Impact on bone of an estrogen receptor-alpha gene loss of function mutation.

CONTEXT: The kindred described is the only known instance of a germ line loss of function mutation of estrogen receptor (ER)-alpha. OBJECTIVE: Our objective was to assess the impact of a loss of function mutation in the ER-alpha gene on histomorphometry, bone volumetric density, bone geometry and skeletal growth, and ER-alpha heterozygosity on spine density and adult height in an extended pedigree. DESIGN AND PARTICIPANTS: A longitudinal follow-up of the propositus with homozygous loss of function mutation of ER-alpha and single contact evaluation of the kindred were performed. MAIN OUTCOME MEASURES: Iliac crest bone biopsy and peripheral quantitative computed tomography of propositus with serial measures of areal spine bone mineral density (aBMD) by dual-energy x-ray absorptiometry and bone age were performed. Members of pedigree were evaluated for ER-alpha mutation carrier status and spine aBMD. RESULTS: Bone biopsy revealed marked osteopenia (cortex: 641 microm), low trabecular volume (10.6%), decreased thickness (76.2 microm), normal trabecular number, and low activation frequency (0.099/yr). Radial periosteal circumference was similar, endosteal circumference larger, and trabecular and cortical volumetric bone mineral density markedly lower (158 and 1092 mg/cm(3), respectively) than controls. Spine aBMD at age 28.5 yr (0.745 g/cm(2)) decreased to 0.684 g/cm(2) (Z score -3.85) in 3.5 yr. Bone age advanced from 15-17.5 yr. Kindred analysis revealed that gene carriers had spine aBMD Z scores less than zero (P = 0.003), but carriers and nonmutant members were similar (-0.84 +/- 0.26 vs. -0.64 +/- 0.16). CONCLUSION: Homozygous ER-alpha disruption markedly affects bone growth, mineral content, and structure but not periosteal circumference. ER-alpha heterozygosity appears to not impair spine aBMD.

Predictors of weight-loss response with glucagon-like peptide-1 receptor agonist treatment among adolescents with severe obesity.

In two previous, separate clinical trials, we demonstrated significant reductions in body mass index (BMI) with exenatide in adolescents with severe obesity. In the present study, we pooled data from these near identical trials to evaluate factors that may predict BMI reduction at 3 months. Data from 32 patients (mean age 14.3 ± 2.2 years; 69% female; mean BMI 39.8 ± 5.8 kg m(-2)) were included. Exenatide treatment consisted of 5 mcg twice daily for 1 month, followed by an increase to 10 mcg twice daily for 2 additional months. Predictor variables included baseline BMI, BMI percent change at 1 month, incidence of nausea or vomiting and baseline appetite and satiety measures. Treatment effects of percent change in BMI from baseline were estimated within predictor subgroups using generalized estimating equations with exchangeable working correlation and robust variance estimation for confidence intervals and P-values to account for paired observations. The pooled data treatment effect on absolute BMI at 3 months was -3.42% (95% confidence interval: -5.41%, -1.42%) compared to placebo. Within treated participants, appetite at baseline (treatment effect in high [-4.28%] vs. low [1.02%], P = 0.028) and sex (treatment effect in female [-4.78%] vs. male [0.76%], P = 0.007) were significant predictors of change in BMI at 3 months. Baseline BMI, BMI percent change at 1 month, age, incidence of nausea, vomiting, or other gastrointestinal symptoms and satiety scores did not predict 3-month responses. Sex and measures of appetite may serve as useful predictors of glucagon-like peptide-1 receptor agonist treatment response among adolescents with severe obesity.