We demonstrate for the first time that physiological estrogen replacement increases spine and hip BMD in girls with AN in a randomized placebo-controlled study.
Adolescents with AN lack estrogen at a time when physiologic estrogen secretion is critical for optimizing bone accrual. Low BMD is common in AN (5
), and bone accrual is profoundly impaired (3
) resulting in lower than optimal peak bone mass, which may impair future bone health. Adolescence is a relatively narrow window in time in which to maximize bone accrual, and deficits incurred at this time may lead to permanent deficits in peak bone mass. In fact, adult women who develop AN during adolescence have lower BMD than those developing the condition in adult life, even when duration of amenorrhea is comparable (25
). Consequently, it is important to identify therapeutic strategies to improve bone accrual in AN during adolescence.
Consistent with previous studies, AN girls had lower spine and hip BMD and corresponding Z-scores, and lower levels of bone turnover markers than normal-weight controls. Importantly, these differences were observed despite higher calcium and vitamin D intake and higher 25(OH)D levels in AN, as reported in earlier studies (26
). AN is associated with a nutritionally acquired resistance to GH with low IGF-1 (7
), in contrast to high IGF-1 levels typically seen during puberty (27
). Another hormonal alteration in AN that may impact BMD and bone accrual is low leptin (28
). AN girls in this study had lower lean mass, estradiol, IGF-1 and leptin than controls.
Although recovery of weight and menses is the optimal strategy for improving bone accrual in AN, studies indicate that weight gain and menses recovery is not sufficient to normalize bone accrual (3
). Importantly, recovery can be difficult to attain and sustain, despite concentrated efforts of a multidisciplinary treatment team. In this study, only five girls in the placebo-treated group resumed regular menses.
Oral estrogen has been effectively used as replacement therapy in normal-weight hypogonadal adolescents (e.g. girls with Turner syndrome) for many years (22
). However, multiple studies show that oral estrogen (given as an oral contraceptive), is not effective in increasing BMD in AN (9
). Although the reason for lack of beneficial effects of oral estrogen on BMD in AN remains speculative, possibilities include non-physiologic dosing and/or suppression of systemic IGF-1 by oral estrogen, as in post-menopausal women (15
). This is particularly an issue in AN, a condition already associated with low IGF-1 (7
). Use of transdermal estrogen, which does not suppress IGF-1, should be a more effective replacement strategy (15
). In fact, a recent exploratory study in girls with Turner syndrome demonstrated that transdermal estrogen caused greater increases in BMD than did oral estrogen (31
). Additionally, small incremental doses of oral estrogen in early puberty (to mimic the early pubertal rise in estrogen) do not suppress IGF-1 (19
) and could be beneficial to bone.
Based on these data, we hypothesized that administration of replacement doses of transdermal estrogen to mature AN girls (BA≥15 years) and small incremental doses of oral estrogen to younger AN girls (with potential to grow based on BA<15 years), should be effective in increasing BMD. Our results support our hypothesis, and we show that physiological estrogen replacement over 18-months is effective in increasing spine and hip BMD Z-scores in AN girls 12–18 years. We also demonstrate that spine and hip BMD changes are lower in AN E− compared with normal-weight controls, whereas AN E+ do not differ from controls for bone accrual. Overall, AN E+ had greater increases in spine and hip BMD and corresponding Z-scores than AN E−. These results became even stronger after controlling for important covariates including baseline age, weight changes, height, years since menarche, duration of amenorrhea or duration since diagnosis.
Changes in IGF-1 levels did not differ in AN E+ versus AN E− consistent with our hypothesis that physiological estrogen replacement would not suppress IGF-1 levels. Levels of CTX, a marker of bone resorption, decreased in girls with AN randomized to estrogen, but the change was not significant when compared with girls with AN randomized to placebo, likely because levels of bone turnover markers were already very suppressed in girls with AN compared with normal-weight girls at baseline, as also reported in earlier studies (32
). A further suppression of bone resoprtion markers following estrogen administration may be difficult to appreciate in a maximally suppressed state of bone turnover. Levels of P1NP, a bone formation marker, did not differ between the groups.
Importantly, we found no difference in prospective changes in weight, lean or fat mass, or in leptin levels, in AN E+ versus AN E−, indicating that physiological estrogen replacement does not cause weight or body composition changes, which may be reassuring to AN girls and enhance compliance. Additionally, adverse events did not differ in AN E+ versus AN E−. Of note, attrition in our study population was high, but consistent with other treatment studies in adolescents with AN (33
In order to normalize and `catch-up' BMD over time, girls with AN may need to not only gain bone mass at a rate comparable to controls (as in this study), but may need to surpass controls. In order for complete catch-up, other hormonal alterations in AN may need to be addressed. For example, it may be important to raise IGF-1 through weight recovery or rhIGF-1 administration. One study in normal-weight women with hypothalamic amenorrhea reported that leptin replacement caused menses resumption in five of eight women, with associated increases in bone formation markers (35
). However, these women had subjective reductions in appetite and lost significant weight. Leptin replacement is thus not a good strategy for improving BMD in AN, in whom low leptin is likely adaptive.
Another possible strategy to increase BMD in AN is to use bisphosphonates. Our group has recently reported an improvement in BMD in adults with AN randomized to bisphosphonates (14
). However, caution is necessary in considering bisphosphonates in adolescents given their long half-life, and also because bisphosphonates are associated with marked reductions in bone turnover, already low in adolescents with AN. In one trial of 12-months of alendronate in AN girls, there was no improvement in spine BMD after controlling for weight changes, although some effect at the femoral neck was reported (13
Our study indicates that physiological estrogen replacement is effective in prospectively halting BMD reductions in AN girls, and may be considered a therapeutic option in girls refractory to weight and menstrual recovery despite ongoing multi-disciplinary therapy. Further studies are necessary to determine strategies that result in complete catch-up of BMD and normalization of peak bone mass acquisition in young women with AN.