to intensify osteoclastic resorption by directly modulating RANKL-induced signal transduction pathways [114]. These effects are likely a consequence of the fact that RANKL is a TNF-superfamily member and functions through many of the same pathways induced by TNF-α itself.
IL-6 is a cytokine which has a wide range of actions. It is secreted by several cell types, including fibroblast, endothelial cells and adipocytes, and its plasma levels are significantly up-regulated in human obesity and insulin resistance [115]. As TNF-α IL-6 also is a well-recognized stimulator of osteoclastogenesis and bone resorption. Several data show that IL-6 mRNA is expressed in preosteoblasts and osteoblasts [116] and that it stimulates osteoblast proliferation and differentiation by controlling the production of local factor [117]. In addition, IL-6 may play a role in bone formation in conditions of high bone turnover [118].
Although ghrelin, a 28-amino-acid acylated peptide, is mainly secreted by the stomach and it represents the principal endogenous ligand for growth hormone secretagogue receptor (GHS-R) type 1a. Ghrelin, which does not meet the definition of an adipokine as it is not secreted by adipose tissue, is involved in the regulation of glucose metabolism and lipogenesis both directly and through interactions with several adipokines. Ghrelin is known to stimulate the differentiation of pre-adipocytes into adipocytes and antagonize lipolysis, and its levels are inversely correlated with BMI and insulin resistance [119]. Moreover, Ghrelin exerts anti-inflammatory and cardio-protective effects through its inhibitory actions on TNF-α, IL-1, and IL-6, and exerts a protective role on bone metabolism acting both directly and indirectly on bone cells function, inhibiting osteoclastogenic precursors and osteoclastogenic cytokines such as TNF-α, IL-1, and IL-6, and modulating osteoblast differentiation and function, through regulation of the GH-insulin-like growth factor axis [120]. In addition, ghrelin interacts with leptin in modulating bone structure in an age-dependent manner, as recently shown [121].
Adipocytes and osteoblasts originate from a common progenitor, a pluripotential mesenchymal stem cell [20], which has an equal propensity to differentiate into adipocytes or osteoblasts or other lines, such as chondrocytes, fibroblast, and endothelial cells, upon the influence of several cell-derived transcription factors. This process is complex, suggesting significant plasticity and multifaceted mechanism(s) of regulation within different cell lineages, among which are adipocytes and osteoblasts [21], [22].
Transdifferentiation is the irreversible switching of differentiated cells that sometimes occurs during disease [122], and it involves partially differentiated cells (e.g. pre-osteoblasts) that switch to another lineage (e.g. adipocytes) [123]. Recently, a correlation between the osteo-adipogenic transdifferentiation of bone marrow cells and numerous bone metabolism diseases has been established [124]. Obesity increases fat bone marrow content in adult premenopausal women with obesity, and greater vertebral marrow fat has been associated with high fat mass and with lower trabecular bone density [125]. Similarly, in obese men, bone marrow fat is inversely associated with cortical bone parameters [126].
Finally, as the observation that bone cells produce specific bone-derived factors, the skeleton has come to be considered an endocrine organ itself [19]. In fact, emerging evidences point to a critical role for the skeleton in several homeostatic processes including energy balance and adipose metabolism, and the connection between fuel utilization and skeletal remodeling seems to begin in the bone marrow with lineage allocation of mesenchymal stromal cells into adipocytes or osteoblasts.
Mature bone cells secrete factors that modulate insulin sensitivity and glucose metabolism, such as osteocalcin (OCN), an osteoblast-specific protein and a major non-collagenous protein in the extracellular matrix [127]. Karsenty and co-authors demonstrated that uncarboxylated OCN, acting as a pro-hormone, can increase β-cell proliferation, insulin secretion, insulin sensitivity, and adiponectin expression [128]. Thus, osteoblasts may be able to regulate glucose metabolism by modulating the bioactivity of OCN. In addition, more recent studies showed that OCN bioactivity is modulated by enhanced sympathetic tone driven by leptin, which has been shown to suppress insulin secretion by β-cells [129], and other recent studies have demonstrated an inverse correlation between serum OCN and plasma glucose levels, supporting a role for this pathway in humans [130]. Thus, a novel picture has emerged linking glucose metabolism, adipose stores, and skeletal activity.
Since its first description more than 20 years ago, OPN has emerged as an active player in many physiological and pathological processes, including biomineralization, tissue remodeling, and inflammation. As an extracellular matrix protein and proinflammatory cytokine, OPN is thought to facilitate the recruitment of monocytes/macrophages and to mediate cytokine secretion in leukocytes. Modulation of immune cell response by OPN has been associated with various inflammatory diseases and may play a pivotal role in the development of adipose tissue inflammation and insulin resistance [131]. Several studies have described OPN as a critical regulator of adipose tissue inflammation, insulin resistance, and diabetes mellitus. OPN expression is drastically up-regulated by 40- and 80-fold in adipose tissue from diet-induced and genetically obese mice, respectively [132]. OPN expression in adipose tissue as well as circulating OPN levels were substantially elevated in obese, diabetic, and insulin resistant patients compared with lean healthy subjects, and conversely that dietary weight loss significantly decreased OPN concentrations [133], [134], [135], [136]. Finally, more recently, simultaneous up-regulation of IL-18 and OPN in peripheral blood mononuclear cells (PBMCs) has been reported in obese individuals as compared to lean subjects. Intriguingly, treatment with a neutralizing IL-18 antibody diminished OPN secretion from PBMCs, indicating that IL-18 regulates OPN expression [137]. These findings point toward a specific pathophysiological role of OPN also in human inflammatory processes linked to obesity-induced adipose inflammation, insulin resistance, type 2 diabetes and its complications.
Conclusions
AN and obesity are the two most important eating disorders, and are characterized by high reduction and increase in body fat content, respectively. In both the disorders the modifications in body composition and the altered hormonal pattern impact skeletal metabolism causing a decline in bone tissue density and quality, often leading to an increased fracture risk.
The importance of body composition changes are based on several observations suggesting potential mechanisms to explain the complex relationship between adipose and bone tissues: 1) adipose tissue, which has long been regarded as a passive energy reservoir, secretes multiple adipose tissue-derived hormones and cytokines involved in energy homeostasis and metabolism regulation; 2) as the demonstration that bone cells secretes specific factors that affect body weight control and glucose homeostasis, fat is considered an endocrine organ itself and a player of an active bone-adipose axis; 3) adipocytes and osteoblasts originate from a common pluripotential mesenchymal stem cell, that has an equal tendency to differentiate into adipocytes or osteoblasts (or other lines) upon the influence of different stimuli on cell-specific transcription factors.
However, the mechanisms by which all these events occur remain, in part, unclear, and further research is necessary to fully characterize the impact of these hormones and cytokines independent of each other and of body compositions.
Funding: Ministero dell’Istruzione, dell’Universitá e della Ricerca, (Grant/Award Number: ‘PRIN 2011 052013’).
References
1. Lucas AR, Melton LJ 3rd, Crowson CS, O’Fallon WM. Long-term fracture risk among women with anorexia nervosa: a population-based cohort study. Mayo Clin Proc 1999;74:972–7.10.1016/S0025-6196(11)63994-3Search in Google Scholar
2. Goulding A, Jones IE, Taylor RW, Williams SM, Manning PJ. Bone mineral density and body composition in boys with distal forearm fractures: a dual-energy x-ray absorptiometry study. J Pediatr 2001;139:509–15.10.1067/mpd.2001.116297Search in Google Scholar
3. Pollock NK, Laing EM, Hamrick MW, Baile CA, Hall DB, Lewis RD. Bone and fat relationships in postadolescent black females: a pQCT study. Osteoporos Int 2010;22:655–65.10.1007/s00198-010-1266-6Search in Google Scholar
4. Von Muhlen D, Safii S, Jassal SK, Svartberg J, Barrett-Connor E. Associations between the metabolic syndrome and bone health in older men and women: the Rancho Bernardo Study. Osteoporos Int 2007;18:1337–44.10.1007/s00198-007-0385-1Search in Google Scholar
5. Beck TJ, Petit MA, Wu G, LeBoff MS, Cauley JA, Chen Z. Does obesity really make the femur stronger? BMD, geometry, and fracture incidence in the women’s health initiative-observational study. J Bone Miner Res 2009;24:1369–79.10.1359/jbmr.090307Search in Google Scholar
6. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev 2005;26:439–51.10.1210/er.2005-0005Search in Google Scholar
7. Steppan CM, Crawford DT, Chidsey-Frink KL, Ke H, Swick AG. Leptin is a potent stimulator of bone growth in ob/ob mice. Regul Pept 2000;92:73–8.10.1016/S0167-0115(00)00152-XSearch in Google Scholar
8. Vendrell J, Broch M, Vilarrasa N, Molina A, Gòmez JM, Gutiérrez C, Simòn I, Soler J, Richart C. Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity. Obes Res 2004;12:962–71.10.1038/oby.2004.118Search in Google Scholar PubMed
9. Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med 2008;14:222–31.10.2119/2007-00119.TilgSearch in Google Scholar PubMed PubMed Central
10. Magni P, Dozio E, Galliera E, Ruscica M, Corsi MM. Molecular aspects of adipokine-bone interactions. Curr Mol Med 2010;10:522–32.10.2174/1566524011009060522Search in Google Scholar
11. Reid IR. Relationships among body mass, its components, and bone. Bone 2002;31:547–55.10.1138/2002055Search in Google Scholar
12. Eriksen EF, Colvard DS, Berg NJ, Graham ML, Mann KG, Spelsberg TC, Riggs BL. Evidence of estrogen receptors in normal human osteoblast-like cells. Science 1988;241:84–6.10.1126/science.3388021Search in Google Scholar
13. Kim HJ. New understanding of glucocorticoid action in bone cells. BMB Rep 2010;43:524–9.10.5483/BMBRep.2010.43.8.524Search in Google Scholar
14. Komm BS, Terpening CM, Benz DJ, Graeme KA, Gallegos A, Korc M, Greene GL, O’Malley BW, Haussler MR. Estrogen binding, receptor mRNA, and biologic response in osteoblast-like osteosarcoma cells. Science 1988;241:81–4.10.1126/science.3164526Search in Google Scholar
15. Migliaccio S, Davis VL, Gibson MK, Gray TK, Korach KS. Estrogens modulate the responsiveness of osteoblast-like cells (ROS 17/2.8) stably transfected with estrogen receptor. Endocrinology 1992;130:2617–24.10.1210/endo.130.5.1572285Search in Google Scholar
16. Gomez-Ambrosi J, Rodrıguez A, Catalan V, Fruhbeck G. The bone-adipose axis in obesity and weight loss. Obes Surg 2008;18:1134–43.10.1007/s11695-008-9548-1Search in Google Scholar
17. Takeda S. Effect of obesity on bone metabolism. Clin Calcium 2008;18:632–7.Search in Google Scholar
18. Gimble JM, Zvonic S, Floyd ZE, Kassem M, Nuttall ME. Playing with bone and fat. J Cell Biochem 2006;98:251–66.10.1002/jcb.20777Search in Google Scholar
19. Fukumoto S, Martrin TJ. Bone as an endocrine organ. Trends Endocrinol Metab 2009;20(5):230–6.10.1016/j.tem.2009.02.001Search in Google Scholar
20. Akune T, Ohba S, Kamekura S, Yamaguchi M, Chung UI, Kubota N, Terauchi Y, Harada Y, Azuma Y, Nakamura K, Kadowaki T, Kawaguchi H. PPARγ insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J Clin Invest 2004;113:846–55.10.1172/JCI200419900Search in Google Scholar
21. Gimble JM, Robinson CE, Wu X, Kelly KA, Rodriguez BR, Kliewer SA, Lehmann JM, Morris DC. Peroxisome proliferatoractivated receptor-gamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells. Mol Pharmacol 1996;50:1087–94.Search in Google Scholar
22. Rodriguez JP, Montecinos L, Rios S, Reyes P, Martinez J. Mesenchymal stem cells from osteoporotic patients produce a type I collagen-deficient extracellular matrix favoring adipogenic differentiation. J Cell Biochem 2000;79:557–65.10.1002/1097-4644(20001215)79:4<557::AID-JCB40>3.0.CO;2-HSearch in Google Scholar
23. Sekiya I, Larson BL, Vuoristo JT, Cui JG, Prockop DJ. Adipogenic differentiation of human adult stem cells from bone marrow stroma (MSCs). J Bone Miner Res 2004;19:256–64.10.1359/JBMR.0301220Search in Google Scholar
24. Martin RB, Zissimos SL. Relationships between marrow fat and bone turnover in ovariectomized and intact rats. Bone 1991;12:123–31.10.1016/8756-3282(91)90011-7Search in Google Scholar
25. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 5th ed., Arlington, VA, USA: American Psychiatric Association Publishing, 2013.10.1176/appi.books.9780890425596Search in Google Scholar
26. Smink Fr, Van Hoeken D, Hoek HW. Epidemiology of eating disorders: incidence, prevalence and mortality rates. Curr Psychiatry Rep 2012;14:406–14.10.1007/s11920-012-0282-ySearch in Google Scholar PubMed PubMed Central
27. Galusca B, Zouch M, Germain N, Bossu C, Frere D, Lang F, Le Bars D, Estour B. Constitutional thinness: unusual human phenotype of low bone quality. J Clin Endocrinol Metab 2008;93:110–17.10.1210/jc.2007-1591Search in Google Scholar PubMed
28. Dede AD, Lyritis JP, Tournis S. Bone disease in anorexia nervosa. Hormones 2014;13:38–56.10.1007/BF03401319Search in Google Scholar PubMed
29. Pasco JA, Henry MJ, Kotowicz MA, Collier GR, Ball MJ, Ugoni AM, Nicholson GC. Serum leptin levels are associated with bone mass in nonobese women. J Clin Endocrinol Metab 2001;86:1884–7.10.1210/jc.86.5.1884Search in Google Scholar
30. Yamauchi M, Sugimoto T, Yamaguchi T, Nakaoka D, Kanzawa M, Yano S, Ozuru R, Sigishita T, Chihara K. Plasma leptin concentrations are associated with bone mineral density and the presence of vertebral fractures in postmenopausal women. Clin Endocrinol 2001;55:341–7.10.1046/j.1365-2265.2001.01361.xSearch in Google Scholar PubMed
31. Ruhl CE, Everhart JE. Relationship of serum leptin concentrations with bone mineral density in the United States population. J Bone Miner Res 2002;17:1896–903.10.1359/jbmr.2002.17.10.1896Search in Google Scholar PubMed
32. Odabaşi E, Ozata M, Turan M, Bingol N, Yonem A, Cakir B, Kutlu M, Ozdemir IC. Plasma leptin concentrations in postmenopausal women with osteoporosis. Eur J Endocrinol 2000;142:170–3.10.1530/eje.0.1420170Search in Google Scholar PubMed
33. Bredella MA, Misra M, Miller KK, Madisch I, Sarwar A, Cheung A, Klibanski A, Gupta R. Distal radius in adolescent girls with anorexia nervosa: trabecular structure analysis with high-resolution flat-panel volume CT. Radiology 2008;249:938–46.10.1148/radiol.2492080173Search in Google Scholar PubMed PubMed Central
34. Lawson EA, Miller KK, Bredella MA, Phan C, Misra M, Meenaghan E, Rosenblum L, Donoho D, Gupta R, Klibansk A. Hormone predictors of abnormal bone microarchitecture in women with anorexia nervosa. Bone 2010;46:458–63.10.1016/j.bone.2009.09.005Search in Google Scholar
35. Biver E, Salliot C, Combescure C, Gossec L, Hardouin P, Legroux-Gerot I, Cortet B. Influence of adipokines and ghrelin on bone mineral density and fracture risk: a systematic review and meta-analysis. J Clin Endocrinol Metab 2011;96:2703–13.10.1210/jc.2011-0047Search in Google Scholar
36. Misra M, Miller KK, Cord J, Prabhakaran R, Herzog DB, Goldstein M, Katzman DK, Klibanski A. Relationships between serum adipokines, insulin levels, and bone density in girls with anorexia nervosa. J Clin Endocrinol Metab 2007;92:2046–52.10.1210/jc.2006-2855Search in Google Scholar
37. Maccarinelli G, Sibilia V, Torsello A, Raimondo F, Pitto M, Giustina A, Netti C, Cocchi D. Ghrelin regulates proliferation and differentiation of osteoblastic cells. J Endocrinol 2005;184:249–56.10.1677/joe.1.05837Search in Google Scholar
38. Fukushima N, Hanada R, Teranishi H, Fukue Y, Tachibana T, Ishikawa H, Takeda S, Takeuchi Y, Fukumoto S, Kangawa K, Nagata K, Kojima M. Ghrelin directly regulates bone formation. J Bone Miner Res 2005;20:790–8.10.1359/JBMR.041237Search in Google Scholar
39. Sun Y, Ahmed S, Smith RG. Deletion of ghrelin impairs neither growth nor appetite. Mol Cell Biol 2003;23:7973–81.10.1128/MCB.23.22.7973-7981.2003Search in Google Scholar
40. Misra M, Miller KK, Stewart V, Hunter E, Kuo K, Herzog DB, Klibanski A. Ghrelin and bone metabolism in adolescent girls with anorexia nervosa and healthy adolescents. J Clin Endocrinol Metab 2005;90:5082–7.10.1210/jc.2005-0512Search in Google Scholar
41. Baldock PA, Sainsbury A, Couzens M, Enriquez RF, Thomas GP, Gardiner EM, Herzog H. Hypothalamic Y2 receptors regulate bone formation. J Clin Invest 2002;109:915–21.10.1172/JCI0214588Search in Google Scholar
42. Baldock PA, Lee NJ, Driessler F, Lin S, Allison S, Stehrer B, Lin EJ, Zhang L, Enriquez RF, Wong IP, McDonald MM, During M, Pierroz DD, Slack K, Shi YC, Yulyaningsih E, Alianova A, Little DG, Ferrari SL, Sainsbury A, Eisman JA, Herzog H. Neuropeptide Y knockout mice reveal a central role of NPY in the coordination of bone mass to body weight. PLoS One 2009;4:e8415.10.1371/journal.pone.0008415Search in Google Scholar
43. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 2000;100:197–207.10.1016/S0092-8674(00)81558-5Search in Google Scholar
44. Bollag RJ, Zhong Q, Phillips P, Min L, Zhong L, Cameron R, Mulloy AL, Rasmussen H, Qin F, Ding KH, Isales CM. Osteoblast-derived cells express functional glucose-dependent insulinotropic peptide receptors. Endocrinology 2000;141:1228–35.10.1210/endo.141.3.7366Search in Google Scholar
45. Wojcik MH, Meenaghan E, Lawson EA, Misra M, Klibanski A, Miller KK. Reduced amylin levels are associated with low bone mineral density in women with anorexia nervosa. Bone 2010;46:796–800.10.1016/j.bone.2009.11.014Search in Google Scholar
46. Migliaccio S, Greco EA, Aversa A, Lenzi A. Age-associated (cardio)metabolic diseases and cross-talk between adipose tissue and skeleton: endocrine aspects. Horm Mol Biol Clin Invest 2014;20:25–38.10.1515/hmbci-2014-0030Search in Google Scholar
47. Chow J, Tobias JH, Colston KW, Chambers TJ. Estrogen maintains trabecular bone volume in rats not only by suppression of bone resorption but also by stimulation of bone formation. J Clin invest 1992;89:74–8.10.1172/JCI115588Search in Google Scholar
48. Majeska RJ, Ryaby JT, Einhorn TA. Direct modulation of osteoblastic activity with estrogen. J Bone Joint Surg Am 1994;76:713–21.10.2106/00004623-199405000-00013Search in Google Scholar
49. Qu Q, Perala-Heape M, Kapanen A, Dahlund J, Salo J, Vaananen HK, Harkonen P. Estrogen enhances differentiation of osteoblasts in mouse bone marrow culture. Bone 1998;22:201–9.10.1016/S8756-3282(97)00276-7Search in Google Scholar
50. Misra M, Klibanski A. Anorexia nervosa, obesity and bone metabolism. Pediatr Endocrinol Rev 2013;11:21–33.10.1530/boneabs.1.W1.2Search in Google Scholar
51. Ferrari S, Bianchi ML, Eisman JA, Foldes AJ, Adami S, Whal DA, Stepan JJ, de Vernejoul MC, Kaufman JM, IOF Committee of Scientific Advisors Working Group on Osteoporosis Pathophysiology. Osteoporosis in young adults: pathophysiology, diagnosis, and management. Osteoporos Int 2012;23:2735–48.10.1007/s00198-012-2030-xSearch in Google Scholar PubMed
52. Grinspoon G, Miller K, Coyle C, Krempin J, Armstrong C, Pitts S, Herzog D, Klibanski A. Severity of osteopenia in estrogen-deficient women with anorexia nervosa and hypothalamic amenorrhea. J Clin Endocrinol Metab 1999;84:2049–55.10.1210/jc.84.6.2049Search in Google Scholar
53. Kasperk C, Fitzsimmons R, Strong D. Studies of the mechanism by which androgens enhance mitogenesis and differentiation in bone cells. J Clin Endocrinol Metab 1990;71:1322–9.10.1210/jcem-71-5-1322Search in Google Scholar PubMed
54. Miller KK, Lawson EA, Mathur V, Wexler TL, Meenaghan E, Misra M, Herzog DB, Klibanski A. Androgens in women with anorexia nervosa and normal weight women with hypothalamic amenorrhea. J Clin Endocrinol Metab 2007;92:1334–9.10.1210/jc.2006-2501Search in Google Scholar PubMed PubMed Central
55. Misra M, Katzman DK, Cord J, Mannng SJ, Mendes N, Herzog DB, Miller KK, Klibanski A. Bone metabolism in adolescent boys with anorexia nervosa. J Clin Endocrinol Metab 2008;93:3029–36.10.1210/jc.2008-0170Search in Google Scholar PubMed PubMed Central
56. Dekkers OM, Horváth-Puhó E, Jørgensen JO, Cannegieter SC, Ehrenstein V, Vandenbroucke JP, Pereira AM, Sørensen HT. Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab 2013;98:2277–84.10.1210/jc.2012-3582Search in Google Scholar PubMed
57. Van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 2002;13:777–87.10.1007/s001980200108Search in Google Scholar PubMed
58. O’Brien CA, Jia D, Plotkin LI, Bellido T, Powers CC, Stewart SA, Manolagas SC, Weinstein RS. Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 2004;145:1835–41.10.1210/en.2003-0990Search in Google Scholar PubMed
59. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest 1998;102:274–82.10.1172/JCI2799Search in Google Scholar PubMed PubMed Central
60. Jia D, O’Brien CA, Stewart SA, Manolagas SC, Weinstein RS. Glucocorticoids act directly on osteoclasts to increase their life span and reduce bone density. Endocrinology 2006;147:5592–9.10.1210/en.2006-0459Search in Google Scholar PubMed PubMed Central
61. Misra M, Miller KK, Almazan C, Ramaswamy K, Lapcharoensap W, Worley M, naubauer G, Herzog DB, Klibanski A. Alterations in cortisol secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab 2004;89:4972–80.10.1210/jc.2004-0723Search in Google Scholar PubMed
62. Lawson EA, Donoho D, Miller KK, Misra M, Meenaghan E, Lydecker J, Wexler T, Herzog DB, Klibanski A. Hypercortisolemia is associated with severity of bone loss and depression in hypothalamic amenorrhea and anorexia nervosa. J Clin Endocrinol Metab 2009;94:4710–16.10.1210/jc.2009-1046Search in Google Scholar PubMed PubMed Central
63. McCarthy TL, Centrella M, Canalis E. Regulatory effects of insulin-like growth factors I and II on bone collagen synthesis in rat calvarial cultures. Endocrinology 1989;124:301–9.10.1210/endo-124-1-301Search in Google Scholar PubMed
64. Sims NA, Clément-Lacroix P, Da Ponte F, Bouali Y, Binart N, Moriggi R, Goffin V, Coschigano K, Gaillard-Kelly M, Kopchick J, Baron R, Kelly PA. Bone homeostasis in growth hormone receptor-null mice is restored by iGF-I but independent of Stat5. J Clin Invest 2000;106:1095–103.10.1172/JCI10753Search in Google Scholar PubMed PubMed Central
65. Counts D, Gwirtsman H, Carlsson L, Lesem M, Cutler G. The effect of anorexia nervosa and refeeding on growth hormone-binding protein, the insulin-like growth factors (IGFs), and the IGF-binding proteins. J Clin Endocrinol Metab 1992;75:762–7.10.1210/jcem.75.3.1381372Search in Google Scholar
66. Misra M, Miller K, Bjornson J, Hackman A, Aggarwal A, Chung J, Ott M, Herzog D, Johnson M, Klibanski A. Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab 2003;88:5615–23.10.1210/jc.2003-030532Search in Google Scholar PubMed
67. Misra M, Miller K, Kuo K, Griffin K, Stewart V, Hunter E, Herzog D, Klibanski A. Secretory dynamics of ghrelin in adolescent girls with anorexia nervosa and healthy adolescents. Am J Physiol Endocrinol Metab 2005;289:E347–56.10.1152/ajpendo.00615.2004Search in Google Scholar
68. Soyka LA, Misra M, Frenchman A, Miller KK, Grinspoon S, Schoenfeld DA, Klibanski A. Abnormal bone mineral accrual in adolescent girls with anorexia nervosa. J Clin Endocrinol Metab 2002;87:4177–85.10.1210/jc.2001-011889Search in Google Scholar
69. Fazeli PK, Lawson EA, Prabhakaran R, Miller KK, Donoho DA, Clemmons DR, Herzog DB, Misra M, Klibanski A. Effects of recombinant human growth hormone in anorexia nervosa: a randomized, placebo-controlled study. J Clin Endocrinol Metab 2010;95:4889–7.10.1210/jc.2010-0493Search in Google Scholar
70. Misra M, McGrane J, Miller KK, Goldstein MA, Ebrahimi S, Weigel T, Klibanski A. Effects of rhIGF-1 administration on surrogate markers of bone turnover in adolescents with anorexia nervosa. Bone 2009;45:493–8.10.1016/j.bone.2009.06.002Search in Google Scholar
71. Grinspoon S, Thomas L, Miller K, Herzog D, Klibanski A. Effects of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa. J Clin Endocrinol Metab 2002;87:2883–91.10.1210/jcem.87.6.8574Search in Google Scholar
72. Pereira RC, Jorgetti V, Canalis E. Triiodothyronine induces collagenase-3 and gelatinase B expression in murine osteoblasts. Am J Physiol 1999;277:E496–504.10.1152/ajpendo.1999.277.3.E496Search in Google Scholar
73. Gouveia CH, Schultz JJ, Bianco AC, Brent GA. Thyroid hormone stimulation of osteocalcin gene expression in ros 17/2.8 cells is mediated by transcriptional and post-transcriptional mechanisms. J Endocrinol 2001;170:667–75.10.1677/joe.0.1700667Search in Google Scholar
74. Varga F, Rumpler M, Zoehrer R, Turecek C, Spitzer S, Thaler R, Paschalis EP, Klaushofer K. T3 affects expression of collagen i and collagen cross-linking in bone cell cultures. Biochem Biophys Res Commun 2010;402:180–5.10.1016/j.bbrc.2010.08.022Search in Google Scholar
75. Eriksen EF, Mosekilde L, Melsen F. Kinetics of trabecular bone resorption and formation in hypothyroidism: evidence for a positive balance per remodeling cycle. Bone 1986;7:101–8.10.1016/8756-3282(86)90681-2Search in Google Scholar
76. Vestergaard P, Mosekilde L. Fractures in patients with hyperthyroidism and hypothyroidism: a nationwide follow-up study in 16,249 patients. Thyroid 2002;12:411–9.10.1089/105072502760043503Search in Google Scholar PubMed
77. Vestergaard P, Rejnmark L, Mosekilde L. Influence of hyper- and hypothyroidism, and the effects of treatment with antithyroid drugs and levothyroxine on fracture risk. Calcif Tissue Int 2005;77:139–44.10.1007/s00223-005-0068-xSearch in Google Scholar PubMed
78. Misra M, Aggarwal A, Miller KK, Almazan C, Worley M, Soyka LA, Herzog DB, Klibanski A. Effects of anorexia nervosa on clinical, hematologic, biochemical, and bone density parameters in community-dwelling adolescent girls. Pediatrics 2004;114:1574–83.10.1542/peds.2004-0540Search in Google Scholar PubMed
79. Miller KK, Lee EE, Lawson EA, Misra M, Minihan J, Grinspoon SK, Gleysteen S, Mickley D, Herzog D, Klibanski A. Determinants of skeletal loss and recovery in anorexia nervosa. J Clin Endocrinol Metab 2006;91:2931–7.10.1210/jc.2005-2818Search in Google Scholar PubMed PubMed Central
80. Misra M, Prabhakaran R, Miller KK, Goldstein MA, Mickley D, Clauss L, Lockhart P, Cord J, Herzog DB, Katzman DK, Klibanski A. Weight gain and restoration of menses as predictors of bone mineral density change in adolescent girls with anorexia nervosa-1. J Clin Endocrinol Metab 2008;93:1231–7.10.1210/jc.2007-1434Search in Google Scholar PubMed PubMed Central
81. Wren TA, Chung SA, Dorey FJ, Bluml S, Adams GB, Gilsanz V. Bone marrow fat is inversely related to cortical bone in young and old subjects. J Clin Endocrinol Metab 2011;96:782–6.10.1210/jc.2010-1922Search in Google Scholar PubMed
82. Di Iorgi N, Mo AO, Grimm K, Wren TA, Dorey F, Gilsanz V. Bone acquisition in healthy young females is reciprocally related to marrow adiposity. J Clin Endocrinol Metab 2010;95:2977–2.10.1210/jc.2009-2336Search in Google Scholar PubMed PubMed Central
83. Di Iorgi N, Rosol M, Mittelman SD, Gilsanz V. Reciprocal relation between marrow adiposity and the amount of bone in the axial and appendicular skeleton of young adults. J Clin Endocrinol Metab 2008;93:2281–6.10.1210/jc.2007-2691Search in Google Scholar PubMed PubMed Central
84. Shen W, Chen J, Gantz M, Punyanitya M, Heymsfield SB, Gallagher D, Albu J, Engelson E, Kotler D, Pi-Sunyer X, Gilsanz V. MRI-measured pelvic bone marrow adipose tissue is inversely related to DXA-measured bone mineral in younger and older adults. Eur J Clin Nutr 2012;66:983–8.10.1038/ejcn.2012.35Search in Google Scholar PubMed PubMed Central
85. Bredella MA, Fazeli PK, Miller KK, Misra M, Torriani M, Thomas BJ, Ghomi RH, Rosen CJ, Klibanski A. Increased bone marrow fat in anorexia nervosa. J Clin Endocrinol Metab 2009;94:2129–36.10.1210/jc.2008-2532Search in Google Scholar PubMed PubMed Central
86. Fazeli PK, Bredella MA, Misra M, Meenaghan E, Rosen CJ, Clemmons DR, Breggia A, Miller KK, Klibanski A. Preadipocyte factor-1 is associated with marrow adiposity and bone mineral density in women with anorexia nervosa. J Clin Endocrinol Metab 2010;95:407–13.10.1210/jc.2009-1152Search in Google Scholar PubMed PubMed Central
87. Fazeli PK, Bredella MA, Freedman L, Thomas BJ, Breggia A, Meenaghan E, Rosen CJ, Klibanski A. Marrow fat and preadipocyte factor-1 levels decrease with recovery in women with anorexia nervosa. J Bone Miner Res 2012;27:1864–71.10.1002/jbmr.1640Search in Google Scholar PubMed PubMed Central
88. Rahman S, Lu Y, Czernik PJ, Rosen CJ, Enerback S, Lecka-Czernik B. Inducible brown adipose tissue, or beige fat, is anabolic for the skeleton. Endocrinology 2013;154:2687–701.10.1210/en.2012-2162Search in Google Scholar PubMed PubMed Central
89. Ponrartana S, Aggabao PC, Hu HH, Aldrovandi GM, Wren TA, Gilsanz V. Brown adipose tissue and its relationship to bone structure in pediatric patients. J Clin Endocrinol Metab 2012;97:2693–8.10.1210/jc.2012-1589Search in Google Scholar PubMed PubMed Central
90. Lee P, Brychta RJ, Collins MT, Linderman J, Smith S, Herscovitch P, Millo C, Chen KY, Celi FS. Cold-activated brown adipose tissue is an independent predictor of higher bone mineral density in women. Osteoporos Int 2013;24:1513–8.10.1007/s00198-012-2110-ySearch in Google Scholar PubMed PubMed Central
91. Bredella MA, Fazeli PK, Freedman LM, Calder G, Lee H, Rosen CJ, Klibanski A. Young women with cold- activated brown adipose tissue have higher bone mineral density and lower Pref-1 than women without brown adipose tissue: a study in women with anorexia nervosa, women recovered from anorexia nervosa, and normal-weight women. J Clin Endocrinol Metab 2012;97:E584–90.10.1210/jc.2011-2246Search in Google Scholar PubMed PubMed Central
92. Bredella MA, Fazeli PK, Lecka-Czernik B, Rosen CJ, Klibanski A. IGFBP-2 is a negative predictor of cold-induced brown fat and bone mineral density in young non-obese women. Bone 2013;53:336–9.10.1016/j.bone.2012.12.046Search in Google Scholar PubMed PubMed Central
93. Rossner S. Obesity: the disease of the twenty-first century. Int J Obes Relat Metab Disord 2002;26(Suppl 4):S2–4.10.1038/sj.ijo.0802209Search in Google Scholar PubMed
94. Albala C, Yanez M, Devoto E, Sostin C, Zeballos L, Santos JL. Obesity as a protective factor for postmenopausal osteoporosis. Int J Obes Relat Metab Disord 1996;20:1027–32.Search in Google Scholar
95. Greco EA, Fornari R, Rossi F, Santiemma V, Prossomariti G, Annoscia C, Aversa A, Brama M, Marini M, Donini LM, Spera G, Lenzi A, Lubrano C, Migliaccio S. Is obesity protective for osteoporosis? Evaluation of bone mineral density in individuals with high body mass index. Int J Clin Pract 2010;64:817–20.10.1111/j.1742-1241.2009.02301.xSearch in Google Scholar PubMed
96. Greco EA, Francomano D, Fornari R, Marocco C, Lubrano C, Papa V, Wannenes F, Di Luigi L, Aversa A, Migliaccio S. Negative association between trunk fat, insulin resistance and skeleton in obese women. World J Diabetes 2013;4:31–9.10.4239/wjd.v4.i2.31Search in Google Scholar PubMed PubMed Central
97. Compston JE, FlahiveJ, Hosmer DV, Watts NB, Siris ES, Silverman S, Saag KG, Roux C, Rossini M, Pfeilschifter J, Nieves JW, Netelenbos JC, March L, LaCroix AZ, Hooven FH, Greenspan SL, Gehlbach SH, Diez-Perez A, Cooper C, Chapurlat Rd, boonen S, Anderson FA Jr, Adami S, Adachi JD, GLOW Investigators. Relationship of weight, height, and body mas index with fracture risk at different sites in postmenopausal women: the Global Longitudinal study of Osteoporosis in Women (GLOW). J Bone Miner Res 2014;29:487–93.10.1002/jbmr.2051Search in Google Scholar PubMed PubMed Central
98. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF. Serum immunoreactive leptin concentrations in normal-weight and obese humans. N Engl J Med 1996;34:292–5.10.1056/NEJM199602013340503Search in Google Scholar PubMed
99. Martin SS, Qasim A, Reilly MP. Leptin resistance: a possible interface of inflammation and metabolism in obesity-related cardiovascular disease. J Am Coll Cardiol 2008;52:1201–10.10.1016/j.jacc.2008.05.060Search in Google Scholar PubMed PubMed Central
100. Thomas T. The complex effects of leptin on bone metabolism through multiple pathways. Curr Opin Pharmacol 2004;4:295–300.10.1016/j.coph.2004.01.009Search in Google Scholar PubMed
101. Kontogianni MD, Dafni UG, Routsias JG, Skopouli FN. Blood leptin and adiponectin as possible mediators of the relation between fat mass and BMD in perimenopausal women. J Bone Miner Res 2004;19:546–55.10.1359/JBMR.040107Search in Google Scholar PubMed
102. Thomas T, Gori F, Khosla S, Jensen MD, Burguera B, Riggs BL. Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology 1999;140:1630–8.10.1210/endo.140.4.6637Search in Google Scholar PubMed
103. Ma W, Zhang X, Shi S, Zhang Y. Neuropeptides stimulate human osteoblast activity and promote gap junctional intracellular communication. Neuropeptides 2013;47:179–86.10.1016/j.npep.2012.12.002Search in Google Scholar PubMed
104. Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, Engel J, Brownlee M, Scherer PE. Structure-function studies of the adipocytes-secreted hormone Acrp30/adiponectin. Implications for metabolic regulation and bioactivity. J Biol Chem 2003;278:9073–85.10.1074/jbc.M207198200Search in Google Scholar PubMed
105. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudio K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with body lipoatrophy and obesity. Nat Med 2001;7:941–6.10.1038/90984Search in Google Scholar PubMed
106. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2002;290:1084–9.10.1006/bbrc.2001.6307Search in Google Scholar PubMed
107. Jurimae J, Rembel K, Jurimae T, Rehand M. Adiponectin is associated with bone mineral density in perimenopausal women. Horm Metab Res 2005;37:297–302.10.1055/s-2005-861483Search in Google Scholar PubMed
108. Ukkola O. Resistin – a mediator of obesity-associated insulin resistance or an innocent bystander? Eur J Endocrinol 2002;147:571–4.10.1530/eje.0.1470571Search in Google Scholar PubMed
109. Thommesen L, Stunes AK, Monjo M, Grosvik K, Tamburstuen MV, Kjobli E, Lyngstadaas SP, Reseland JE, Syversen U. Expression and regulation of resistin in osteoblasts and osteoclasts indicate a role in bone metabolism. J Cell Biochem 2006;99:824–34.10.1002/jcb.20915Search in Google Scholar PubMed
110. Fasshauer M, Klein J, Krahlisch S, Lossner U, Klier M, Bluher M, Paschke R. GH is a positive regulator of tumor necrosis factor-alpha-induced adipose related protein in 3T3-L1 adipocytes. J Endocrinol 2003;178:523–31.10.1677/joe.0.1780523Search in Google Scholar PubMed
111. Hotamisligil G, Arner P, Caro J, Atkinson R, Spiegelman B. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 1995;95:2409–15.10.1172/JCI117936Search in Google Scholar PubMed PubMed Central
112. Pacifici R, Brown C, Puscheck E, Friedrich E, Slatopolsky E, Maggio D, McCracken R, Avioli LV. Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells. Proc Natl Acad Sci USA 1991;88:5134–8.10.1073/pnas.88.12.5134Search in Google Scholar PubMed PubMed Central
113. Wei S, Kitaura H, Zhou P, Patrick Ross, Teitelbaum SL. IL-1 mediates TNF-induce osteoclastogenesis. J Clin Invest 2005;115:282–90.10.1172/JCI200523394Search in Google Scholar
114. Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Woodring J, Pacifici R. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-α. J Clin Invest 2000;106:1229–37.10.1172/JCI11066Search in Google Scholar PubMed PubMed Central
115. Vozarova B, Weyer C, Hanson K, Tataranni PA, Bogardus C, Pratley RE. Circulating IL-6 in relation to adiposity, insulin action and insulin secretion. Obes Res 2001;9:414–7.10.1038/oby.2001.54Search in Google Scholar PubMed
116. Dodds A, Merry K, Littlewood A, Gowen M. Expression of mRNA for IL1 beta, IL6 and TGF beta 1 in developing human bone and cartilage. J Histochem Cytochem 1994;42:733–44.10.1177/42.6.8189035Search in Google Scholar PubMed
117. Taguchi Y, Yamamoto M, Yamate T, Lin SC, Mocharla H, De Togni P, Nakayama N, Boyce BF, Abe E, Manolagas SC. Interleukin-6-type cytokines stimulate mesenchymal progenitor differentiation toward the osteoblastic lineage. Proc Assoc Am Physicians 1998;110:559–74.Search in Google Scholar
118. Sims NA, Jenkins BJ, Quinn JM, Walkley CR, Purton LE, Boetell DD, Gillespie MT. Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways. J Clin Invest 2004;113:379–89.10.1172/JCI19872Search in Google Scholar PubMed PubMed Central
119. Van der Lely AJ, Tschop M, Heiman ML, Ghigo E. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 2004;25:426–57.10.1210/er.2002-0029Search in Google Scholar PubMed
120. Soeki T, Kishimoto I, Schwenke DO, Tokudome T, Horio T, Yoshida M, Hosoda H, Kangawa K. Ghrelin suppresses cardiac sympathetic activity and prevents early left ventricular remodeling in rats with myocardial infarction. Am J Physiol Heart Circ Physiol 2007;294:H426–32.10.1152/ajpheart.00643.2007Search in Google Scholar PubMed
121. Van der Velde M, Van der Eerden BC, Sun Y, Almring JM, Van der Ley AJ, Delhhanty PJ, Smith RG, Van Leeuwen JP. An age-dependent interaction with leptin unmasks ghrelin’s bone protective effects. Endocrinology 2012;154:3951.10.1210/en.2012-1277Search in Google Scholar PubMed PubMed Central
122. Burke ZD, Tosh D. Therapeutic potential of transdifferentiated cells. Clin Sci (Lond) 2005;108:309–21.10.1042/CS20040335Search in Google Scholar PubMed
123. Schilling T, Kuffner R, Klein-Hitpass L, Zimmer R, Jakob F, Schutze N. Microarray analyses of transdifferentiated mesenchymal stem cells. J Cell Biochem 2008;103:413–33.10.1002/jcb.21415Search in Google Scholar PubMed
124. Song L, Tuan RS. Transdifferentiation potential of human mesenchymal stem cells derived from bone marrow. FASEB J 2004;18:980–2.10.1096/fj.03-1100fjeSearch in Google Scholar PubMed
125. Bredella MA, Torriani M, Ghomi RH, Thomas BJ, Brick DJ, Gerweck AV, Rosen CJ, Klibanski A, Miller KK. Vertebral bone marrow fat is positively associated with visceral fat and inversely associated with IGF-1 in obese women. Obesity (Silver Spring) 2011;19:49–53.10.1038/oby.2010.106Search in Google Scholar PubMed PubMed Central
126. Bredella MA, Lin E, Gerweck AV, Landa MG, Thomas BJ, Torriani M, Bouxsein ML, Miller KK. Determinants of bone microarchitecture and mechanical properties in obese men. J Clin Endocrinol Metab 2012;97:4115–22.10.1210/jc.2012-2246Search in Google Scholar PubMed PubMed Central
127. Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G. Endocrine regulation of energy metabolism by the skeleton. Cell 2007;130:456–69.10.1016/j.cell.2007.05.047Search in Google Scholar PubMed PubMed Central
128. Ferron M, Hinoi E, Karsenty G, Ducy P. Osteocalcin differentially regulates beta cell and dipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci USA 2008;105:5266–70.10.1073/pnas.0711119105Search in Google Scholar PubMed PubMed Central
129. Hinoi E, Gao N, Jung DY, Yadav V, Yoshizawa T, Myers MG Jr, Chua SC Jr, Kim JK, Kaestner KH, Karsenty G. The sympathetic tone mediates leptin’s inhibition of insulin secretion by modulating osteocalcin bioactivity. J Cell Biol 2008;183:1235–42.10.1083/jcb.200809113Search in Google Scholar
130. Covey SD, Wideman RD, McDonald C, Unniappan S, Huynh F, Asadi A, Speck M, Webber T, Chua SC, Kieffer TJ. The pancreatic beta cell is a key site for mediating the effects of leptin on glucose homeostasis. Cell Metab 2006;4:291–302.10.1016/j.cmet.2006.09.005Search in Google Scholar
131. Scatena M, Liaw L, Giachelli CM. Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler Thromb Vasc Biol 2007;27:2302–9.10.1161/ATVBAHA.107.144824Search in Google Scholar
132. Kiefer FW, Zeyda M, Todoric J, Huber J, Geyeregger R, Weichhart T, Aszmann O, Ludvik B, Silberhumer GR, prager G, Stulnig TM. Osteopontin expression in human and murine obesity: extensive local up-regulation in adipose tissue but minimal systemic alterations. Endocrinology 2008;149:1350–7.10.1210/en.2007-1312Search in Google Scholar
133. Sarac F, Basoglu OK, Gunduz C, Bayrak H, Biray Avci C, Akcicek F. Association of osteopontin and tumor necrosis factor-alpha levels with insulin resistance in obese patients with obstructive sleep apnea syndrome. J Endocrinol Invest 2011;4:528–33.Search in Google Scholar
134. You JS, Ji HI, Chang KJ, Yoo MC, Yang HI, Jeong, IK, Kim KS. Serum osteopontin concentration is decreased by exercise-induced fat loss but is not correlated with body fat percentage in obese humans. Mol Med Rep 2013;8:579–84.10.3892/mmr.2013.1522Search in Google Scholar
135. Faje A, Klibanski A. Body composition and skeletal health: too heavy? Too thin? Curr Osteoporos Rep 2012;10:208–16.10.1007/s11914-012-0106-3Search in Google Scholar
136. Kaye WH. Neuropeptide abnormalities in anorexia nervosa. Psychit Res 1996;62:65–74.10.1016/0165-1781(96)02985-XSearch in Google Scholar
137. Ahmad R, Al-Mass A, Al-Ghawas D, Shareif N, Zghoul N, Melhem M, Hasan A, Al-Ghimlas F, Dermime S, Behbehani K. Interaction of osteopontin with il-18 in obese individuals: implications for insulin resistance. PLoS One 2013;8:639–44.10.1371/journal.pone.0063944Search in Google Scholar PubMed PubMed Central
©2016 Walter de Gruyter GmbH, Berlin/Boston