A high prevalence of hemodynamic, hematologic, endocrine, and bone density abnormalities are reported in this large group of community-dwelling adolescent girls with AN. Although a number of these consequences of AN are known to occur in hospitalized adolescents, the occurrence of these findings, including significant bradycardia, low blood pressure, and pubertal delay, in girls who are treated for AN on an outpatient basis is of concern and suggests the need for vigilant clinical monitoring, including that of endocrine and bone density parameters.

Anorexia nervosa (AN) is increasingly common in adolescent girls and occurs at a time of peak bone mass formation. Osteopenia is common in adolescent girls with AN, and in a cross-sectional study, we have reported low bone formation markers in such girls. To determine the impact of chronic undernutrition on bone mineral accrual in contrast to healthy controls, we prospectively measured bone mineral density (BMD) and body composition by dual energy x-ray absorptiometry, bone metabolism markers, and nutritional and hormonal status at baseline, 6 months, and 12 months in 19 adolescent girls with AN (mean +/- SEM, 15.4 +/- 0.4 yr) and 19 controls of comparable chronological and skeletal age. Overall, nutritional status in subjects with AN improved (mean percentage increase in body mass index from baseline, 9.2 +/- 1.9% and 15.2 +/- 2.6% at 6 and 12 months, respectively), with 11 subjects having recovered weight at 12 months. However, lumbar BMD at 12 months (AN, 0.88 +/- 0.02 g/cm(2), vs. control, 0.98 +/- 0.03 g/cm(2); P = 0.008) remained significantly reduced in AN compared with controls, even in recovered subjects. This was due to significant increases in lumbar BMD in controls vs. no change in AN subjects over the year (0.003 +/- 0.001 g/cm(2).month vs. 0.000 +/- 0.001 g/cm(2).month, respectively; P = 0.04). The most significant determinant of change in lumbar BMD at 12 months was change in lean body mass in both AN (r = 0.62; P = 0.008) and control (r = 0.80; P = 0.0006) groups. There were significant increases in surrogate markers of bone turnover in subjects with AN compared with controls as assessed by osteocalcin (AN, 0.9 +/- 0.4 micro g/liter.month, vs. control, -1.1 +/- 0.4 micro g/liter.month; P = 0.0007), bone-specific alkaline phosphatase (AN, 0.6 +/- 0.5 U/liter.month, vs. control, -1.5 +/- 0.4 U/liter.month; P = 0.002), deoxypyridinoline [AN, 0.1 +/- 0.1 nmol/mmol creatinine (cr).month, vs. control, -0.4 +/- 0.1 nmol/mmol cr.month; P = 0.005], and N-telopeptide (AN, 4 +/- 4 nmol BCE/mmol cr/month, vs. control, -9 +/- 4 nmol BCE/mmol cr/month; P = 0.01). Changes in IGF-I levels over the year were highly correlated with changes in bone turnover over the same period in AN (osteocalcin, r = 0.77; P = 0.001; deoxypyridinoline, r = 0.66; P = 0.01). A rise in N-telopeptide over the year was correlated with an increase in all bone mineral measures, including lumbar bone mineral content (r = 0.58; P = 0.03) and BMD (r = 0.53; P = 0.05) and total bone mineral content (r = 0.69; P = 0.006) and BMD (r = 0.69; P = 0.006) in the AN group. Therefore, despite recovery over 1 yr, poor bone mineral accrual persists in adolescent girls with AN in contrast to rapid bone accrual in healthy girls. Normalization of bone turnover markers occurs in association with nutritional recovery and an increase in the nutritionally dependent bone trophic factor IGF-I. A rise in bone turnover markers may be an early indicator of increase in BMD in recovering girls with AN.

Osteopenia is a frequent, often persistent, complication of anorexia nervosa (AN) in adolescent girls and occurs during a critical time in bone development. Little is known about bone metabolism in this patient population. Therefore, we measured bone density (BMD) and body composition by dual energy x-ray absorptiometry, nutritional status, bone turnover, calcium, and hormonal status in 19 adolescent girls with AN (mean Ϯ SEM, 16.0 Ϯ 0.4 yr) and 19 bone age-matched controls. The mean duration of AN was 19 Ϯ 5 months. Spinal (L1-L4) osteopenia was common in AN. Lumbar anterioposterior BMD was more than 1 SD below the mean in 42% of patients, and lateral spine BMD was more than 1 SD below in 63% of patients compared with controls. Lean body mass significantly predicted lumbar bone mineral content (r ϭ 0.75; P Ͻ 0.0001) in controls only. In AN, duration of illness was the most significant predictor of spinal BMD (lumbar: r ϭ Ϫ0.44; P ϭ 0.06; lateral: r ϭ Ϫ0.59; P ϭ 0.008). AN adolescents with mature BA (15 yr and greater) were hypogonadal [estradiol, 16.2 Ϯ 1.9 vs. 23.3 Ϯ 1.6 pg/mL (P ϭ 0.01); free testosterone, 0.70 Ϯ 0.17 vs. 1.36 Ϯ 0.14 pg/mL (P ϭ 0.01)] although dehydroepiandrosterone sulfate and urinary free cortisol levels did not differ. Leptin levels were reduced in AN (2.9 Ϯ 2.1 vs. 16.5 Ϯ 1.8 ng/mL; P Ͻ 0.0001). Insulinlike growth factor I (IGF-I) was reduced in AN to 50% of control levels (219 Ϯ 41 vs. 511 Ϯ 35 ng/mL; P Ͻ 0.0001) and correlated with all measures of nutritional status, particularly leptin (r ϭ 0.80; P Ͻ 0.0001). Surrogate markers of bone formation, serum osteocalcin (OC) and bone-specific alkaline phosphatase (BSAP), were significantly (P ϭ 0.02) reduced in AN vs. controls (OC, 39.1 Ϯ 6.4 vs. 59.2 Ϯ 5.2 ng/mL; BSAP, 27.9 Ϯ 4.0 vs. 40.6 Ϯ 3.4 U/L). The majority of the variation in bone formation in AN was due to IGF-I levels (OC: r 2 ϭ 0.72; P ϭ 0.002; BSAP: r 2 ϭ 0.53; P ϭ 0.01) in stepwise regression analyses. Bone resorption was comparable in patients and controls. These data demonstrate that bone formation is reduced and uncoupled to bone resorption in mature adolescents with AN in association with low bone density. Lean body mass was a significant predictor of BMD in controls, but not AN patients. The major correlate of bone formation in AN was the nutritionally dependent bone trophic factor, IGF-I. Reduced IGF-I during the critical period of bone mineral accumulation may be an important factor in the development of osteopenia in adolescents with AN.

Despite outpatient follow-up, community-dwelling girls with AN continue to have lower fat and higher fiber intakes than do healthy adolescents, which results in lower calorie intakes. Nutritionally related hormones are associated with specific nutrient intakes.