Bone Health in Obesity and the Cross Talk between Fat and Bone

C H A P T E R

28 Bone Health in Obesity and the Cross Talk between Fat and Bone Sowmya Krishnan *, Venkataraman Kalyanaraman y *

Department of Pediatrics, University of Oklahoma Health Sciences Center, Children’s Medical Research Institute Diabetes and Metabolic Research Program, Harold Hamm Oklahoma Diabetes Center, Oklahoma City, OK, USA and y Department of Medicine, University of Oklahoma Health Sciences Center, Harold Hamm Oklahoma Diabetes Center, Oklahoma City, Oklahoma; VA Medical Center, Oklahoma City, Oklahoma

INTRODUCTION The problem of obesity is burgeoning all over the world and is increasingly affecting children in both developed and developing countries [1]. Childhood obesity carries with it a huge morbidity including early atherosclerotic changes in major vessels [2]. Paralleling the obesity epidemic is the prevalence of type 2 diabetes, which is being increasingly diagnosed in children [3]. This has brought a lot of attention to the cardiovascular burden imposed by early childhood obesity. That there could be other ramifications of childhood obesity, apart from cardiovascular health, is also now being recognized. Both type 1 and type 2 diabetes are associated with an increase risk for fractures [4e6]. There were an estimated 1.31 million new hip fractures in 1990, and the prevalence of disability resulting from hip fractures was estimated to be 4.48 million [7]. Worldwide osteoporotic fractures accounted for 0.83% of the global burden of noncommunicable disease. In Europe, osteoporotic fractures accounted for more disability-adjusted life years than many other chronic noncommunicable diseases [8]. All these data underscore the importance of paying attention to bone health in this population. In this chapter we will briefly address the issue of bone health in obesity and diabetes, especially in relation to children, and discuss the recently described link between bone and energy metabolism.

Global Perspectives on Childhood Obesity

BONE MINERAL DENSITY AS A SURROGATE MARKER FOR BONE STRENGTH Osteoporosis is defined as a “skeletal disorder characterized by compromised bone strength, predisposing to an increased risk of fracture” [9]. In adults, the use of densitometry has been shown to predict probability of fractures [10]. Dual-energy x-ray absorptiometry (DXA) is the most commonly used tool to measure bone density, as it is safe, noninvasive, and has low radiation exposure. Most of the data on the use of densitometry come from studies on postmenopausal women where densitometry has been shown to be especially useful to detect threshold levels for at risk individuals. The World Health Organization has developed criteria for the diagnosis of osteoporosis in postmenopausal women based on bone mineral density measurements (BMD) that is 2.5 standard deviations or more below the average value for a young adult (T-score  2.5). Increasingly, DXA as a tool to measure bone density is being used in other populations like elderly men and atrisk children. A word of caution is in order before we delve into the data on bone density measurements in the obese population. The utility of DXA to detect subjects at risk for clinically significant fracture in this population is still to be proven. One should also keep

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in mind that DXA is just a measurement of bone mineral density and various other markers of bone strength like bone size, shape, geometry, and microarchitecture are not being measured. But DXA measurements of bone density is the best available tool for us so far, and it can be used as a surrogate marker of bone strength and most of the clinical data available to date uses this instrument.

RELATION OF BONE MASS TO BODY WEIGHT That there is a relationship between body mass index (BMI) and bone density is clearly evident in conditions like anorexia nervosa in which this has been extensively studied. This condition, which is characterized by distorted body image and extreme thinness, also is associated with low BMD [11]. BMD improvement can lag behind weight gain in this condition [12]. Various other studies have documented a direct relationship between body mass index and BMD [13], though this effect tends to plateau after a certain BMI. Studies on the association between body mass index and BMD are listed in Table 28.1. In general, body fat tends to be protective against postmenopausal osteoporosis. This could be

TABLE 28.1

due to the possible aromatization of circulating androgens by the adipose tissue to estrogens.

FAT MASS OR LEAN MASS: WHAT INFLUENCES BONE MASS? Recent years have shown an explosion of studies trying to delineate the exact relationship between each body composition variable with bone mineral density. Most studies support the conclusion that lean body mass (LBM) influences bone density positively [14, 15], though the effect may depend on the bone mass parameter being used and the bone site being measured. The influence of fat mass on bone density is still unclear with some studies showing a positive association [15, 16] and some a negative association [14, 17] (Table 28.2). Khosla et al. reported that the relationship between bone mass and body composition variable is dependent on the area of bone mass being measured with varying relationship of bone mass at different sites in relation to these body composition variables. They also showed that the relationship was affected by the menopausal status of these women [16]. Similarly Chen et al. showed that bone mineral mass status is more closely related to LBM than fat mass, though changes in regional BMD

Relationship between Body Mass Index with Bone Mineral Density

Study

Results

Age of subjects

Felson et al. (1993) [51]

Body mass index explained variation in BMD for all sites in women and BMD in weight bearing sites in men

Mean age 76 years

Chen et al. (1997) [18]

Increased body weight associated with increased bone density

Postmenopausal Chinese women

Ravn et al. (1999) [13]

Women in the lowest tertiles of body fat or BMI had 12% lower BMD at baseline

Postmenopausal women

Goulding et al. (2001) [22]

Children with history of fractures were more obese and had lower areal and volumetric BMD

3 to 19 years of age

Rocher et al. (2008) [52]

Whole body bone mineral areal density (BMAD) lower but lumbar spine BMAD higher in obese children

9- to 12-year-old children

TABLE 28.2

Relationship between Various Body Composition Variables to Body Mineral Density

Study

Results

Comments

Khosla et al. [16] (1996)

Both fat mass and lean body mass affect bone mass and the effect depends on the bone mass parameter used, skeletal site measured, and menopausal status of women

Premenopausal and postmenopausal women (21 to 94 years)

Zhao et al. [53] (2007)

Negative correlation between fat mass and bone mass

Young adults of Chinese and Caucasian descent

Janicka et al. [14] (2007)

Lean mass has a significant correlation with bone mass but negative to no effect of fat mass on bone mass

Sexually mature adolescents and young adults (13 to 21 years)

Sayers et al. [15] (2009)

Lean mass has a positive relation with cortical bone mineral content

Mean age of 15.5 years

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annually correlated with fat mas [18]. This differential effect of fat mass and LBM on different parts of the skeleton could be due to varying mechanism of actions of these body composition variables. Although LBM may contribute to the muscle mass and the skeletal loading and thus provide a direct mechanical affect on the bone, the fat mass may exert its effect by various adipokines secreted and by production of estrogen through aromatization [16].

with diabetes had higher femoral neck BMD compared to those without, independent of abdominal obesity. Animal studies have shown altered bone mass, geometry, and mechanical properties with type 2 diabetes [28]. This warrants concern, and the increased fracture incidence seen with type 2 diabetes may be secondary to other defects in bone health apart from bone mineralization.

VITAMIN D BONE MASS IN OBESE CHILDREN Data on BMD in obese children are conflicting with some reports of increased BMD [19e20] and some of decreased BMD [21, 22] when adjusted for fat mass. This could be due to different sites of measurement as obesity could exhibit differential effects on the skeleton depending on the site of measurement. Childhood is characterized by intense acquisition of bone mineral. Furthermore, studying bone mineral density during this period has inherent biases because of the influence of sexual maturity and height on bone mineral density interpretations. Most studies are cross-sectional in nature and the effect of fat mass on BMD may very well depend on the duration of obesity and possibly various other factors including genetically determined bone mass and associated inflammation. There have also been reports of increased fracture incidence in obese children [22, 23]. It is unclear at this time if this is due to defective bone density or a higher load sustained on fall by obese children. These results need to be replicated in further longitudinal studies.

Any discussion about bone health is not complete without highlighting the role of vitamin D. Vitamin D plays a critical role in bone mineralization and its deficiency is known to cause rickets. Recently though, the role of Vitamin D in insulin sensitivity and secretion has garnered a lot of interest. Low vitamin D levels have been described in relation to increased adiposity [29]. It has been postulated that increased body fat sequesters the vitamin D, leading to decreased bioavailability as it is a fat-soluble vitamin. Additionally, vitamin D status has been linked to insulin sensitivity [30] with short-term trials of vitamin D shown to improve insulin sensitivity in obese men [31]. Vitamin D deficiency could be the possible link behind the increased fracture frequency seen in obese children, though this hypothesis needs to be tested. Vitamin D is the “hot” vitamin of this period, and we are sure to see more research elucidating the link between vitamin D status and various metabolic parameters related to obesity.

BONE AND ENERGY METABOLISM BMD AND FRACTURE RISK IN DIABETES Both type 1 diabetes and type 2 diabetes are characterized by a higher incidence of fractures [4]. Bone mineral density data, though, are conflicting in these two types of diabetes. Type 1 diabetes has always been associated with decreased BMD [24], whereas the data in type 2 diabetes are unclear with some studies showing it to be increased [25] and some showing it to be decreased [26]. The picture is further complicated by the presence of obesity in most patients with type 2 diabetes and the varying duration of type 2 diabetes before diagnosis that is characteristic in this condition. Kinjo et al. looked at BMD in subjects with and without the metabolic syndrome in a large cohort from the third National Health and Nutrition Examination Survey (NHANES III) [27]. They found that the femoral neck BMD was higher in patients with metabolic syndrome than in those without (p < 0.0001). Additionally they found that the subgroup of patients

Osteoblasts and adipocytes originate from common precursor bone marrow mesenchymal cells. Complex signaling cascades direct their development into either osteoblasts or adipocyte cell lineage. Conditions associated with enhanced bone marrow adiposity are associated with low bone mineral content [32, 33]. Medications like thiazolidinediones that enhance the differentiation of bone marrow mesenchymal cells into adipocyte lineage are associated with increased marrow adiposity and heightened risk of fractures [34]. Though the close relation between fat and bone cells has been recognized for a long time, recent discoveries suggest that the skeleton plays an important role in energy metabolism. Hormones secreted from the adipocyte (adipokines) influence bone mass and similarly hormones secreted from osteoblasts have been shown to influence insulin secretion, sensitivity, and the action of adipokines in mice studies. We will briefly review these agents here.

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Adipocyte-Derived Hormones (Adipokines)

Amylin

Leptin

Amylin is cosecreted with insulin. It causes proliferation of osteoblasts and increases indices of bone formation [43]. Increased amylin levels seen in adiposity may be associated with the increase in bone mass.

Leptin is one of the well-known adipokine (hormones secreted from adipose tissue), and its role in energy metabolism has been well described. Specifically it is secreted after eating and acts on the ventromedial hypothalamus to cause satiety. Various investigators have studied Leptin’s action on bone. Specifically Gordeladze et al. showed the effect of leptin on bone mineralization and osteoclastic signaling [35]. Cultured iliac cell osteoblasts were incubated with leptin and studied for markers of various cell proliferation markers, cell apoptosis, and collagen synthesis. Leptin exposure was shown to increase the expression of transforming growth factor, insulin-like growth factor-1, collagen-1a, and osteocalcin mRNA. The CD44 osteocyte marker gene expression was increased, and they postulated that leptin exposure enhances transition of osteoblasts to preosteocytes. Leptin also inhibits osteoclast generation and increases osteoprotegerin messenger RNA and protein expression in peripheral blood mononuclear cells [36]. Leptin treatment in leptin deficient ob/ob mice increases whole body bone mineral content (BMC) [37]. That leptin can have the opposite effect of enhancing bone resorption when administered centrally was shown by elegant experiments done by Ducy et al. [38]. This was postulated to be due to its action via the sympathetic nervous system. In vivo, the peripheral action of leptin seems to dominate, as evidenced by increased bone mass seen with leptin treatment in leptin-deficient ob/ob mice [39]. Adiponectin Adiponectin is another adipokine secreted by adipocytes. Its levels decrease in obesity and diabetes and may increase with weight loss. Higher adiponectin levels are seen with decreased BMD in cross-sectional studies [40] and need to be clarified by further longitudinal studies.

Preptin Preptin is a hormone secreted by beta cells of the pancreas and has been shown to be anabolic to bone [44].

Others IL-6 levels are increased in overweight and obese children and adults. It has been shown to be an osteoresorptive factor and could cause decreased BMD associated with inflammation [45]. IL-6 knockout mice, though, have normal bone pathology. Various other peptides have been shown to have an effect on bone, especially glucagon-like peptides 1 and 2 (GLP-1, GLP-2) [46, 47] and glucose dependent insulinotropic polypeptide (GIP). These peptides are secreted with feeding and may mediate the decreased bone resorption seen after feeding. In addition, ghrelin has an important anabolic action on bone [48]. Osteocalcin Osteocalcin is a protein secreted by osteoblasts that has been known to play a major part in bone mineralization. Animal experiments have shown that the uncarboxylated form to increase beta cell proliferation, insulin secretion, insulin sensitivity, and adiponectin expression [49]. Human studies have shown that osteocalcin level is inversely related to insulin resistance as measured by homeostasis model assessment of insulin resistance [50]. Osteocalcin receptors have not yet been described in humans, and elucidation of its role in energy metabolism in humans needs further research.

CONCLUSION

Resistin Resistin levels are increased proportional to obesity status. An inverse relationship has been described between resistin levels and BMD [41].

Pancreatic Hormones Insulin BMD is directly related to fasting insulin concentration [42]. Osteoblasts have been shown to have insulin receptors that may mediate the anabolic action of insulin on bone. Additionally the influence of insulin on bone may be mediated by indirect effects via its action on sex hormone production in ovary and sex hormone binding globulin production from liver.

The association between adiposity status and BMD is still not very clear. Although body fat seems to be protective against postmenopausal osteoporosis, childhood obesity seems to have an adverse affect on bone health. This difference could be because of the different sites being measured and different hormonal milieu (premenopausal/postmenopausal status, Tanner stages). Similarly, the bone mineral density data in type 2 diabetes is unclear, but this population seems to be definitely at risk for fractures at all locations including hip fractures. There have been few reports already of increased fractures in obese children, but there are no data on children or young adults with type 2 diabetes. This is concerning, and childhood

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obesity may be one of the most important modifiable factors to prevent later osteoporotic fractures. The recently described link between bone and energy metabolism is intriguing and holds tremendous therapeutic potential. There yet may be other hormones that have not been described so far that link bone and energy metabolism.

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