The effects of anorexia nervosa on bone metabolism in female adolescents.

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 +/- SEM, 16.0+/-0.4 yr) and 19 bone age-matched controls. The mean duration of AN was 19+/-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 = 0.75; P < 0.0001) in controls only. In AN, duration of illness was the most significant predictor of spinal BMD (lumbar: r = -0.44; P = 0.06; lateral: r = -0.59; P = 0.008). AN adolescents with mature BA (15 yr and greater) were hypogonadal [estradiol, 16.2+/-1.9 vs. 23.3+/-1.6 pg/mL (P = 0.01); free testosterone, 0.70+/-0.17 vs. 1.36+/-0.14 pg/mL (P = 0.01)] although dehydroepiandrosterone sulfate and urinary free cortisol levels did not differ. Leptin levels were reduced in AN (2.9+/-2.1 vs. 16.5+/-1.8 ng/mL; P < 0.0001). Insulin-like growth factor I (IGF-I) was reduced in AN to 50% of control levels (219+/-41 vs. 511+/-35 ng/mL; P < 0.0001) and correlated with all measures of nutritional status, particularly leptin (r = 0.80; P < 0.0001). Surrogate markers of bone formation, serum osteocalcin (OC) and bone-specific alkaline phosphatase (BSAP), were significantly (P = 0.02) reduced in AN vs. controls (OC, 39.1+/-6.4 vs. 59.2+/-5.2 ng/mL; BSAP, 27.9+/-4.0 vs. 40.6+/-3.4 U/L). The majority of the variation in bone formation in AN was due to IGF-I levels (OC: r2 = 0.72; P = 0.002; BSAP: r2 = 0.53; P = 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.

Cell-cycle defect of DNA repair in progeria skin fibroblasts.

We examined the temporal regulation of DNA repair during synchronous cell proliferation in normal and progeroid human fibroblasts. Ultraviolet light-induced (254 nm, 20 J/m2) unscheduled DNA synthesis was measured at 4-h intervals after serum stimulation, for up to 32 h. Normal cells regulated DNA repair in a defined temporal sequence, showing a peak in the induction of DNA repair just before DNA synthesis. Progeroid skin fibroblasts failed to show an increase in nucleotide excision repair before scheduled DNA synthesis, but the background level of DNA repair was not significantly different from that in controls. Regulation of repair in progeroid human fibroblasts appeared similar, but not identical to that previously reported by Gupta and Sirover (1984b) for xeroderma pigmentosum complementation group C. Our results suggest that patients with Hutchinson-Gilford progeria may have a defect in DNA repair; the results offer nominal evidence that the average level of UV-induced DNA is decreased, and that individuals with this disease lack both the normal enhancement of DNA repair before scheduled DNA synthesis and the temporal control of DNA repair.