Effects of Anorexia Nervosa on Bone Mass in Adolescents

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), The Hospital for Sick Children

This study is to determine the effects of anorexia nervosa on bone mass and hormone levels in adolescents. Whether administration of estrogen, a normal hormone present during puberty, can help maintain bone development in girls with anorexia nervosa will be determined.

Adolescence is a critical time for bone mineral accretion as between 60-90% of peak bone mass is established during this period, and peak bone mass is a major determinant of bone density and osteoporosis risk during adulthood. Anorexia nervosa (AN) is the third most common chronic illness among adolescent girls, with a prevalence of 0.2-1.0%. Therefore, AN occurs at a time during which patients are the most vulnerable to disruption of bone mineral accretion. Osteopenia is a major co-morbid complication of AN in 50-75% of female adolescents and adult women with this eating disorder. Women with the onset of the disorder during adolescence have more severe osteopenia than women with onset during adulthood. Little is known about the pathogenesis of osteopenia in this adolescent population and there are no established therapies. Improved understanding of bone mineral metabolism and factors which predict recovery of bone mineral accretion are critical in the development of therapeutic strategies to preserve and maximize bone mass in girls with the onset of AN during adolescence. Estrogen is known to be a critical factor in the development of peak bone mass. Although AN is associated with profound estrogen deficiency, there are no controlled studies investigating the effects of estrogen administration in this population. This research proposal will address critical unanswered questions regarding bone abnormalities in adolescents with anorexia nervosa. Defining changes in bone formation with weight recuperation and hormonal variables would provide insight into the factors essential for bone mineral accretion during adolescence, as well as those that predict recovery. Determination of dose-dependent estrogen effects in this population will be key in targeting interventions during the time of active disease, with the long-term goal of preserving peak bone mass accretion in this vulnerable group of patients. Data obtained from women with post-menopausal osteoporosis or from women with AN cannot be extrapolated to adolescent patients who are in an active period of bone growth and mineralization as well as remodeling. Given the increasing prevalence of AN and its profound consequences on bone health, these studies will provide much needed data to enable treatment strategies for this severe co-morbid disease.

Mature girls with anorexia nervosa (AN) (bone age 15 or greater): Transdermal estradiol (100 mcg) with cyclic progesterone (days 1-10 of each month). Immature girls with AN (bone age less than 15 years): Ethinyl estradiol (3.75 mcg daily for the first 6 months, 7.5 mcg daily for the next 6 months, and 11.25 mcg daily for the final 6 months of the study

Bone density at the spine (lumbar 1-4 vertebrae) was measured using dual energy x-ray absorptiometry (DXA) at baseline, 6 months, 12 months and 18 months. The primary outcome was the percent change in bone density at the spine from baseline to 18 months. Areal bone density is measured as g/cm2. The unit of measure for the percent change in bone density is 'percent' Percent change in bone density= [[Bone density at 18 months- Bone density at baseline)*100/Bone density at baseline]%

Bone density at the spine (lumbar 1-4 vertebrae) was measured using dual energy x-ray absorptiometry (DXA) at baseline, 6 months, 12 months and 18 months. The other primary outcome was the change in spine bone density Z-score from baseline to 18 months. The bone density Z-score is a standard deviation score that compares one's bone density to the mean for age and gender, and the Z-score, therefore, does not have any units. It is simply referred to as a Z-score. Change in bone density Z-score= [Bone density Z-score at 18 months- Bone density Z-score at baseline]

P1NP is a surrogate marker of bone formation that is measured in serum. P1NP levels were measured at baseline, 6, 12 and 18 months. A secondary outcome was the change in P1NP levels from baseline to 18 months: [P1NP at 18 months - P1NP at baseline). The unit is ng/ml

Inclusion Criteria: Females Only with Anorexia Nervosa and Amenorrhea 12-18 years Normal-weight girls 12-18 years with no past or present history of an eating disorder Exclusion Criteria: Diseases affecting bone metabolism (including untreated thyroid disease, premature ovarian failure, diabetes, cancer, pituitary, renal disease or bone fracture within the past six months) Use of prescription medications affecting bone metabolism within three months Suicidality Psychosis Substance abuse Hematocrit <30 % Potassium <3.0 mmol/L Glucose <50 mg/dl.

Misra M, Katzman D, Miller KK, Mendes N, Snelgrove D, Russell M, Goldstein MA, Ebrahimi S, Clauss L, Weigel T, Mickley D, Schoenfeld DA, Herzog DB, Klibanski A. Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa. J Bone Miner Res. 2011 Oct;26(10):2430-8. doi: 10.1002/jbmr.447.

Misra M, Katzman DK, Estella NM, Eddy KT, Weigel T, Goldstein MA, Miller KK, Klibanski A. Impact of physiologic estrogen replacement on anxiety symptoms, body shape perception, and eating attitudes in adolescent girls with anorexia nervosa: data from a randomized controlled trial. J Clin Psychiatry. 2013 Aug;74(8):e765-71. doi: 10.4088/JCP.13m08365.

Faje AT, Fazeli PK, Katzman DK, Miller KK, Breggia A, Rosen CJ, Mendes N, Klibanski A, Misra M. Sclerostin levels and bone turnover markers in adolescents with anorexia nervosa and healthy adolescent girls. Bone. 2012 Sep;51(3):474-9. doi: 10.1016/j.bone.2012.06.006. Epub 2012 Jun 15.