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... 2002; Wang et al. 2007). We have shown that parathyroid hormone increases bone formation in hypophysectomized rats. This response is accompanied by an increase in skeletal IGF-I mRNA levels with no rise in circulating IGF-I, illustrating the important role of locally produced IGF-I. However, equally compelling data support a role for circulating IGF-I in the regulation of bone metabolism. IGFs circulate bound to binding proteins which either potentiate or antagonize IGF-I activity in specific tissues, and the circulating levels of these binding proteins are regulated by a variety of factors (Jones & Clemmons 1995) Liver IGF-I-deficient (Lid) mice and acid labile subunit (a key component in the IGF-I serum transport complex) knockout (Alsko) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-I levels, respectively. The double knockout mice (LA), however, exhibited growth inhibitions and osteopenia that were reversed by IGF-I treatment (Yakar et al. 2002). More recent findings using a variety of model systems support a regulatory role for systemic IGF-I on bone metabolism (Yakar et al. 2002; Mohan et al. 2003; Wang et al. 2004; Mohan & Baylink 2005...

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...f these teens reported engaging in binge drinking (5+ drinks on the same occasion) and 2.1 million classified themselves as heavy drinkers (5+ drinks per occasion on more than 5 days within the last month) (Department of Health and Human Services 2010). Rates of alcohol use, including binge and heavy drinking, have declined slightly since 2002; however alcohol consumption still occurs regularly in over 27% of American teenagers (Department of Health and Human Services 2010). High rates of alcohol consumption in youth were also reported in a 2008 survey of Australian secondary school students (White & Smith 2009). The European School Survey Project on Alcohol and Other Drugs, a survey of adolescent students in 35 European countries, reports even higher rates of alcohol use for European adolescents. The 2007 survey reported that within the month preceding the survey, 61% of students drank, 43% drank heavily, and 18% had been intoxicated (Hibell et al. 2009). However, none of these surveys provide insight regarding www.intechopen.com Osteogenesis 58 the effects of underage drinking on bone growth or, if an injury were to occur, on bone repair following the injury. Globally, risky alcohol use among adole...

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...normalization of leptin levels in alcohol-fed growing rats corrects the detrimental effects of alcohol on bone growth, architecture and turnover. 8. Osteoblasts and adipocytes As discussed, we have shown that alcohol consumption increases bone marrow adiposity and decreases both bone formation and peak bone mass in a rat model for chronic alcohol abuse (Maddalozzo et al. 2009). Adipocytes and osteoblasts are derived from bone marrow mesenchymal stromal cells (Vaananen 2005; Gimble et al. 2006) (Figure 4). An inverse association between bone mass and bone marrow adiposity is commonly observed (Pei & Tontonoz 2004; Morita et al. 2006) and, although yet to be firmly established, several lines of evidence suggest that there is a cause and effect relationship. A deficiency in PPAR, a key mediator of adipocyte differentiation, reduced fat and enhanced osteogenesis (Akune et al. 2004), suggesting that suppression of adipogenesis leads to increased bone formation. Based primarily on cell culture studies, some investigators have concluded that increased adipocyte differentiation inevitably occurs at the expense of osteoblast differentiation. If correct, the increase in bone marrow fat in alcohol-fed rats may...

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...udies suggesting that alcohol impairs leptin signaling by inducing target organ resistance to the hormone (Gordeladze et al. 2002). Fig. 3. Evidence for decreased leptin levels in serum of alcohol-fed rats compared to ad labium-fed (Ad lib) controls. Four-week-old male rats were fed alcohol containing (35%caloric intake) or control diets for 3 months. Data are mean ± SE, *P<0.05. Leptin, in addition to having central actions mediated through the hypothalamus, has the potential to act directly on target organs, including bone (Burguera et al. 2001; Reseland et al. 2001; Gordeladze et al. 2002; Thomas 2004). The putative hypothalamic-mediated and direct pathways of leptin action on bone metabolism have been reviewed by Hamrick (Hamrick et al. 2004; Hamrick & Ferrari 2008). By transplanting bone marrow cells from leptin receptor-deficient db/db mice into WT mice, we have shown that the physiological actions of leptin on bone turnover are primarily due to peripheral leptin signaling (Unpublished data). Leptin deficiency results in skeletal abnormalities that, in many ways, are similar to effects of chronic alcohol abuse. Specifically, leptin deficiency and alcohol consumption in growing rodents ea...

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... alcohol on bone formation. Osteoblasts generate IGF-I and the growth factor is deposited into bone matrix where it is retained until released by osteoclast-mediated bone resorption. IGF-I located in bone matrix is thought to be osteoblast-derived but its origin has not been rigorously investigated. IGF-I in bone matrix, irrespective of origin, helps couple bone formation to bone resorption during bone remodeling; IGF-I released from the matrix during bone resorption acts in concert with other matrix-derived growth factors (e.g., TGF-ß) to induce renewed bone formation (Centrella et al. 1991; Mohan & Baylink 1991). Additionally, IGF-I incorporated into bone matrix plays a role in mediating bone healing when released following a fracture (Okazaki et al. 2003). Fig. 6. mRNA levels of IGF-I in distal femur are reduced within 8 h of administration of alcohol (1 g/kg) and return to normal by 24 hours. Values are man ± SE, n=4-5/group. *p <0.05 compared to time 0. 9.3 Parathyroid hormone may reverse alcohol-induced inhibition of bone formation by increasing IGF-I gene expression in skeletal tissues The molecular mechanisms that mediate the bone anabolic response to parathyroid hormone are incompletely unders...

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...nes & Clemmons 1995) Liver IGF-I-deficient (Lid) mice and acid labile subunit (a key component in the IGF-I serum transport complex) knockout (Alsko) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-I levels, respectively. The double knockout mice (LA), however, exhibited growth inhibitions and osteopenia that were reversed by IGF-I treatment (Yakar et al. 2002). More recent findings using a variety of model systems support a regulatory role for systemic IGF-I on bone metabolism (Yakar et al. 2002; Mohan et al. 2003; Wang et al. 2004; Mohan & Baylink 2005). Taken together, the above findings suggest that locally produced as well as circulating IGF-I are both important to skeletal growth and remodeling and are likely to have overlapping but not identical actions. There is mounting evidence that the skeletal effects of growth hormone, via IGF-I signaling, are impaired by alcohol consumption. Chronic alcohol abuse results in decreased serum IGF levels, reduced mRNA levels for IGF-I in liver and altered hepatic synthesis of IGF binding proteins (Turner et al. 1998; Lang et al. 2000). Locally, alcohol decreases IGF-I gene expression in bone (Turner ...

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...e turnover forms of osteoporosis, bone loss in alcohol-fed rats is relatively slow (Hogan et al. 2001; Turner et al. 2001), a finding consistent with the slow rate of bone loss observed in adult chronic alcohol abusers (Odvina et al. 1995; Pumarino et al. 1996). Chronic consumption of high levels of alcohol during growth reduces peak bone mass by inhibiting bone acquisition. However, there is conflicting evidence as to whether alcohol also impacts the extent of mineralization of bone matrix. Some, but not all, studies suggest that heavy drinking results in under-mineralization of bone matrix (Schnitzler & Solomon 1984; Turner et al. 1987; Diamond et al. 1989; Bikle et al. 1993; Schnitzler et al. 1994). To investigate this issue more fully, we determined the effects of alcohol consumption on bone formed following osteoinduction by demineralized bone matrix. In this model, ectopic bone is induced to form at extraskeletal sites in an animal by subcutaneous implantation of demineralized bone matrix. Used clinically in orthopedic practice to augment bone formation during fracture repair, osteoinduction is an ideal method to investigate the effect of alcohol on mineralization because experiments can be designed ...

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...lizabeth Doran and Urszula T. Iwaniec Oregon State University, USA 1. Introduction Heavy drinking during adolescence may have immediate as well as long-term detrimental consequences to bone health. The growing skeleton is especially prone to fracture and alcohol may exacerbate fracture risk. Furthermore, a disproportionate amount of peak bone mass is acquired during adolescence. Alcohol, by decreasing bone formation, may decrease peak bone mass, predisposing the skeleton to early onset osteoporosis. Although it is well known that heavy drinking can have detrimental skeletal effects in adults (Turner 2000), few studies have focused specifically on the skeletal consequences of underage drinking in human subjects, in part, due to the difficulty in performing alcohol intervention studies in underage drinkers. As a result, the significance of alcohol consumption during this interval of rapid bone accretion on skeletal health is largely unknown. Thus, relevant animal models are critical for identifying the effects and mechanisms of action of alcohol on bone metabolism during bone growth. This chapter will focus on the detrimental effects of alcohol on the maturing skeleton using the laboratory rat a...

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...ng leptin levels. Further studies are required to determine whether www.intechopen.com Detrimental Effects of Alcohol on Bone Growth 67 normalization of leptin levels in alcohol-fed growing rats corrects the detrimental effects of alcohol on bone growth, architecture and turnover. 8. Osteoblasts and adipocytes As discussed, we have shown that alcohol consumption increases bone marrow adiposity and decreases both bone formation and peak bone mass in a rat model for chronic alcohol abuse (Maddalozzo et al. 2009). Adipocytes and osteoblasts are derived from bone marrow mesenchymal stromal cells (Vaananen 2005; Gimble et al. 2006) (Figure 4). An inverse association between bone mass and bone marrow adiposity is commonly observed (Pei & Tontonoz 2004; Morita et al. 2006) and, although yet to be firmly established, several lines of evidence suggest that there is a cause and effect relationship. A deficiency in PPAR, a key mediator of adipocyte differentiation, reduced fat and enhanced osteogenesis (Akune et al. 2004), suggesting that suppression of adipogenesis leads to increased bone formation. Based primarily on cell culture studies, some investigators have concluded that increased adipocyte diffe...

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...of alcohol on energy metabolism 6.2.1 Energy metabolism Bone growth during adolescence is tightly coupled to energy availability (Devlin et al. 2010). Regulation of energy metabolism involves the integration of signals from the digestive system, pancreas, liver, adipose tissue, hypothalamus and pituitary. The messengers that signal energy status and induce physiological adaptations consist of hormones, adipokines, cytokines, growth factors and neuronal networks. Alcohol consumption influences food intake and energy balance by altering the production and target organ response to these signals (Leibowitz 2005; Pravdova & Fickova 2006). As a consequence, we hypothesize that alcohol disrupts the tight coupling between energy availability and bone growth, maturation and turnover. 6.2.2 Effect of alcohol on energy intake Alcohol has profound, dose-dependent effects on energy intake. Low concentrations of alcohol in the diet (0.5% and 3% caloric intake) were shown to enhance food consumption in rats (Turner et al. 2001; Turner & Iwaniec 2010). In contrast, higher alcohol concentrations generally suppress energy intake. Heavy alcohol consumption reduces bone formation in growing rats compared to pair-fe...

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...the highest overall fracture rate is adolescent males (Goulding 2007). Heavy alcohol consumption may contribute to the high rate of fractures in this group. 3. Effects of alcohol on bone metabolism in growing animals 3.1 Animal models for investigating the effects and underlying mechanisms of action of alcohol on the maturing skeleton Due to size and cost considerations, rats and mice are generally the preferred animals for investigating the actions of alcohol on bone metabolism. The reader is directed to our review of the strengths and weaknesses of rodents as animal models for osteoporosis (Iwaniec & Turner 2008). In brief, rodents are similar to humans in that bone grows by a combination of endochondral ossification and periosteal bone formation. Similarly, following the pubertal growth spurt, endochondral ossification slows in magnitude and ultimately ceases (Martin et al. 2003), while periosteal bone formation continues at a slow rate throughout the remainder of life. Humans, rats and mice undergo age-related bone loss, but it is unclear whether the mechanisms for the bone loss are the same across species. Once formed, bone in humans is continuously remodeled. By repairing fatigue damage to bone, b...

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...ter is important because reduced cancellous bone mass plays a key role in the etiology of osteoporotic fractures. Studies designed to evaluate bone growth have shown that alcohol inhibits the rate of bone elongation as well as addition of bone onto periosteal and endocortical endocortical surfaces of rapidly growing male rats (Figure 1) (Turner et al. 1987). These reductions in bone growth contribute to a decrease in bone mass. Similar changes were observed by Sampson and colleagues in growing female Sprague Dawley rats fed alcohol (Sampson et al. 1996; Hogan et al. 1997; Sampson et al. 1997; Sampson & Spears 1999). Fig. 1. Representative microcomputed tomography images of tibiae from rats fed control or alcohol diets. In this study, 4-week-old male rats were fed a liquid diet containing alcohol for 4 months. Except for isocaloric replacement of ethanol with maltose dextran, the controls were fed the same diet ad libitum. Chronic alcohol consumption (35% caloric intake) during post pubertal growth reduced peak bone mass as illustrated above for the tibia. Bone formation is the product of osteoblast number and osteoblast activity. In growing rats, high levels of alcohol consumption were consistently foun...

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...ergy metabolism 6.2.1 Energy metabolism Bone growth during adolescence is tightly coupled to energy availability (Devlin et al. 2010). Regulation of energy metabolism involves the integration of signals from the digestive system, pancreas, liver, adipose tissue, hypothalamus and pituitary. The messengers that signal energy status and induce physiological adaptations consist of hormones, adipokines, cytokines, growth factors and neuronal networks. Alcohol consumption influences food intake and energy balance by altering the production and target organ response to these signals (Leibowitz 2005; Pravdova & Fickova 2006). As a consequence, we hypothesize that alcohol disrupts the tight coupling between energy availability and bone growth, maturation and turnover. 6.2.2 Effect of alcohol on energy intake Alcohol has profound, dose-dependent effects on energy intake. Low concentrations of alcohol in the diet (0.5% and 3% caloric intake) were shown to enhance food consumption in rats (Turner et al. 2001; Turner & Iwaniec 2010). In contrast, higher alcohol concentrations generally suppress energy intake. Heavy alcohol consumption reduces bone formation in growing rats compared to pair-fed controls. However, pair-...

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...eogenesis (Akune et al. 2004), suggesting that suppression of adipogenesis leads to increased bone formation. Based primarily on cell culture studies, some investigators have concluded that increased adipocyte differentiation inevitably occurs at the expense of osteoblast differentiation. If correct, the increase in bone marrow fat in alcohol-fed rats may play a causative role in the decrease in bone formation. In support of this idea, alcohol increased PPAR expression, increased adipocyte differentiation and decreased osteoblast differentiation in an immortalized mesenchymal stem cell line (Wezeman & Gong 2004). It should be mentioned, however, that a close inverse association between bone marrow fat and bone formation is not always apparent (Menagh et al. 2010; Turner & Iwaniec 2011). This has led us to suggest that changes in osteoblast differentiation are not inevitably coupled to changes in adipocyte differentiation. Instead, we have proposed that some regulatory factors have opposite effects on osteoblast and adipocyte differentiation but others have actions that are limited to one or the other cell lineage. Fig. 4. Osteoblasts and adipocytes are derived from bone marrow stromal cells. They pro...

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...y, changes in hormonal regulators of energy homeostasis may alter the relationship between alcohol consumption and energy expenditure. For example, estrogen acts physiologically to reduce energy intake and increases expenditure. In ovariectomized rats, estrogen deficiency results in increased weight gain which is due to a combination of hyperphagia and reduced energy expenditure. Similar to estrogen, alcohol increased energy expenditure in ovariectomized rats. As a consequence, pair-fed ovariectomized rats consuming a control diet gain more weight than animals fed the alcohol containing diet (Kidder & Turner 1998). 6.2.4 Body composition Body composition was altered in sexually mature male rats fed alcohol (35% caloric intake) for 3 months. The alcohol-fed animals had less peripheral fat and a lower whole body bone mineral content compared to age-matched controls (Maddalozzo et al. 2009). In spite of an overall reduction in fat mass, bone marrow adiposity was increased in the rats fed alcohol (Maddalozzo et al. 2009). Similar to rodents, reduced peripheral fat and increased bone marrow adiposity is associated with chronic alcohol abuse in men (Liangpunsakul et al. 2010). In contrast, in a recent study ...

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...growth factors and neuronal networks. Alcohol consumption influences food intake and energy balance by altering the production and target organ response to these signals (Leibowitz 2005; Pravdova & Fickova 2006). As a consequence, we hypothesize that alcohol disrupts the tight coupling between energy availability and bone growth, maturation and turnover. 6.2.2 Effect of alcohol on energy intake Alcohol has profound, dose-dependent effects on energy intake. Low concentrations of alcohol in the diet (0.5% and 3% caloric intake) were shown to enhance food consumption in rats (Turner et al. 2001; Turner & Iwaniec 2010). In contrast, higher alcohol concentrations generally suppress energy intake. Heavy alcohol consumption reduces bone formation in growing rats compared to pair-fed controls. However, pair-feeding underestimates the detrimental skeletal effects of alcohol consumption because self-selected caloric restriction in alcohol-fed rats also has detrimental effects on bone homeostasis (Maddalozzo et al. 2009). www.intechopen.com Osteogenesis 64 6.2.3 Effect of alcohol on energy expenditure Total energy expenditure reflects the sum of basal metabolic rate and energy consumed performing physical activity...

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...concluded that increased adipocyte differentiation inevitably occurs at the expense of osteoblast differentiation. If correct, the increase in bone marrow fat in alcohol-fed rats may play a causative role in the decrease in bone formation. In support of this idea, alcohol increased PPAR expression, increased adipocyte differentiation and decreased osteoblast differentiation in an immortalized mesenchymal stem cell line (Wezeman & Gong 2004). It should be mentioned, however, that a close inverse association between bone marrow fat and bone formation is not always apparent (Menagh et al. 2010; Turner & Iwaniec 2011). This has led us to suggest that changes in osteoblast differentiation are not inevitably coupled to changes in adipocyte differentiation. Instead, we have proposed that some regulatory factors have opposite effects on osteoblast and adipocyte differentiation but others have actions that are limited to one or the other cell lineage. Fig. 4. Osteoblasts and adipocytes are derived from bone marrow stromal cells. They produce factors that act locally to influence bone growth and turnover. Whereas leptin and IGF-I enhance bone formation, adiponectin and TNF- inhibit osteoblast differentiation. T...

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...quired to restore the bone that had been lost. 6. Mechanisms of action of alcohol on the growing skeleton 6.1 Alcohol is an endocrine disruptor Bone metabolism is under tight endocrine control and it is well established that excessive alcohol consumption disrupts numerous endocrine functions. For example, alcohol consumption has been reported to alter the levels and skeletal responses to estrogen, vitamin D and parathyroid hormone (Dumitrescu & Shields 2005; Ronis et al. 2007; Sibonga et al. 2007). Each of these hormones play a key role in bone metabolism. As previously reviewed (Turner 2000; Turner & Sibonga 2001), disturbances in signaling by these hormones may contribute to the skeletal response to alcohol in adults. Less investigated, however, are the effects of alcohol on pituitary- (e.g., growth hormone) and adipocytederived (e.g, leptin) hormones. Disruption of signalling of hormones that function to integrate growth and energy metabolism by alcohol has not been intensively studied, but may be especially important to the effects of underage drinking on bone growth and maturation. As discussed below, alcohol alters local production and/or circulating levels of bone regulating hormones, proinflamma...