obesity reviews
doi: 10.1111/obr.12117
Etiology and Pathophysiology/Obesity Comorbidities
Bone health in eating disorders N. Zuckerman-Levin1, Z. Hochberg2,3 and Y. Latzer1,4
1
Eating Disorders Clinic, Psychiatric Division,
Rambam Medical Center, Haifa, Israel; 2
Pediatric Endocrinology, Meyer Children’s
Hospital, Rambam Medical Center, Haifa, Israel; 3Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; 4Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
Received 3 June 2013; revised 11 September 2013; accepted 13 September 2013
Address for correspondence: Dr. N Zuckerman-Levin, Eating Disorders Clinic, Psychiatric Division, Rambam Medical Center, Haifa 9602, Israel. E-mail: [email protected]
Summary Eating disorders (EDs) put adolescents and young adults at risk for impaired bone health. Low bone mineral density (BMD) with ED is caused by failure to accrue peak bone mass in adolescence and bone loss in young adulthood. Although ED patients diagnosed with bone loss may be asymptomatic, some suffer bone pains and have increased incidence of fractures. Adolescents with ED are prone to increased prevalence of stress fractures, kyphoscoliosis and height loss. The clinical picture of the various EDs involves endocrinopathies that contribute to impaired bone health. Anorexia nervosa (AN) is characterized by low bone turnover, with relatively higher osteoclastic (bone resorptive) than osteoblastic (bone formation) activity. Bone loss in AN occurs in both the trabecular and cortical bones, although the former is more vulnerable. Bone loss in AN has been shown to be influenced by malnutrition and low weight, reduced fat mass, oestrogen and androgen deficiency, glucocorticoid excess, impaired growth hormone–insulin-like growth factor 1 axis, and more. Bone loss in AN may not be completely reversible despite recovery from the illness. Treatment modalities involving hormonal therapies have limited effectiveness, whereas increased caloric intake, weight gain and resumption of menses are essential to improved BMD. Keywords: Adolescents, anorexia nervosa, bone, eating disorders, endocrinology. obesity reviews (2014) 15, 215–223
Introduction In recent years, the incidence of eating disorders (EDs) all over the world has increased, and the age group widened to include pre-pubertal children, adolescents and young adults (1). The EDs are grouped into several clinical entities: anorexia nervosa (AN), bulimia nervosa (BN), binge ED (BED) and EDs not otherwise specified (EDNOS; partial/subclinical) (2). AN is the most studied ED, and its prevalence is high among adolescents and young adults (3). EDs are less common in men and may remain undiagnosed for a longer period. In the last decade, AN is increasingly recognized in men (4).
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EDs put adolescents and young adults at risk for impaired bone health. Low bone mineral density (BMD) with ED is caused by failure to accrue peak bone mass in adolescence and bone loss in young adulthood (5–7). Although ED patients diagnosed with bone loss may be asymptomatic, some suffer bone pains and have increased incidence of fractures. Adolescents with ED are prone to increased prevalence of stress fractures, kyphoscoliosis and height loss (8,9). ED patients also demonstrate more severe periodontal disease than healthy controls (10). The clinical picture of the various EDs involves endocrinopathies that contribute to impaired bone health 215 15, 215–223, March 2014
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(11). Skeletal involvement was mainly studied in adolescents and young adult women with AN. Bone loss in ED is often irreversible, and treatment modalities are limited. This review summarizes medical approaches to understanding, preventing and treating bone loss in ED patients.
Bone loss characteristics in ED The aetiology of bone disease in ED is complex and multifaceted. AN is an ED that is characterized by significant bone loss and low bone turnover because of the fact that osteoclastic activity (bone resorption) is higher than the osteoblastic activity (bone formation) (6,7,12). The mechanism involved in bone loss in ED is different from that of senile or glucocorticoid-related bone loss, which results from high bone turnover. Bone loss in AN is an early event and can occur within 12 months of the disease onset (13). In young adolescents, at times when the mineral density of normal bones is on the rise, an average annual bone loss of 1% has been described (14). Bone loss in AN occurs in both the trabecular and cortical bones (15), although it is more evident in the former (16). Volumetric measurement of BMD in AN patients demonstrates that not only is the mineral content of the bone reduced, but also the bone size is reduced, as measured in the vertebral body and femoral neck width (17). Adolescent girls with AN also exhibit impaired bone strength (18).
Evaluation of bone health in ED BMD is commonly measured by dual-energy x-ray absorptiometry, evaluating areal BMD. This method underestimates the BMD in short-statured individuals, such as children and pre-pubertal adolescents, and patients with AN, and should be corrected for height/size. Methods that allow evaluation of volumetric density and bone structure are better suited for AN patients, These include quantitative computed tomography (CT), which measures 3-D volumetric BMD, quantitative ultrasonography, and more recently, flat-panel volume CT. Evaluating BMD in AN patients is recommended 6–12 months after amenorrhoea (19), when it highly predicts significant reduction in BMD. In parallel, bone metabolism may be assessed by bone formation and bone resorption markers (20). Bone markers have limited clinical utility.
Incidence and clinical picture of bone loss in ED About half of the adolescents with AN were found to have age-corrected BMD z-scores of less than −1 at one or more skeletal sites, and 11% were found to have z-scores of less than −2 (7). Unlike girls, adolescent boys with AN have
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greater involvement of cortical bone in the hip and femoral neck, rather than of the spine (21). A recent study described impaired hip geometry in adolescent boys with AN, associated with lower lean mass (22). Adolescents with AN have impaired bone formation, as evidenced by a reduction in surrogate markers of bone formation, such as serum osteocalcin (OC) and bonespecific alkaline phosphatase, when compared with healthy controls (6). Bone resorption markers were found to be comparable (6) in AN patients and healthy controls (6) or lower (12). Flat-panel volume CT demonstrated abnormal trabecular structure in adolescent girls with AN as compared with normal-weight control subjects, despite normal BMD (23). As the onset of AN in adolescence often parallels peak bone mass accrual, it may lead to permanent deficits in bone mineral accrual. Adolescent girls with AN who recovered demonstrate persistence of impaired bone health for over a year (24). Bone loss in adult AN patients is associated with increased markers of resorption, such as serum Nteleopeptide (NTX) and urinary deoxypyridinoline (DPD), and decreased or normal markers of bone formation, such as serum OC (25). Osteopenia with decreased BMD is described in up to 92% of young adults with AN, and osteoporosis occurs in 38–50% (5). There is paucity of data on men with ED especially regarding bone health. Fewer men than women with AN have osteopenia (occurring in 36%) or osteoporosis (occurring in 26%), yet those have been shown to be more severe (26,27). This difference in severity may be related to testosterone’s effect on bone and body composition. Testosterone has both anabolic and anti-resorptive effects (via aromatization to E2) on both trabecular and cortical bone (28). Testosterone also affects body composition; mainly lean body mass, which predicts BMD. Women with AN, whose onset occurred during adolescence have a lower bone mass than women with AN whose onset occurred during adulthood (16). It has been also reported in women with AN whose trabecular bone thickness and separation are both abnormal (29), and their bones are weaker than those of healthy controls (30). Abnormal bone structure and low BMD contribute to the outcome of bone loss in AN, causing increased fracture rate. Failure to achieve peak bone mass has been shown to cause stress fractures in adolescents and young adults with AN (31), as well as osteoporotic fractures later in life. An increased fracture rate has been reported in AN, and also in BN and ED-NOS many years after diagnosis (32). It is important to note that patients with BN and ED-NOS may have had previous AN (26,33). Women with AN who had amenorrhoea for more than 6 years have a sevenfold increase in the rate of fractures compared with healthy controls (32), and studies of © 2013 The Authors obesity reviews © 2013 International Association for the Study of Obesity
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long-term outcome in AN indicate that at 11.7 years follow-up, 44% of unrecovered women with AN are osteoporotic (34). In a longitudinal study in women with AN, the cumulative incidence of any fracture at 40 years after diagnosis was 57% (35). Normal-weight BN in women is associated with low BMD only when there is a past history of low weight, menstrual disturbances or amenorrhoea (26,33,36). The incidence of bone loss in BN is not known, because of the heterogeneity of this group of patients.
Pathogenesis of bone loss Several mechanisms underlie the low BMD in AN and including (i) low caloric intake and malnutrition with low serum insulin-like growth factor 1 (IGF1) levels; (ii) low body weight and small amounts of adipose tissue with low serum leptin and high peptide YY (PYY) levels; (iii) impaired thyroid function; (iv) hypogonadism with low serum sex steroid levels and (v) high circulating cortisol. Studies of bone loss focused on AN patients and less is known about other EDs.
Nutrition Nutritional markers, such as body mass index, fat and lean body mass and IGF1 correlate with low bone density in AN (6,7,20,21,24,37,38). Food restriction is the main contributor to bone loss and even acute fasting decreases bone formation (39). Food restriction when combined with excessive exercise in healthy women have adverse effects on bone formation and resorption (40). These two are additive effects, acting through different mechanisms. Weight gain is associated with the recovery of bone formation (24,41–43), as evidenced by the normalization of bone turnover markers – serum OC and bone-specific alkaline phosphatase, urinary NTX and DPD, and by increased serum IGF1 levels. However, normalization of bone resorption markers may be delayed and approach reference values in women with AN only when menses resumes, reflecting effect of oestrogen on bone resorption (41). Weight gain in AN is also associated with improved linear growth in adolescents at the time of pubertal growth spurt (42).
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Sex hormones Oestrogens are bone anti-resorptive agents because they inhibit osteoclast-mediated bone resorption by activating the RANK–RANKL system (48). Oestrogens stimulate osteoclast apoptosis and inhibit osteocyte apoptosis, while maintaining osteocyte viability (49). Accordingly, BMD decreases with increasing duration of amenorrhoea in women with AN (16,50). Moreover, the bone loss in women with AN is more severe than that found in normalweight women with functional hypothalamic amenorrhoea (50). Whereas weight gain in young women with AN can improve femoral neck BMD, the resumption of menses also improves spinal vertebrae BMD, and such findings demonstrate the effect of oestrogen on trabecular bone density (51). It has also been reported that low-weight eumenorrhoeic women with AN have higher body fat, leptin and IGF1 than amenorrhoeic women with the same weight. The eumenorrhoeic women had reduced hip BMD and less reduced spinal BMD in comparison with amenorrhoeic women (52), owing to higher oestradiol and hence better trabecular bone development in eumenorrhoeic subjects. Both women and men with AN are androgen deficient (21,53).Low levels of free testosterone, and in some studies, of dehydroepiandrosterone sulfate (DHEAS) are found in women with AN (54). Anabolic androgen deficiency contribute to bone loss in AN (55).
Hypercortisolism Patients with ED demonstrate dys-regulation of the hypothalamic–pituitary–adrenal axis with elevated serum cortisol levels (56–58). An excess of catabolic glucocorticoids in AN would theoretically contribute to bone loss by stimulating osteoclasts, inhibiting osteoblasts and negatively affecting mineral balance and the growth hormone (GH)–IGF1 axis (59). Indeed, the urinary free cortisol is inversely correlated with spinal vertebrae BMD in AN (16), and serum cortisol levels are inversely correlated with markers of bone formation (serum OC and c-terminal propeptide of type 1 procollagen) (57), and elevated serum cortisol is associated with the severity of bone loss (60).
Minerals and vitamins Minerals – such as calcium, phosphorus and magnesium and vitamin D (44) are nutrients that are essential for bone mineralization. Calcium metabolism may be abnormal in ED (45). Patients with AN are usually not calcium or vitamin D deficient (24,46). Bioavailability of vitamin D in AN patients is similar to normal-weighted controls, and vitamin D dosing may not differ (47). © 2013 The Authors obesity reviews © 2013 International Association for the Study of Obesity
GH–IGF1 axis The GH–IGF1 axis in ED is characterized by GH resistance and IGF1 deficiency (61–63). Starvation interferes with IGF1 secretion in the liver causing IGF1 deficiency. GH effects on linear growth of bones are IGF1 independent, so that height is normal, unless profound malnutrition occurs. The combination of GH resistance and IGF1 deficiency
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contributes to the low BMD in AN because of loss of the anabolic effect of GH on bone, which is mediated by IGF1. Low-serum IGF1 levels are associated with reduced serum OC levels, which are considered a specific marker of osteoblast function (64). In adolescent girls with AN, serum IGF1 levels, but not serum GH levels, correlate with lower BMD and bone formation markers (6,24,62,65).
leptin regulates bone remodelling processes through a direct stimulatory effect on osteoblast differentiation and bone formation, as well as an indirect inhibitory effect through the hypothalamus (ventromedial nucleus) in the sympathetic nervous system (84,85).
PYY
The hypothalamic–pituitary–thyroid axis plays a key role in skeletal development, accretion of peak bone mass and regulation of bone turnover (66,67). Thyroid hormones exert an anabolic effect on bone and regulate IGF1 signalling in growth plate cells (68,69). Typical changes occur in peripheral thyroid hormones in ED, with low-normal serum thyroid-stimulating hormone levels, normal or low serum thyroxine (T4) levels, and low serum triiodothyronine (T3) levels, while tissue thyroid or reverse T3 levels are elevated (70–72). Low serum T3 levels may interfere with bone metabolism in patients with AN (73).
PYY is an anorexigenic 36-amino acid peptide primarily produced in the L-cells of the colon in proportion to caloric intake and increases after food intake (86). PYY actions are mediated via activation of the Y-receptors. Y2 receptor knockout mice have increased BMD, by increased osteoblastic activity via hypothalamic signalling, and thus PYY may play a role in regulating bone mass (87). High serum PYY levels might contribute to reduced food intake and decreased bone formation in AN, as evidenced by an association with bone turnover markers (88). In patients with AN, high PYY predicts lower bone density (89). This inverse correlation between PYY levels and bone turnover markers is consistent with increased bone formation in rodents (87).
Oxytocin
Ghrelin
Oxytocin is a hypothalamic hormone that is stored and released from the posterior pituitary, and is important in parturition and lactation. Oxytocin is involved in energy homeostasis and has an anabolic effect on bone (74,75). Initial reports hint that low overnight oxytocin levels in AN are associated with low BMD and low fat mass (76,77), but the evidence is still preliminary.
Ghrelin is an orexigenic gastric peptide hormone and promotes osteoblastic proliferation and differentiation in vitro (86). Although patients with AN have elevated serum ghrelin levels (90,91), the results of few in vivo studies (92) have demonstrated a weak association between serum ghrelin levels and BMD in AN.
Thyroid hormones
Amylin Adiponectin Adiponectin is an adipocytokine that mediates insulin sensitivity and resistance through its effects on peroxisome proliferator-activated receptor gamma. Adiponectin high and low molecular weight forms may differ. Adiponectin serum levels have been reported to be elevated, unchanged, or low in AN (77–79). Serum adiponectin is an inverse predictor of bone density in adolescents with AN (77). High adiponectin serum levels may contribute to the low BMD in AN by increasing osteoclast activity (80).
Leptin Leptin is a fat-derived anorexigenic hormone (81). Serum leptin levels are typically decreased in AN because of the scarcity of adipose tissue, and lower basal and pulsatile secretions have been reported as compared with healthy subjects (82). Leptin has been shown to have both central and peripheral anabolic effects on bone (83) and low leptin levels are associated with low bone mass (77). Indeed,
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Amylin is a peptide hormone that is secreted by pancreatic β-cells. Amylin contributes to glycaemic control by slowing gastric emptying and promoting satiety. A recent study found that low serum amylin levels are associated with low BMD in women with AN (93).
Bone composition Bone marrow fat is increased in adolescent and adult women with AN (94,95), and is inversely correlated with BMD. Correlation was also found between bone marrow fat, preadipocyte factor 1 and BMD in women with AN (96). Further research is needed to understand the role of bone marrow fat (97) in the pathogenesis of bone loss in ED.
Treatment of bone loss in ED Studies of treatment modalities of bone loss in ED, especially in AN, have been focused on all the known © 2013 The Authors obesity reviews © 2013 International Association for the Study of Obesity
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mechanisms that contribute to this morbidity, as treating of one or more of the contributing factors have not improved bone health (98,99). Undernutrition, as the fundamental mechanism, has been mainly addressed. Spontaneous weight recovery in adolescents and women with AN is followed by improved bone health (51,100). Nutritional rehabilitation has an anabolic effect on bone metabolism and remains the mainstay of therapy for the osteopenia and osteoporosis of AN (24,41–43). As patients with AN are usually not calcium or vitamin D deficient, supplementation with calcium and vitamin D does not improve bone density in these patients (24,46) Amenorrhoea and oestrogen deficiency play an important role in bone health in ED. However, administration of oestrogen therapy alone does not improve bone density in adolescents or adults with AN (64,101–104) until their weight recovers (41). In fact, high-dose oestrogens, which are present in oral contraceptives (OCP) may further decrease the levels of IGF1, an important bone trophic hormone (105). In contrast to OCP, low doses of transdermal oestrogen that mimic early pubertal rise, increased BMD in adolescent girls with AN (106). As recently demonstrated, transdermal oestradiol may improve BMD in adolescent girls with AN, via inhibition of Pref-1 (107). Short-term replacement therapy with testosterone or DHEAS improves some bone turnover markers and BMD in women with AN (54,108). Recently, a study demonstrated that transdermal testosterone administration did not improve BMD, but increased lean body mass (109). DHEA administration appeared to improve hip and spinal BMD, but treatment effect was abolished after adjusting for weight gain (54). No clinical research has studied the effect of testosterone on BMD in hypogonadal AN male patients. Treatment targeted at the GH–IGF1 axis is also being studied. Supraphysiologic GH (110) did not increase IGF1 levels in women with AN. Weight recovery is associated with increased IGF1 levels (24). Combined IGF1–oestrogen treatment in adult women with AN increases spinal vertebrae BMD and serum levels of bone formation markers and decreases bone resorption markers (64). Thyroid replacement therapy in AN may lead to undesirable weight and muscle mass loss (11), and hasten the deterioration of bone loss. Thyroid hormone has no therapeutic effect on AN-related osteopenia. Physical activity, mainly weight-bearing exercise, is important for bone health in AN because it increases BMD (111). However, recommending physical activity to AN patients is controversial and should be discussed with each patient because excessive physical activity in combination with malnutrition can exacerbate weight loss (112,113). © 2013 The Authors obesity reviews © 2013 International Association for the Study of Obesity
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Bisphosphonates reduce bone turnover by decreasing osteoclastic bone resorption. Bisphosphonates have a long half-life and a strong affinity for bone, as demonstrated by their absorption into its matrix. Hence, they are not yet recommended for treating the low-turnover bone loss in AN. Among the few studies that have been conducted, some showed improved bone density in AN patients treated with risedronate (109,114,115), but BMD remained below normal for age. Cannabinoids are known to regulate eating behaviour within the central nervous system, and intestine and adipose tissue, interacting with melanocortins, leptin and ghrelin. The endocannabinoid system is underactive and the global type 1 cannabinoid receptor type 1 is up regulated in ED (116). The few studies in AN that have been conducted using cannabinoids failed to achieve the expected appetite stimulation and weight gain that can improve bone health (117–119).
Prognosis of bone loss in ED Bone loss is one of the debilitating long-term health sequelae of ED. In recovered women with ED, despite improved weight and resumption of menses, bone loss may persist and the low BMD remains irreversible (9,24,33,34,41,120,121). Good prognostic factors include early and sustained therapy, while bad prognosis is related to prolonged course and chronicity, extremely low body weight, and the early onset of disease in adolescence before or during the attainment of peak bone mass (9). Nutritional rehabilitation is critical for other therapies to have their optimal effect on bone health.
Conclusions Malnourishment places adolescents and young adults with EDs at considerable risk for bone loss or failure to attain appropriate peak bone mass. This is likely associated with an increased risk of bone pains and fractures even in remitted patients. Reduced BMD in AN patients is associated with reduced caloric and mineral intake and hormonal dysfunction, such as hypogonadotrophic hypogonadism, all leading to typical low bone turnover. Bone loss may not be completely reversible in recovered AN patients. Therefore there is a great importance for early diagnosis and treatment, in particular the establishment of appropriate target weight range, improved caloric intake and resumption of menses as essential to improved BMD. Other treatment modalities are also being studied.
Conflict of interest statement No conflict of interest was declared.
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doi: 10.1111/obr.12117
Etiology and Pathophysiology/Obesity Comorbidities
Bone health in eating disorders N. Zuckerman-Levin1, Z. Hochberg2,3 and Y. Latzer1,4
1
Eating Disorders Clinic, Psychiatric Division,
Rambam Medical Center, Haifa, Israel; 2
Pediatric Endocrinology, Meyer Children’s
Hospital, Rambam Medical Center, Haifa, Israel; 3Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; 4Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
Received 3 June 2013; revised 11 September 2013; accepted 13 September 2013
Address for correspondence: Dr. N Zuckerman-Levin, Eating Disorders Clinic, Psychiatric Division, Rambam Medical Center, Haifa 9602, Israel. E-mail: [email protected]
Summary Eating disorders (EDs) put adolescents and young adults at risk for impaired bone health. Low bone mineral density (BMD) with ED is caused by failure to accrue peak bone mass in adolescence and bone loss in young adulthood. Although ED patients diagnosed with bone loss may be asymptomatic, some suffer bone pains and have increased incidence of fractures. Adolescents with ED are prone to increased prevalence of stress fractures, kyphoscoliosis and height loss. The clinical picture of the various EDs involves endocrinopathies that contribute to impaired bone health. Anorexia nervosa (AN) is characterized by low bone turnover, with relatively higher osteoclastic (bone resorptive) than osteoblastic (bone formation) activity. Bone loss in AN occurs in both the trabecular and cortical bones, although the former is more vulnerable. Bone loss in AN has been shown to be influenced by malnutrition and low weight, reduced fat mass, oestrogen and androgen deficiency, glucocorticoid excess, impaired growth hormone–insulin-like growth factor 1 axis, and more. Bone loss in AN may not be completely reversible despite recovery from the illness. Treatment modalities involving hormonal therapies have limited effectiveness, whereas increased caloric intake, weight gain and resumption of menses are essential to improved BMD. Keywords: Adolescents, anorexia nervosa, bone, eating disorders, endocrinology. obesity reviews (2014) 15, 215–223
Introduction In recent years, the incidence of eating disorders (EDs) all over the world has increased, and the age group widened to include pre-pubertal children, adolescents and young adults (1). The EDs are grouped into several clinical entities: anorexia nervosa (AN), bulimia nervosa (BN), binge ED (BED) and EDs not otherwise specified (EDNOS; partial/subclinical) (2). AN is the most studied ED, and its prevalence is high among adolescents and young adults (3). EDs are less common in men and may remain undiagnosed for a longer period. In the last decade, AN is increasingly recognized in men (4).
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EDs put adolescents and young adults at risk for impaired bone health. Low bone mineral density (BMD) with ED is caused by failure to accrue peak bone mass in adolescence and bone loss in young adulthood (5–7). Although ED patients diagnosed with bone loss may be asymptomatic, some suffer bone pains and have increased incidence of fractures. Adolescents with ED are prone to increased prevalence of stress fractures, kyphoscoliosis and height loss (8,9). ED patients also demonstrate more severe periodontal disease than healthy controls (10). The clinical picture of the various EDs involves endocrinopathies that contribute to impaired bone health 215 15, 215–223, March 2014
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(11). Skeletal involvement was mainly studied in adolescents and young adult women with AN. Bone loss in ED is often irreversible, and treatment modalities are limited. This review summarizes medical approaches to understanding, preventing and treating bone loss in ED patients.
Bone loss characteristics in ED The aetiology of bone disease in ED is complex and multifaceted. AN is an ED that is characterized by significant bone loss and low bone turnover because of the fact that osteoclastic activity (bone resorption) is higher than the osteoblastic activity (bone formation) (6,7,12). The mechanism involved in bone loss in ED is different from that of senile or glucocorticoid-related bone loss, which results from high bone turnover. Bone loss in AN is an early event and can occur within 12 months of the disease onset (13). In young adolescents, at times when the mineral density of normal bones is on the rise, an average annual bone loss of 1% has been described (14). Bone loss in AN occurs in both the trabecular and cortical bones (15), although it is more evident in the former (16). Volumetric measurement of BMD in AN patients demonstrates that not only is the mineral content of the bone reduced, but also the bone size is reduced, as measured in the vertebral body and femoral neck width (17). Adolescent girls with AN also exhibit impaired bone strength (18).
Evaluation of bone health in ED BMD is commonly measured by dual-energy x-ray absorptiometry, evaluating areal BMD. This method underestimates the BMD in short-statured individuals, such as children and pre-pubertal adolescents, and patients with AN, and should be corrected for height/size. Methods that allow evaluation of volumetric density and bone structure are better suited for AN patients, These include quantitative computed tomography (CT), which measures 3-D volumetric BMD, quantitative ultrasonography, and more recently, flat-panel volume CT. Evaluating BMD in AN patients is recommended 6–12 months after amenorrhoea (19), when it highly predicts significant reduction in BMD. In parallel, bone metabolism may be assessed by bone formation and bone resorption markers (20). Bone markers have limited clinical utility.
Incidence and clinical picture of bone loss in ED About half of the adolescents with AN were found to have age-corrected BMD z-scores of less than −1 at one or more skeletal sites, and 11% were found to have z-scores of less than −2 (7). Unlike girls, adolescent boys with AN have
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greater involvement of cortical bone in the hip and femoral neck, rather than of the spine (21). A recent study described impaired hip geometry in adolescent boys with AN, associated with lower lean mass (22). Adolescents with AN have impaired bone formation, as evidenced by a reduction in surrogate markers of bone formation, such as serum osteocalcin (OC) and bonespecific alkaline phosphatase, when compared with healthy controls (6). Bone resorption markers were found to be comparable (6) in AN patients and healthy controls (6) or lower (12). Flat-panel volume CT demonstrated abnormal trabecular structure in adolescent girls with AN as compared with normal-weight control subjects, despite normal BMD (23). As the onset of AN in adolescence often parallels peak bone mass accrual, it may lead to permanent deficits in bone mineral accrual. Adolescent girls with AN who recovered demonstrate persistence of impaired bone health for over a year (24). Bone loss in adult AN patients is associated with increased markers of resorption, such as serum Nteleopeptide (NTX) and urinary deoxypyridinoline (DPD), and decreased or normal markers of bone formation, such as serum OC (25). Osteopenia with decreased BMD is described in up to 92% of young adults with AN, and osteoporosis occurs in 38–50% (5). There is paucity of data on men with ED especially regarding bone health. Fewer men than women with AN have osteopenia (occurring in 36%) or osteoporosis (occurring in 26%), yet those have been shown to be more severe (26,27). This difference in severity may be related to testosterone’s effect on bone and body composition. Testosterone has both anabolic and anti-resorptive effects (via aromatization to E2) on both trabecular and cortical bone (28). Testosterone also affects body composition; mainly lean body mass, which predicts BMD. Women with AN, whose onset occurred during adolescence have a lower bone mass than women with AN whose onset occurred during adulthood (16). It has been also reported in women with AN whose trabecular bone thickness and separation are both abnormal (29), and their bones are weaker than those of healthy controls (30). Abnormal bone structure and low BMD contribute to the outcome of bone loss in AN, causing increased fracture rate. Failure to achieve peak bone mass has been shown to cause stress fractures in adolescents and young adults with AN (31), as well as osteoporotic fractures later in life. An increased fracture rate has been reported in AN, and also in BN and ED-NOS many years after diagnosis (32). It is important to note that patients with BN and ED-NOS may have had previous AN (26,33). Women with AN who had amenorrhoea for more than 6 years have a sevenfold increase in the rate of fractures compared with healthy controls (32), and studies of © 2013 The Authors obesity reviews © 2013 International Association for the Study of Obesity
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long-term outcome in AN indicate that at 11.7 years follow-up, 44% of unrecovered women with AN are osteoporotic (34). In a longitudinal study in women with AN, the cumulative incidence of any fracture at 40 years after diagnosis was 57% (35). Normal-weight BN in women is associated with low BMD only when there is a past history of low weight, menstrual disturbances or amenorrhoea (26,33,36). The incidence of bone loss in BN is not known, because of the heterogeneity of this group of patients.
Pathogenesis of bone loss Several mechanisms underlie the low BMD in AN and including (i) low caloric intake and malnutrition with low serum insulin-like growth factor 1 (IGF1) levels; (ii) low body weight and small amounts of adipose tissue with low serum leptin and high peptide YY (PYY) levels; (iii) impaired thyroid function; (iv) hypogonadism with low serum sex steroid levels and (v) high circulating cortisol. Studies of bone loss focused on AN patients and less is known about other EDs.
Nutrition Nutritional markers, such as body mass index, fat and lean body mass and IGF1 correlate with low bone density in AN (6,7,20,21,24,37,38). Food restriction is the main contributor to bone loss and even acute fasting decreases bone formation (39). Food restriction when combined with excessive exercise in healthy women have adverse effects on bone formation and resorption (40). These two are additive effects, acting through different mechanisms. Weight gain is associated with the recovery of bone formation (24,41–43), as evidenced by the normalization of bone turnover markers – serum OC and bone-specific alkaline phosphatase, urinary NTX and DPD, and by increased serum IGF1 levels. However, normalization of bone resorption markers may be delayed and approach reference values in women with AN only when menses resumes, reflecting effect of oestrogen on bone resorption (41). Weight gain in AN is also associated with improved linear growth in adolescents at the time of pubertal growth spurt (42).
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Sex hormones Oestrogens are bone anti-resorptive agents because they inhibit osteoclast-mediated bone resorption by activating the RANK–RANKL system (48). Oestrogens stimulate osteoclast apoptosis and inhibit osteocyte apoptosis, while maintaining osteocyte viability (49). Accordingly, BMD decreases with increasing duration of amenorrhoea in women with AN (16,50). Moreover, the bone loss in women with AN is more severe than that found in normalweight women with functional hypothalamic amenorrhoea (50). Whereas weight gain in young women with AN can improve femoral neck BMD, the resumption of menses also improves spinal vertebrae BMD, and such findings demonstrate the effect of oestrogen on trabecular bone density (51). It has also been reported that low-weight eumenorrhoeic women with AN have higher body fat, leptin and IGF1 than amenorrhoeic women with the same weight. The eumenorrhoeic women had reduced hip BMD and less reduced spinal BMD in comparison with amenorrhoeic women (52), owing to higher oestradiol and hence better trabecular bone development in eumenorrhoeic subjects. Both women and men with AN are androgen deficient (21,53).Low levels of free testosterone, and in some studies, of dehydroepiandrosterone sulfate (DHEAS) are found in women with AN (54). Anabolic androgen deficiency contribute to bone loss in AN (55).
Hypercortisolism Patients with ED demonstrate dys-regulation of the hypothalamic–pituitary–adrenal axis with elevated serum cortisol levels (56–58). An excess of catabolic glucocorticoids in AN would theoretically contribute to bone loss by stimulating osteoclasts, inhibiting osteoblasts and negatively affecting mineral balance and the growth hormone (GH)–IGF1 axis (59). Indeed, the urinary free cortisol is inversely correlated with spinal vertebrae BMD in AN (16), and serum cortisol levels are inversely correlated with markers of bone formation (serum OC and c-terminal propeptide of type 1 procollagen) (57), and elevated serum cortisol is associated with the severity of bone loss (60).
Minerals and vitamins Minerals – such as calcium, phosphorus and magnesium and vitamin D (44) are nutrients that are essential for bone mineralization. Calcium metabolism may be abnormal in ED (45). Patients with AN are usually not calcium or vitamin D deficient (24,46). Bioavailability of vitamin D in AN patients is similar to normal-weighted controls, and vitamin D dosing may not differ (47). © 2013 The Authors obesity reviews © 2013 International Association for the Study of Obesity
GH–IGF1 axis The GH–IGF1 axis in ED is characterized by GH resistance and IGF1 deficiency (61–63). Starvation interferes with IGF1 secretion in the liver causing IGF1 deficiency. GH effects on linear growth of bones are IGF1 independent, so that height is normal, unless profound malnutrition occurs. The combination of GH resistance and IGF1 deficiency
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contributes to the low BMD in AN because of loss of the anabolic effect of GH on bone, which is mediated by IGF1. Low-serum IGF1 levels are associated with reduced serum OC levels, which are considered a specific marker of osteoblast function (64). In adolescent girls with AN, serum IGF1 levels, but not serum GH levels, correlate with lower BMD and bone formation markers (6,24,62,65).
leptin regulates bone remodelling processes through a direct stimulatory effect on osteoblast differentiation and bone formation, as well as an indirect inhibitory effect through the hypothalamus (ventromedial nucleus) in the sympathetic nervous system (84,85).
PYY
The hypothalamic–pituitary–thyroid axis plays a key role in skeletal development, accretion of peak bone mass and regulation of bone turnover (66,67). Thyroid hormones exert an anabolic effect on bone and regulate IGF1 signalling in growth plate cells (68,69). Typical changes occur in peripheral thyroid hormones in ED, with low-normal serum thyroid-stimulating hormone levels, normal or low serum thyroxine (T4) levels, and low serum triiodothyronine (T3) levels, while tissue thyroid or reverse T3 levels are elevated (70–72). Low serum T3 levels may interfere with bone metabolism in patients with AN (73).
PYY is an anorexigenic 36-amino acid peptide primarily produced in the L-cells of the colon in proportion to caloric intake and increases after food intake (86). PYY actions are mediated via activation of the Y-receptors. Y2 receptor knockout mice have increased BMD, by increased osteoblastic activity via hypothalamic signalling, and thus PYY may play a role in regulating bone mass (87). High serum PYY levels might contribute to reduced food intake and decreased bone formation in AN, as evidenced by an association with bone turnover markers (88). In patients with AN, high PYY predicts lower bone density (89). This inverse correlation between PYY levels and bone turnover markers is consistent with increased bone formation in rodents (87).
Oxytocin
Ghrelin
Oxytocin is a hypothalamic hormone that is stored and released from the posterior pituitary, and is important in parturition and lactation. Oxytocin is involved in energy homeostasis and has an anabolic effect on bone (74,75). Initial reports hint that low overnight oxytocin levels in AN are associated with low BMD and low fat mass (76,77), but the evidence is still preliminary.
Ghrelin is an orexigenic gastric peptide hormone and promotes osteoblastic proliferation and differentiation in vitro (86). Although patients with AN have elevated serum ghrelin levels (90,91), the results of few in vivo studies (92) have demonstrated a weak association between serum ghrelin levels and BMD in AN.
Thyroid hormones
Amylin Adiponectin Adiponectin is an adipocytokine that mediates insulin sensitivity and resistance through its effects on peroxisome proliferator-activated receptor gamma. Adiponectin high and low molecular weight forms may differ. Adiponectin serum levels have been reported to be elevated, unchanged, or low in AN (77–79). Serum adiponectin is an inverse predictor of bone density in adolescents with AN (77). High adiponectin serum levels may contribute to the low BMD in AN by increasing osteoclast activity (80).
Leptin Leptin is a fat-derived anorexigenic hormone (81). Serum leptin levels are typically decreased in AN because of the scarcity of adipose tissue, and lower basal and pulsatile secretions have been reported as compared with healthy subjects (82). Leptin has been shown to have both central and peripheral anabolic effects on bone (83) and low leptin levels are associated with low bone mass (77). Indeed,
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Amylin is a peptide hormone that is secreted by pancreatic β-cells. Amylin contributes to glycaemic control by slowing gastric emptying and promoting satiety. A recent study found that low serum amylin levels are associated with low BMD in women with AN (93).
Bone composition Bone marrow fat is increased in adolescent and adult women with AN (94,95), and is inversely correlated with BMD. Correlation was also found between bone marrow fat, preadipocyte factor 1 and BMD in women with AN (96). Further research is needed to understand the role of bone marrow fat (97) in the pathogenesis of bone loss in ED.
Treatment of bone loss in ED Studies of treatment modalities of bone loss in ED, especially in AN, have been focused on all the known © 2013 The Authors obesity reviews © 2013 International Association for the Study of Obesity
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mechanisms that contribute to this morbidity, as treating of one or more of the contributing factors have not improved bone health (98,99). Undernutrition, as the fundamental mechanism, has been mainly addressed. Spontaneous weight recovery in adolescents and women with AN is followed by improved bone health (51,100). Nutritional rehabilitation has an anabolic effect on bone metabolism and remains the mainstay of therapy for the osteopenia and osteoporosis of AN (24,41–43). As patients with AN are usually not calcium or vitamin D deficient, supplementation with calcium and vitamin D does not improve bone density in these patients (24,46) Amenorrhoea and oestrogen deficiency play an important role in bone health in ED. However, administration of oestrogen therapy alone does not improve bone density in adolescents or adults with AN (64,101–104) until their weight recovers (41). In fact, high-dose oestrogens, which are present in oral contraceptives (OCP) may further decrease the levels of IGF1, an important bone trophic hormone (105). In contrast to OCP, low doses of transdermal oestrogen that mimic early pubertal rise, increased BMD in adolescent girls with AN (106). As recently demonstrated, transdermal oestradiol may improve BMD in adolescent girls with AN, via inhibition of Pref-1 (107). Short-term replacement therapy with testosterone or DHEAS improves some bone turnover markers and BMD in women with AN (54,108). Recently, a study demonstrated that transdermal testosterone administration did not improve BMD, but increased lean body mass (109). DHEA administration appeared to improve hip and spinal BMD, but treatment effect was abolished after adjusting for weight gain (54). No clinical research has studied the effect of testosterone on BMD in hypogonadal AN male patients. Treatment targeted at the GH–IGF1 axis is also being studied. Supraphysiologic GH (110) did not increase IGF1 levels in women with AN. Weight recovery is associated with increased IGF1 levels (24). Combined IGF1–oestrogen treatment in adult women with AN increases spinal vertebrae BMD and serum levels of bone formation markers and decreases bone resorption markers (64). Thyroid replacement therapy in AN may lead to undesirable weight and muscle mass loss (11), and hasten the deterioration of bone loss. Thyroid hormone has no therapeutic effect on AN-related osteopenia. Physical activity, mainly weight-bearing exercise, is important for bone health in AN because it increases BMD (111). However, recommending physical activity to AN patients is controversial and should be discussed with each patient because excessive physical activity in combination with malnutrition can exacerbate weight loss (112,113). © 2013 The Authors obesity reviews © 2013 International Association for the Study of Obesity
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Bisphosphonates reduce bone turnover by decreasing osteoclastic bone resorption. Bisphosphonates have a long half-life and a strong affinity for bone, as demonstrated by their absorption into its matrix. Hence, they are not yet recommended for treating the low-turnover bone loss in AN. Among the few studies that have been conducted, some showed improved bone density in AN patients treated with risedronate (109,114,115), but BMD remained below normal for age. Cannabinoids are known to regulate eating behaviour within the central nervous system, and intestine and adipose tissue, interacting with melanocortins, leptin and ghrelin. The endocannabinoid system is underactive and the global type 1 cannabinoid receptor type 1 is up regulated in ED (116). The few studies in AN that have been conducted using cannabinoids failed to achieve the expected appetite stimulation and weight gain that can improve bone health (117–119).
Prognosis of bone loss in ED Bone loss is one of the debilitating long-term health sequelae of ED. In recovered women with ED, despite improved weight and resumption of menses, bone loss may persist and the low BMD remains irreversible (9,24,33,34,41,120,121). Good prognostic factors include early and sustained therapy, while bad prognosis is related to prolonged course and chronicity, extremely low body weight, and the early onset of disease in adolescence before or during the attainment of peak bone mass (9). Nutritional rehabilitation is critical for other therapies to have their optimal effect on bone health.
Conclusions Malnourishment places adolescents and young adults with EDs at considerable risk for bone loss or failure to attain appropriate peak bone mass. This is likely associated with an increased risk of bone pains and fractures even in remitted patients. Reduced BMD in AN patients is associated with reduced caloric and mineral intake and hormonal dysfunction, such as hypogonadotrophic hypogonadism, all leading to typical low bone turnover. Bone loss may not be completely reversible in recovered AN patients. Therefore there is a great importance for early diagnosis and treatment, in particular the establishment of appropriate target weight range, improved caloric intake and resumption of menses as essential to improved BMD. Other treatment modalities are also being studied.
Conflict of interest statement No conflict of interest was declared.
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