Key Findings

  • Physiologic estrogen replacement increases spine and hipbone mass density in girls with anorexia nervosa.

  • These differences were observed despite higher calcium and vitamin D intake and higher 25(OH)D levels in girls with anorexia nervosa, as reported in an earlier study.

  • Small, incremental doses of oral estrogen in early puberty (to mimic the early pubertal rise in estrogen) do not suppress IGF-1 and could be beneficial to bone.

Anorexia nervosa is prevalent in adolescents, who are in a critical period for bone mineral density (BMD) development. The condition, which is characterized by low weight, nutritional deficiencies and the associated hormonal aberrations, is often linked to diminished bone mineral growth. An effective strategy to improve the effects of anorexia nervosa on BMD had yet to be identified, until now.

This study, published in the Journal of Bone and Mineral Research and conducted by a team of doctors led by Madhusmita Misra, MD, MPH Division Chief, of Pediatric Endocrinology at Massachusetts General Hospital for Children, demonstrated for the first time an effective method of increasing bone mineral density in girls with anorexia nervosa.

The Call for a Physiological Approach

About 0.2 to 1% of adolescent girls suffer from anorexia nervosa, and of those, 50% have BMD scores of less than -1 at one or more bone sites (normal bone density is -1 or above). These girls continue to have low bone mass throughout their lives in comparison to normal-weight girls. In addition to weight and menstrual recovery, it is important to develop therapy to increase bone accrual while patients work toward recovery.

Since it has been proven that high estrogen doses given orally do not improve BMD, the researchers set out to study the impact of physiologic estrogen doses, given in a manner that mimics puberty, on BMD. In oral contraceptives, high estrogen doses suppress IGF-1, an important hormone for bone development. However, low oral estrogen doses that mimic early puberty increases in estrogen and transdermal (via patches on the skin) replacement doses of estrogen do not suppress IGF-1. These are both considered physiological approaches. The researchers hypothesized that physiologic estrogen administration would cause BMD measures to increase in anorexia nervosa girls.

The subjects in this study included 110 patients who suffered from anorexia nervosa and 40 normal-weight (control) patients. All subjects were girls, ages 12 to 18, of similar maturity. The subjects with anorexia nervosa were randomized and double blind given physiologic estrogen replacement or. Mature girls with anorexia nervosa were randomized to receive transdermal 17b-estradiol (100-mg patch applied twice weekly), while immature girls with anorexia nervosa were randomized to escalating doses of oral ethinyl estradiol (3.75 mg daily for the first 6 months, 7.5 mg daily for the second 6 months, and 11.25 mg daily for the last 6 months) or placebo for 18 months.

Normal-weight control girls were followed for 18 months without intervention at the same time points and per the same study protocol as randomized subjects with anorexia nervosa. The researchers then used dual-energy X-ray absorptiometry to assess BMD at the spine and hip and body composition at baseline and 6, 12, and 18 months.

A Step Toward Recovery

The results were promising. Girls with anorexia nervosa who received the transdermal estrogen treatment had greater increases in BMD Z-scores at the spine and hip than those who did not, even after controlling for baseline age and weight.

This demonstrated, for the first time, that physiologic estrogen replacement increases spine and hip BMD in girls with anorexia nervosa. Importantly, these differences were observed despite higher calcium and vitamin D intake and higher 25(OH)D levels in girls with anorexia nervosa, as reported in an earlier study.

These results were in line with a recent exploratory study in girls with Turner syndrome that demonstrated that transdermal estrogen caused greater increases in BMD than did oral estrogen. They also proved that small, incremental doses of oral estrogen in early puberty (to mimic the early pubertal rise in estrogen) do not suppress IGF-1and could be beneficial to bone.

This is an important factor to consider when designing treatment regimes for girls recovering from anorexia nervosa. In order to normalize BMD over time, girls with anorexia nervosa not only may need to gain bone mass at a rate comparable with control girls but also may need to surpass control girls. In order for complete catch-up, other hormonal alterations in anorexia nervosa may need to be addressed as well. Further studies are necessary to determine these strategies to normalize peak bone mass on these young women’s path to recovery.

_____________________________________________________________________________

Citation: Misra M, Katzman DK, Miller KK, Mendes N, Snelgrove D, Russell M, Goldstein MA, Ebrahimi S, Clauss L, Weigel T, Mickley D, Schoenfeld D, Herzog DB, Klibanski A. Physiologic Estrogen Replacement Increases Bone Density in Adolescent Girls with Anorexia Nervosa. J Bone Miner Res 2011;26:2430-8

Funding: This work was supported by National Institutes of Health Grants R01 DK 062249, K23 RR018851, M01-RR-01066, and 1 UL1 RR025758-03.