Objectives

1) To determine the impact of adolescent eating disordered (ED) behaviours on bone accrual and bone development. To determine the role of factors such as caloric restriction, delayed puberty, excessive exercise, gender in explaining the effect of ED behaviours on bone health in adolescence.

2) To investigate the long-term impact of ED on bone mass in perimenopausal women.

3) To inform the development of effective strategies to prevent long-term consequences on bone health in subjects with ED

Background

Eating disorders (ED) are chronic disorders and affect about 5-10% of the population (Hoek and Van Hoeken, 2003).

Adolescent ED and bone development: ED have a peak incidence in adolescence, a crucial time for physical and skeletal development. Pubertal years are the period in the life course when bone mass reaches its highest level. The level of bone mass attained at this age is a key determinant of long-term bone health and risk of osteoporotic fractures in later life (Ott, 1991).

Past research focusing on bone density in ED has shown that restrictive ED (such as anorexia nervosa (AN) and atypical anorexia nervosa/ Eating Disorder not otherwise specified-EDNOS) are associated with reduced bone mass. This is probably secondary to low weight, reduced fat mass and hormonal abnormalities secondary to poor nutrition (ref). Whilst recovery from the ED has been shown to lead to improvements in bone density, several studies show that bone density remains lower than in individuals who have not experienced an ED, particularly in cases where the ED onset was in adolescent years (Biller et al., 1989; Hartman et al., 2000; Wentz et al., 2007; Bolton et al., 2005).

Binge- type ED (such as bulimia nervosa and binge eating disorder) have been less well studied, and appear not to affect bone density to the same extent as restrictive ED, particularly if normal weight is maintained (Misra, 2008). However, higher fracture risk was also shown in these women compared to controls (Vestergaard et al., 2003).

Studies investigating bone density in adolescents with restrictive ED as measured by dual energy X-ray absorptiometry (DXA) have shown low bone density at the spine, hip and femoral neck (Misra, 2008); as well as reduced bone turnover. These effects are apparent in both girls and boys (Castro et al., 2002). Follow-up studies of adolescents have reported some improvement in bone density with nutritional restoration, mainly in areas of trabecular bone, such as the spine. Several studies, however, have shown fewer improvements in bone density at cortical sites despite recovery from the ED ((Herzog et al., 1993; Mika et. al, 2007). Given that the adolescent years provide a narrow window of opportunity in which to optimize bone mass accrual, disruption during these years might lead to permanent deficits.

Long-term bone health: Osteopenia, osteoporosis and higher fracture risk have all been shown as a short and long-term consequence of ED (Hartman et al., 2000; Ward et al., 1997; Vestergaard et al., 2003). The latter study showed a 2.5-fold increased risk of any fracture in patients with AN compared to general population controls, and a 5-fold increased risk of hip and spine fractures. As highlighted above there is evidence that ED affect long-term bone health, with little increase in mean bone density after weight recovery in adult women with AN (Rigotti et al., 1991; Hartman et al., 2000).

Gaps in the literature:Most studies in the field to date rely on small clinical samples, and are likely to represent more severely ill subjects attending in- or out-patient services and not be generalisable to all ED. Length of follow-up has often been limited to 1-2 years. Moreover, DXA provides an overall estimate of bone mass but does not directly measure aspects like cortical thickness and cross sectional area that determine overall bone strength. Techniques like peripheral quantitative computed tomography (pQCT) can provide detailed information about cortical bone geometry and strength, but only one study to date has used this method to study bone changes in adolescents with ED (Milos et al.,2007). In light of our recent finding that fat mass is an important positive determinant of cortical bone size and thickness (Sayers & Tobias, 2009), we are particularly interested in examining whether adolescent ED predicts weaker cortical bones due to reduced fat mass.

To our knowledge there are: (1) no studies on a general population sample of adolescents able to link temporal relationships between ED behaviours and bone development; and (2) very few long-term studies on bone health in relation to ED. Both would allow a clear identification of causal biological mechanisms, and take into account the role of confounders. The current lack of evidence impacts on available prevention and early treatment for patients with ED.

This study is unique in that data have already been collected prospectively and independently on bone density and ED behaviours in about 6,000 adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC); and on lifetime ED history and bone density in 5,500 mothers from the same cohort. This longitudinal prospective study will allow: (1) determining precise temporal relationships between predictor (ED behaviours) and outcome (bone density and cortical bone size and thickneness); (2) generalisability of findings (general population sample); (3) focusing on causal biological mechanism taking into account the role of confounders (thanks to the wealth of data available in ALSPAC).

Methodology

Theoretical/conceptual framework: This is a longitudinal study which will rely on data prospectively collected as part of the ALSPAC study. The ALSPAC study is a longitudinal prospective cohort of 14,000 mothers and their children. Women were enrolled in the study in pregnancy. Children have been followed up at regular intervals from birth up to age 18.

Research questions:do adolescent eating disordered behaviours (not only clinical ED) negatively affect bone accrual and bone development during puberty, including children with subclinical disorders not currently viewed as being at risk? Do reductions in fat mass contribute to these deleterious effects of ED behaviours on bone development particularly those on cortical bone? This being the case, are reductions in fat mass in the context of ED behaviours particularly harmful, reflecting the fact that they are achieved by dietary restriction as opposed to by increased physical activity? What is the long-term impact of eating disorders (ED) on bone mass? Can effective strategies be developed to prevent long-term consequences on bone mass in subjects with ED?

Methods:

Outcomes:

1) Total DXA scans have been performed on the children/adolescents at ages: 11.5 (n = 7159), age 13.5 (n = 6147), age 15.5 (n= 5509) and age 17.5 (approximately 4000). In addition, hip DXA scans have been performed at age 13.5 and 17.5, and pQCT scans of the mid tibia at 15.5 and 17.5. Standard DXA and pQCT parameters related to bone development have been derived and will serve as the main outcomes. Data on fractures has also been collected at regular intervals.

2) Total body and hip DEXA scans have been performed on the ALSPAC mothers between ages 42 and 47.

Women will be sent a 1-page questionnaire on osteoporosis and fractures.

Predictors:

1) Data on adolescent ED behaviours have also been collected at age 13, 14 and 16, on 8,000 adolescents (as part of an NIHR clinician scientist award).

2) Data have been collected on maternal lifetime ED behaviours (at maternal age 46-47). We have interviewed all women screening positive for lifetime ED for complete details on ED lifetime history (n=900) and a random sample of screen negative women (n=400) (as part of an NIHR clinician scientist award).

Other explanatory variables (mediators and/or confounders):

1)- Data are also available on pubertal timing and anthropometric measures at all the above ages on ~8,000 adolescents.

-Total body fat and lean mass as measured by total body DXA

-Physical activity as measured in the children by accelerometry at multiple time points

-Detailed information on diet in the children using a combination of diet diaries and food frequency questionnaires

2) Data on maternal menstrual history and Hormone replacement therapy (HRT) have also been collected.

-Extensive information on socio economic status

Analyses: Univariate and multivariate logistic models will be sued to determine the effect of relevant predictors on outcomes. Longitudinal statistic modelling will be used for longitudinal repeated data and to model hypothesised relationships.

Timeplan:

Oct 2011-March 2012: data entry, data clearing and extraction of data specific for this study. Sending out additional questionnaires to mothers.

March 2012-October 2012: initial analyses of data relating to adolescents. Receipt of all maternal additional questionnaires

October 2013-March 2013: data entry of maternal additional questionnaires. Write up of findings in relation to adolescents. Initial analyses of data on mothers.

March 2013-October 2013: complete all analyses, write up and dissemination.