Anorexia nervosa (AN) is prevalent in adolescents and is associated with decreased bone
mineral accrual at a time critical for optimizing bone mass. Low BMD in AN is a consequence of nutritional and hormonal alterations, including
hypogonadism and low
estradiol levels. Effective therapeutic strategies to improve BMD in adolescents with AN have not been identified. Specifically, high
estrogen doses given as an
oral contraceptive do not improve BMD. The impact of physiologic
estrogen doses that mimic puberty on BMD has not been examined. We enrolled 110 girls with AN and 40 normal-weight controls 12 to 18 years of age of similar maturity. Subjects were studied for 18 months. Mature girls with AN (bone age [BA] ≥15 years, n = 96) were randomized to 100 µg of 17β-estradiol (with cyclic
progesterone) or placebo transdermally for 18 months. Immature girls with AN (BA < 15 years, n = 14) were randomized to incremental low-dose oral
ethinyl-estradiol (3.75 µg daily from 0 to 6 months, 7.5 µg from 6 to 12 months, 11.25 µg from 12 to 18 months) to mimic pubertal
estrogen increases or placebo for 18 months. All BMD measures assessed by dual-energy X-ray absorptiometry (DXA) were lower in girls with AN than in control girls. At baseline, girls with AN randomized to
estrogen (AN E + ) did not differ from those randomized to placebo (AN E-) for age, maturity, height, BMI,
amenorrhea duration, and BMD parameters. Spine and hip BMD Z-scores increased over time in the AN E+ compared with the AN E- group, even after controlling for baseline age and weight. It is concluded that physiologic
estradiol replacement increases spine and hip BMD in girls with AN.