AN is a psychiatric disease that affects young women of reproductive age disproportionately and is complicated by severe bone loss (1
), which we demonstrate in this study to be rapid, at an average annual rate of about 2.5%. Because there are no effective therapies available, it is particularly important to identify endogenous factors that contribute to skeletal gain during recovery from AN. Although we and other groups have investigated mechanisms of bone loss in women with AN, there are few published data regarding the determinants of skeletal recovery in this population. Our data suggest that resumption of menstrual function is a critical factor in recovery of lumbar spine bone density, independent of weight gain. In contrast, weight gain is an important determinant of hip bone density recovery. Importantly, our data also suggest that recovery of lean body mass may be a particularly important component of weight gain to achieve skeletal recovery in women who are recovering from AN.
We have previously established that AN is complicated by osteopenia in 92% and osteoporosis in 38% of women with AN, with fewer than 15% of women having normal bone density at all skeletal sites (1
). However, the rate of bone loss in women with active AN has not been well characterized. In this study, we demonstrate rapid bone loss, at an average annual rate of about 2.5%, in women with active AN. These data provide additional evidence supporting the importance of early intervention for women with AN, a psychiatric disease with serious medical consequences, including bone loss.
Data regarding skeletal recovery during weight recovery in women with AN are scant, and most published papers report fewer than 30 cases of women with AN (9
). Some of these reports suggest that weight recovery results in increases in BMD, whereas others are not able to demonstrate increases in bone density in women recovering from AN. Most studies suggest that residual bone loss is common after recovery from AN. The two largest studies, each of 51 women with AN, demonstrated increases in BMD in weight-recovering patients, although not to normal, even after several years of weight recovery (15
). One of these studies, by Hotta et al.
), reported that BMD did not increase in the Japanese cohort studied, unless body mass index was greater than 16.4 ± 0.3 kg/m2
. To our knowledge, no published studies have investigated the differential effects of weight increase, menstrual function resumption, and changes in body composition on skeletal recovery.
The data reported in this manuscript regarding determinants of skeletal recovery in women with AN are consistent with our previous data regarding determinants of bone loss in this population. We have demonstrated that duration of amenorrhea (1
) and weight (1
) are both important determinants of BMD. When we specifically investigated body composition, lean body mass has been shown to be a particularly important determinant of BMD (18
). Therefore, interventions aimed at increasing muscle as part of a program designed to increase weight may also be effective at increasing BMD in women with AN. We have also demonstrated that endocrine predictors of bone loss in AN include IGF-I (17
) and testosterone (20
). Further studies to determine the role of these endocrine factors, if any, in skeletal recovery in women recovering from AN are merited.
Although in the current study weight improvement resulted in an increased mean hip BMD, compared with non-weight gainers among women not receiving oral contraceptives, weight gainers who were receiving oral contraceptives demonstrated no such skeletal gains. It is important to note that this study was not a randomized, placebo-controlled study and that the results could have been influenced by factors leading to the prescribing of oral contraceptives for some women and not others. Therefore, our data cannot prove or disprove that oral contraceptives inhibit skeletal recovery. They are consistent with the results of our published randomized trials demonstrating no effect of exogenous estrogens to increase BMD in women with AN (21
). It could be hypothesized that the effect of oral contraceptives to decrease both endogenous IGF-I and testosterone might play a role in preventing an increase in BMD. We did not have sufficient blood samples or numbers of patients to test this hypothesis. Our results are also consistent with those of Polatti et al.
), who compared change in BMD over 5 yr among 200 healthy women, aged 19–22 yr, who received either oral contraceptive pills (OCP) containing 20 μ
g of ethinyl estradiol or no treatment. Women who received no treatment demonstrated a 7.8% increase in BMD over the 5-yr period, in contrast to women in the OCP group, who did not experience any increase in BMD at all. The authors postulated that the lack of BMD increase was attributable to suppression of endogenous gonadal steroids plus an insufficient replacement dose for achievement of peak bone mass. In contrast, studies using higher-dose OCPs (containing 30–40 μ
g of ethinyl estradiol) in healthy women (24
) and women with hypothalamic amenorrhea (28
) have not demonstrated detrimental effects on BMD, and some have even reported increases in BMD. Of note, none of these studies was placebo controlled.
Our data demonstrate that resumption of menstrual function may be particularly important for improvement of spinal bone mass. Although most women who resumed menses had also experienced an increase in weight, we demonstrated an independent effect of resumption of menstrual function on spinal bone density improvement. Spinal bone loss is more prevalent than hip bone loss in AN (1
). Our findings are consistent with the known effects of estrogens on bone and may also reflect increases in other gonadal steroids, including testosterone, in ovulating women. Our two previous randomized trials, which do not demonstrate an effect of estrogen to improve BMD in AN (21
), do not contradict these findings. Exogenous estrogens may exert different effects on bone in women of reproductive age with undernutrition from endogenous estrogens by decreasing endogenous IGF-I and testosterone levels or from exogenous gonadal steroids in postmenopausal women. An alternative explanation for our findings might be that resumption of menses reflects nutritional recovery, whereas oral contraceptive use clearly does not. However, it is important to note that effects of resumption of menstrual function to increase spine BMD remained significant after controlling for increases in weight. Therefore, a hormonal effect independent of nutritional recovery is likely.
Limitations of this study include its relatively small numbers, relatively arbitrary definitions of recovery, use of two-dimensional aereal BMDs, and lack of long-term menstrual history information. It is important to acknowledge that criteria used for recovery in this manuscript, although standard, are arbitrary. Therefore, in addition to the dichotomous statistical analysis, we also performed univariate analyses and ANCOVAs, with percent weight change as a continuous variable, to investigate the robustness of our analyses. Such analyses yielded similar results to those using recovery cutoffs. Specifically, changes in weight predicted changes in hip, although not spine, BMD. Although we elicited the number of months since the last menstrual period, we did not have detailed information about menstrual function in the years before the bone density measurement. We therefore could not determine whether there was a dose-response effect of number of menstrual cycles, or more importantly ovulations, which would require hormone data, on increases in BMD. Another limitation of the study was the use of aereal BMDs, which are influenced by bone size and other factors. Further studies to confirm our findings and determine the mechanisms (endocrine and other) of skeletal recovery in recovering women with AN will be important.
In summary, resumption of menstrual function was an important predictor of spinal skeletal recovery, whereas weight improvement was an important predictor of hip BMD recovery. Whether the importance of menstrual function resumption primarily reflects nutritional recovery or the direct effects of endogenous gonadal steroids on bone mass cannot be determined from this study. However, our data clearly demonstrate an effect on bone density independent of weight gain. Lean body mass appears to be the most important component of weight gain for skeletal recovery. Therefore, improvements in weight, with increases in lean body mass a critical component, and reproductive function are both needed for skeletal recovery in women with AN.