Estrogen Replacement and Bone Density in Teens with AN

Patients may need to reach BMD levels above those of their healthy peers.

Reprinted from Eating Disorders Review
November/December 2011 Volume 22, Number 6
©2011 Gürze Books

Unfortunately, the onset of anorexia nervosa (AN) often occurs when normal bone accrual is underway. This normal accrual of bone during adolescence is essential to optimize peak bone mass, which affects the risk of fractures later in life. Could estrogen replacement in physiologic doses that mimic puberty preserve bone mineral density (BMD) in teens with AN?

Yes, say a team of researchers from Massachusetts General Hospital and Harvard Medical School. As recently reported by Madhusmita Misra, MD, MPH, her group showed for the first time that controlled physiologic estradiol replacement increased spine and hip BMD in a group of girls with AN (J Bone and Mineral Res 2011; 26:2430).

Dr. Misra and colleagues enrolled 110 girls with AN and 40 normal-weight controls 12 to 18 years of age and of similar maturity in an 18-month trial. Mature girls with a bone age of at least 15 years (n=96) were randomized to receive 100 mcg of 17-beta estradiol with cyclic progesterone in transdermal patches applied twice weekly or placebo for 18 months. Immature girls with a bone age less than 15 years (n=14) were randomized to incremental low-dose oral ethinyl estradiol (3.75 mcg daily for from 0 to 6 months, then 7.5 mcg from 6 to 12 months, then 11.25 mcg from 12 to 18 months, to mimic pubertal estrogen increase), or to placebo for 18 months. At 18 months, all the girls underwent dual-energy x-ray absorptiometry (DXA) to measure BMD.

Girls with AN who received estrogen had greater increases in BMD-Z scores at the spine and hip than did girls with AN who received the placebo. BMD changes were predicted inversely by baseline age and positively by weight changes. In addition, BMD changes were predicted inversely by height and years since menarche. After controlling for baseline height, age, years since menarche, duration of amenorrhea, and weight changes, differences between the two groups became even greater. Adverse effects did not differ significantly between the treatment and control group.

The authors noted that oral estrogen has been used effectively as replacement therapy in normal-weight hypogonadal teens, such as girls with Turner syndrome. However, many studies have shown that oral estrogen given as an oral contraceptive does not increase BMD in girls with AN. The reason for this lack of efficacy with oral contraceptives is still speculative but may be due to nonphysiologic dosing and/or suppression of systemic insulin-like growth factor-1 (IGF-1) by oral estrogen, as occurs in postmenopausal women. Transdermal estrogen, which does not suppress IGF-1, should thus be a more effective approach to increasing BMD. IGF-1 levels did not differ in the two study groups, which was consistent with the authors’ hypothesis that physiologic estrogen replacement wouldn’t suppress IGF-1 levels. Levels of carboyx-terminal collagen crosslinks (CTX), a serum marker of bone resorption, decreased in girls with AN randomized to receive estrogen, but the change was not significantperhaps because levels of bone turnover makers were already very suppressed.

One area that still needs to be addressed, according to the authors, is that in order to normalize and “catch up” BMD over time, girls with AN may not only need to gain bone mass at a rate comparable to that of control girls (as in this study) but may need to surpass that of healthy girls. To do so, other hormonal alterations in AN may need to be addressed; examples would be raising IGF-1 though weight recovery or administration of recombinant human IGF-1. Another strategy might be to use bisphosphonates; however, the authors caution that these products have a long half-life and are associated with marked reductions in bone turnover, which is already reduced in teenagers with AN.

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