20 ()%15 D M eB 10 n i p s n ieg 5 n a h C 0 −5 10 ) (% 5 D M B g len 0 i e g n a h C−5 −10 Journal of Osteoporosis 5 r = 0.48, P < 0.02 r = 0.43, P < 0.05 1000 1200 1400 1600 1800 Resting metabolic rate (kcal/d) at 90% IBW 2000 1000 1200 1400 1600 1800 Resting metabolic rate (kcal/d) at 90% IBW 2000 Figure 1: Correlation between resting metabolic rate of patients at 90% IBW and % change in spine BMD. Each circle represents the data point of a patient. Figure 2: Correlation between resting metabolic rate of patients at 90% IBW and % change in leg BMD. Each circle represents the data point of a patient. controls, indicating near recovery of bone mass and gonadal function. Interestingly, no signiﬁcant correlation between REE and changes in BMD was found in this group. 4. Discussion The etiology of the increase in REE with refeeding in AN patients has been the subject of much debate. This is the ﬁrst report showing signiﬁcant correlations between REE and changes in BMD with nutritional rehabilitation. This correlation is apparent in only women who have not yet re- gained menses, suggesting a physiologic event with bone as a possible metabolic sink or energy drain. Previous studies have not attempted to correlate REE and FFMI in AN patients although REE was disproportionately elevated compared to increases in lean body mass [5]. This is the ﬁrst study to show no correlation between REE and height-normalized FFM indices in AN patients despite high correlation in the normal population [17]. The absence of correlation found in our study along with the dispropor- tionate REE elevations previously reported suggest that the increase in REE with refeeding is not accounted for by lean body mass but by another physiologic system undergoing marked energy utilization. During refeeding, the signiﬁcant correlations between REE and changes in BMD along with the elevated osteocalcin and the increase in IGF-1 to induce bone collagen formation suggest bone recovery from the osteopenic or osteoporotic state as a source of the increased REE. The observed correla- tion of REE with change in BMD in amenorrheic subjects with low BMDs and the lack of correlation in the group with resumed menses and near-normal BMDs suggest that the latter group no longer needs to channel the energy towards bone. Indeed, whereas the group who remained amenorrheic continued to exhibit elevated urine NTX, the group who regained menses demonstrated normalization of urine NTX, indicating a return to the normal state of bone resorption. The recent discovery of bone remodeling as a physiologic phenomenon requiring a large amount of energy but serving an evolutionary advantage [7] further supports the notion of bone as a metabolic sink, for the utilization of REE for bone recovery would serve a survival purpose. Indeed, the endocrine manifestations of AN typ- ically result from mechanisms designed to preserve energy [18]. Many studies relate osteopenia and osteoporosis in AN to nutrition, but observations linking resumption of menses to bone recovery [19–21] may be explained by the notion that only after substantial bone recovery occurs are suﬃcient energy stores available for gonadal recovery. The etiology of bone loss in AN is multifactorial, and nutritional factors, particularly IGF-1, have been recognized to likely have an important role [22]. The dramatic increases in REE seen with nutritional rehabilitation and weight gain appear to be related to bone recovery. Indeed, a comprehensive study in AN following bone indices showed the powerful anabolic eﬀect of nutritional rehabilitation on bone [10]. However, in this study, the authors state that menstrual resumption was required to suppress bone resorption and allow maximal appropriate bone recovery. Yet a quantitative eﬀect of re- gained menses on bone mass remains unclear. In our study, the group who regained menses had near-normal BMDs and no correlation between REE and changes in BMD, suggesting that the majority of bone recovery had already occurred such that resumption of menses would not lead to further signiﬁcant change. Instead of favorably predicting BMD recovery, menstrual return may indicate adequate re- placement of energy stores. One potential regulator linking disordered eating, amen- orrhea, and bone is leptin, a fat cell hormone disproportion- ately lowered by fasting. Leptin thresholds have been asso- ciated with increased gonadotropins [2] and leptin adminis- tration with resumption of ovulation in hypothalamic amen- orrheic women [23]. Recently, leptin receptors were also