Skeletal Effects of Sleeve Gastrectomy in Adolescents and Young Adults: A 2-Year Longitudinal Study.

CONTEXT: Vertical sleeve gastrectomy (VSG) is an increasingly common tool to achieve weight loss and improve metabolic health in adolescents and young adults with obesity, although it may adversely affect bone health. OBJECTIVE: This work aimed to evaluate the effect of VSG on bone health in youth. METHODS: An observational 2-year study was conducted at a tertiary care center of 66 patients aged 13 to 24 years with moderate-to-severe obesity meeting criteria for VSG. The patients underwent VSG (n = 30) or nonsurgical (n = 36) management per the decision of patient and clinical team. Main outcome measures included dual-energy x-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HRpQCT) measures of bone mineral density (BMD), geometry, and microarchitecture. RESULTS: VSG patients achieved 25.3 ± 2.0% weight loss at 2 years (P < .001) while control subjects gained 4.0 ± 2.0% (P = .026). Total hip BMD declined 8.5 ± 1.0% following VSG compared with 0.1 ± 1.0% gain in controls (P < .001), with similar results at the femoral neck (P < .001). Total volumetric BMD (vBMD) decreased both at the distal radius and tibia following VSG (P < .001) driven primarily by trabecular vBMD loss (P < .001). Two-year changes in cortical vBMD did not differ between groups, though cortical porosity decreased following VSG both at the radius and tibia (P = .048 and P < .001). Cortical thickness increased in controls but not in VSG (P = .022 and P = .002 for between-group comparisons at the radius and tibia, respectively). Following VSG, estimated failure load decreased at the radius and did not demonstrate the physiologic increases at the tibia observed in controls. CONCLUSION: VSG leads to progressive changes in bone health over 2 years, and may lead to increased skeletal fragility in adolescents and young adults.

Impact of sleeve gastrectomy on bone outcomes in adolescents vs. adults with obesity.

BACKGROUND: Sleeve gastrectomy (SG) is the most common metabolic and bariatric surgery (MBS) procedure in adolescents and adults. Only few studies have assessed bone outcomes following SG and it is unknown whether skeletal changes differ by age group. Recent studies have identified marrow adipose tissue (MAT) as a novel biomarker for bone quality with studies in adults showing high MAT in those with visceral adiposity and a reciprocal increase in MAT with bone loss. OBJECTIVE: To determine the impact of SG on volumetric BMD (vBMD) and MAT in adolescents and adults with obesity. We hypothesized that SG would lead to a decrease in vBMD and increase in MAT but that these changes would be less pronounced in adolescents compared to adults. MATERIALS AND METHODS: The study was IRB-approved and HIPAA-compliant. Written informed consent/assent was obtained. We examined 10 adolescents (mean age 17.8 ± 2.5 years, mean BMI 43.5 ± 5.6 kg/m2) and 10 sex, race, and BMI-matched adults (mean age 49.5 ± 13.6 years, mean BMI 43.7 ± 5.9 kg/m2), before and 12 months after SG. At baseline and 12 months, subjects underwent quantitative CT of the lumbar spine (L1-L2) to assess trabecular vBMD, single voxel proton MR spectroscopy at 3 T (PRESS pulse sequence without water suppression) at L1-L2 to quantify MAT, and MRI of the abdomen to assess visceral (VAT) and subcutaneous adipose tissue (SAT). RESULTS: At baseline, adolescents had lower MAT (p = 0.0002) and higher vBMD (p = 0.050) compared to adults. Adolescents and adults lost 27.9 ± 6.5 vs. 25.0 ± 11.2% of body weight (p < 0.0001 for within group change), while there was no significant difference between groups (p = 0.455). There was a significant reduction in vBMD in adults (-3.9 ± 3.9%, p = 0.005) and a trend for a reduction in adolescents (-3.7 ± 7.5%, p = 0.119), with no significant difference between groups (p = 0.944). Lumbar MAT content increased in both adults and adolescents (p ≤ 0.034), while the difference was not significant between groups (p = 0.281). In adolescents and adults, 12-month percent change in weight and BMI was positively associated with % change in MAT (p ≤ 0.042). 12-month percent change in MAT was positively associated with 12-month % change in SAT in adolescents and 12-month percent change in VAT in adults (p ≤ 0.045). CONCLUSION: SG in adolescents and adults with severe obesity is associated with a reduction in lumbar vBMD and an increase in lumbar MAT, although the reduction in adolescents did not reach statistical significance, with no significant differences in these endpoints between groups. Our results suggest detrimental effects of bariatric surgery on bone for patients across the life span.

Effect of Transdermal Estradiol and Insulin-like Growth Factor-1 on Bone Endpoints of Young Women With Anorexia Nervosa.

CONTEXT: Anorexia nervosa (AN) is prevalent in adolescent girls and is associated with bone impairment driven by hormonal alterations in nutritional deficiency. OBJECTIVE: To assess the impact of estrogen replacement with and without recombinant human insulin-like growth factor-1 (rhIGF-1) administration on bone outcomes. DESIGN: Double-blind, randomized, placebo-controlled 12-month longitudinal study. PARTICIPANTS: Seventy-five adolescent and young adult women with AN age 14 to 22 years. Thirty-three participants completed the study. INTERVENTION: Transdermal 17-beta estradiol 0.1 mg/day with (i) 30 mcg/kg/dose of rhIGF-1 administered subcutaneously twice daily (AN-IGF-1+) or (ii) placebo (AN-IGF-1-). The dose of rhIGF-1 was adjusted to maintain levels in the upper half of the normal pubertal range. MAIN OUTCOME MEASURES: Bone turnover markers and bone density, geometry, microarchitecture, and strength estimates. RESULTS: Over 12 months, lumbar areal bone mineral density increased in AN-IGF-1- compared to AN-IGF-1+ (P = 0.004). AN-IGF-1+ demonstrated no improvement in areal BMD in the setting of variable compliance to estrogen treatment. Groups did not differ for 12-month changes in bone geometry, microarchitecture, volumetric bone mineral density (vBMD), or strength (and results did not change after controlling for weight changes over 12 months). Both groups had increases in radial cortical area and vBMD, and tibia cortical vBMD over 12 months. Levels of a bone resorption marker decreased in AN-IGF-1- (P = 0.042), while parathyroid hormone increased in AN-IGF-1+ (P = 0.019). AN-IGF-1- experienced irregular menses more frequently than did AN-IGF-1+, but incidence of all other adverse events did not differ between groups. CONCLUSIONS: We found no additive benefit of rhIGF-1 administration for 12 months over transdermal estrogen replacement alone in this cohort of young women with AN.

Changes in marrow adipose tissue in relation to changes in bone parameters following estradiol replacement in adolescent and young adult females with functional hypothalamic amenorrhea.

CONTEXT: Low energy availability causes disruption of hypothalamic gonadotropin-releasing hormone secretion leading to functional hypothalamic amenorrhea (FHA) and hypoestrogenism, which in turn contributes to decreased bone mineral density (BMD) and increased bone marrow adipose tissue (MAT). Transdermal estradiol administration in physiologic doses increases BMD in adolescents and adults with FHA. However, the impact of estrogen replacement on MAT in relation to changes in BMD has not been studied in adolescents and young adults. We hypothesized that physiologic estrogen replacement would lead to decreases in MAT, associated with increases in BMD. METHODS AND MATERIALS: We studied 15 adolescent and young adult females with FHA (14-25 years). All participants received a17ß- estradiol transdermal patch at a dose of 0.1 mg/day (applied twice weekly) for 12 months. Participants also received cyclic progestin for 10-12 days each month. We quantified MAT (lipid/water ratio) of the fourth lumbar (L4) vertebral body and femoral diaphysis by single proton (1H)-magnetic resonance spectroscopy, and compartmental volumetric BMD of the distal radius and tibia using high-resolution peripheral quantitative computed tomography. RESULTS: Transdermal estradiol therapy over 12 months resulted in a decrease in MAT at the lumbar (L4) vertebra from 0.92 ± 0.55 at baseline to 0.63 ± 0.29 at 12-months (p = 0.008), and an increase in radial and tibial cortical vBMD (p = 0.006, p = 0.0003). Changes in L4 MAT trended to be inversely associated with changes in radial cortical vBMD (rho = -0.47, p = 0.08). CONCLUSION: We show that in adolescent and young adult girls with FHA, MAT decreases following transdermal estrogen therapy and these changes are associated with increased cortical vBMD.

Effects of Sleeve Gastrectomy on Bone Marrow Adipose Tissue in Adolescents and Young Adults with Obesity.

CONTEXT: Sleeve gastrectomy (SG), the most common metabolic and bariatric surgery in adolescents, is associated with bone loss. Marrow adipose tissue (MAT) is a dynamic endocrine organ that responds to changes in nutrition and might serve as a novel biomarker for bone health. Two types of MAT have been described, which differ in anatomic location-proximal regulated MAT vs distal constitutive MAT. OBJECTIVE: To determine the effects of SG on volumetric bone mineral density (vBMD) and MAT in adolescents with obesity. We hypothesized that SG would lead to a decrease in vBMD and differential changes in MAT. DESIGN: 12-month prospective study in 52 adolescents with moderate-to-severe obesity (38 female; mean age:17.5 ±â€…2.2 years; mean BMI 45.2 ±â€…7.0 kg/m2), comprising 26 subjects before and after SG and 26 nonsurgical controls. MAIN OUTCOME MEASURES: Lumbar vBMD by quantitative computed tomography; MAT of the lumbar spine, femur and tibia by proton magnetic resonance spectroscopy; abdominal fat and thigh muscle by magnetic resonance imaging. RESULTS: Adolescents lost 34.1 ±â€…13.1 kg after SG vs 0.3 ±â€…8.4 kg in the control group (P < 0.001). Lumbar vBMD decreased in the SG group (P = 0.04) and this change was associated with a reduction in weight and muscle area (P < 0.05) and an increase in lumbar MAT (P = 0.0002). MAT of the femur and tibia decreased after SG vs controls (P < 0.05); however, the differences were no longer significant after controlling for change in weight. CONCLUSION: SG in adolescents decreased lumbar vBMD associated with an increase in lumbar MAT and decrease in extremity MAT. This demonstrates differential changes of regulated MAT in the lumbar spine and constitutive MAT in the distal skeleton in adolescents in response to SG.

Impact of sleeve gastrectomy on hip structural analysis in adolescents and young adults with obesity.

BACKGROUND: Sleeve gastrectomy (SG), the most commonly performed metabolic and bariatric surgery, is associated with reductions in areal bone mineral density at multiple sites, and changes in bone structure at the distal radius and tibia without reductions in strength estimates at these peripheral sites. Data are lacking regarding effects on hip strength estimates. OBJECTIVE: To evaluate effects of SG on measures of hip structural analysis in adolescents and young adults over 12 months using dual-energy x-ray absorptiometry. SETTINGS: Translational and Clinical Research Center. METHODS: We enrolled 48 youth 14- to 22-years old with moderate-to-severe obesity; 24 underwent SG and 24 controls were followed without surgery (18 females, 6 males in each group). Hip structure was assessed using dual-energy x-ray absorptiometry at baseline and 12 months. Analyses are adjusted for age, sex, race, and the baseline bone measure. RESULTS: The SG group lost 25.9% weight versus .3% in controls. Compared with controls, SG had reductions in narrow neck, intertrochanteric and femoral shaft bone mineral density Z-scores (P ≤ .012). Furthermore, SG had greater reductions in narrow neck and intertrochanteric region (but not femoral shaft) cross-sectional area, cortical thickness, cross-sectional moment of inertia and section modulus, and increases in buckling ratio (P ≤ .039). Differences were attenuated after adjusting for 12-month body mass index change. At 12 months, differences were minimal after adjusting for age, sex, race, and weight. CONCLUSIONS: Over 12 months, SG had negative effects at the narrow neck and intertrochanteric regions of the hip, but not the femoral shaft. Reduced body mass index may compensate for these deleterious effects on bone.

Bone density, microarchitecture and strength estimates in white versus African American youth with obesity.

BACKGROUND: African Americans (AA) have more favorable bone density and microarchitecture compared to Whites (W), which may explain their observed lower fracture rates. Obesity has deleterious effects on bone microarchitecture and strength estimates and is associated with an increase in fracture risk. Adolescence and young adulthood are periods of active bone accrual and also periods characterized by an increasing prevalence of obesity. The effect of obesity on the relationship between race and bone parameters remains unclear, particularly in youth. OBJECTIVE: To assess differences in BMD, bone microarchitecture and strength estimates in AA and W adolescents and young adults with moderate to severe obesity. We hypothesized that racial differences in bone endpoints in lean youth would also be noted in youth with moderate to severe obesity. METHODS: We evaluated 24 AA and 48 W adolescent and young adults with a mean age of 18.2 ± 2.4 years and a median body mass index (BMI) of 44.8 (40.5-49.4) kg/m2 who underwent dual energy X-ray absorptiometry (DXA), high resolution peripheral quantitative computed tomography (HRpQCT), extended cortical analysis (ECA) and micro-finite element analysis (FEA) to obtain measures of volumetric bone mineral density (vBMD), bone geometry, microarchitecture, and strength estimates at the distal radius and tibia. RESULTS: We found no differences between AA and W for total fat and lean mass, and areal BMD Z-scores (p > 0.05 for all). At the distal radius, no significant differences were detected in vBMD, bone geometry or microarchitecture (p > 0.05 for all); however, stiffness and failure load were higher in the AA group (p = 0.031 and 0.047 respectively). At the distal tibia, cortical vBMD was higher in AA vs. W (p = 0.012), while trabecular number was higher and trabecular separation lower in W vs. AA (p ≤ 0.028). Stiffness and failure load trended higher in AA vs. W (p = 0.052 and p = 0.048, respectively). Groups did not differ for any other bone parameter (p > 0.05). CONCLUSION: Racial differences in bone endpoints appear to be less marked in those with moderate to severe obesity, suggesting that effects of obesity may blunt the effect of race on bone endpoints.

Depressive and anxiety symptoms and suicidality in adolescent and young adult females with moderate to severe obesity before and after weight loss surgery.

Data are conflicting regarding the impact of weight loss on mood and anxiety in adolescent and young adult females with moderate to severe obesity (OB), who are at increased risk for mood dysfunction compared with normal-weight females (NW). We examined depressive and anxiety symptoms in 94 females 13-21 years old: 39 in the NW group (body mass index [BMI]: 5th -85th percentiles) and 55 in the OB group (BMI >40 kg/m2 or >35 kg/m2 with comorbidities). Fifteen participants in the OB group who underwent bariatric surgery (gastric bypass or sleeve gastrectomy) and 15 getting routine care were re-assessed after 6 months. The Beck Depression Inventory-II (BDI-II) and State-Trait Anxiety Inventory (STAI) assessed depressive and anxiety symptoms, respectively. The OB group had higher BDI-II and STAI T-scores (P < .0001), a higher prevalence of clinical depression and anxiety (P < .001), and reported greater suicidal ideation (P = .02) vs the NW group. The bariatric surgery and non-surgical groups did not differ for changes in BDI-II and STAI T-Scores and suicidality over 6-month follow-up, despite greater weight loss in the former. Depressive and anxiety symptoms and suicidality were more frequently observed in the OB vs NW group. These symptoms did not improve following bariatric surgery despite significant weight loss, underscoring the need to investigate determinants of emergence and resolution of these symptoms in the OB group.

Bone outcomes following sleeve gastrectomy in adolescents and young adults with obesity versus non-surgical controls.

BACKGROUND: Sleeve gastrectomy is the most commonly performed weight loss surgery in adolescents with moderate-to-severe obesity. While studies in adults have reported on the deleterious effects of gastric bypass surgery on bone structure and strength estimates, data are lacking for the impact of sleeve gastrectomy on these measures in adolescents. OBJECTIVE: To evaluate the impact of sleeve gastrectomy on bone outcomes in adolescents and young adults over 12 months using dual energy X-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HRpQCT). PARTICIPANTS AND METHODS: We enrolled 44 youth 14-22 years old with moderate to severe obesity; 22 underwent sleeve gastrectomy and 22 were followed without surgery (16 females and 6 males in each group). At baseline and 12 months, DXA was used to assess areal bone mineral density (aBMD), HRpQCT of the distal radius and tibia was performed to assess bone geometry, microarchitecture and volumetric BMD (vBMD), and finite element analysis to assess strength estimates (stiffness and failure load). These analyses were adjusted for age, sex, race and the bone measure at baseline. Fasting blood samples were assessed for calcium, phosphorus, and 25(OH) vitamin D (25OHD) levels. RESULTS: Over 12-months, the surgical group lost 27.2% of body weight compared to 0.1% in the non-surgical (control) group. Groups did not differ for changes in 25OHD levels (p = 0.186). Compared to controls, the surgical group had reductions in femoral neck and total hip aBMD Z-scores (p ≤ 0.0006). At the distal tibia, compared to controls, the surgical group had reductions in cortical area and thickness and trabecular number, and increases in trabecular area and separation (p ≤ 0.026). At the distal radius, the surgical group had greater reductions in trabecular vBMD, than controls (p = 0.010). The surgical group had an increase in cortical vBMD at both sites (p ≤ 0.040), possibly from a decrease in cortical porosity (p ≤ 0.024). Most, but not all, differences were attenuated after adjusting for 12-month change in BMI. Groups did not differ for changes in strength estimates over time, except that increases in tibial stiffness were lower in the surgical group (p = 0.044) after adjusting for 12-month change in BMI. CONCLUSIONS: Over 12 months, weight loss associated with sleeve gastrectomy in adolescents had negative effects on areal BMD and certain HRpQCT parameters. However, bone strength estimates remained stable, possibly because of a simultaneous decrease in cortical porosity and increase in cortical volumetric BMD. Additional research is necessary to determine the relative contribution(s) of weight loss and the metabolic effects of surgery on bone outcomes, and whether the observed effects on bone stabilize or progress over time.

Racial differences in lumbar marrow adipose tissue and volumetric bone mineral density in adolescents and young adults with obesity.

BACKGROUND: Areal bone mineral density (BMD) of the lumbar spine by DXA is greater in Black compared to White adolescents. Bone strength is determined not only by BMD but also its microenvironment, and marrow adipose tissue (MAT) has been shown to be an important determinant of skeletal integrity, independent of BMD. Racial differences in volumetric BMD (vBMD) and MAT in adolescents and young adults with obesity are unknown. OBJECTIVE: To assess racial differences in lumbar vBMD and MAT in Black and White adolescents and young adults with obesity and to assess body composition determinants of bone parameters. We hypothesized that Blacks will have higher vBMD and lower MAT of the lumbar spine compared to Whites. METHODS: The study group comprised 77 adolescents/young adults, 25 Black and 52 White, (mean age 18.2 ± 2.5 years, range 13 to 24 years) with moderate to severe obesity (mean body mass index (BMI) 46.2 ± 7.3 kg/m2, range 35.5 to 69.7 kg/m2). Groups were similar in age, BMI, and sex distribution (p > 0.84). Subjects underwent QCT of the lumbar spine (L1-L2) for assessment of vBMD with the use of a calibration phantom and 1H-MRS/MRI for quantification of lumbar MAT content (L1-L2) and abdominal fat and thigh muscle mass. Groups were compared by Student's t-test or Wilcoxon test. Correlation analysis was performed to assess associations between bone parameters and body composition. RESULTS: Black adolescents/young adults with obesity had higher vBMD compared to Whites (p < 0.0001), while there was no significant difference in lumbar MAT (p = 0.64). There were also no significant differences in body composition measures between groups (p ≥ 0.28). An inverse association between MAT and vBMD was observed in Whites (r = -0.47, P = 0.001) but not in Blacks (p = 0.6). There were no significant associations between body composition measures and bone parameters (p > 0.1). CONCLUSION: There are racial differences in lumbar vBMD in adolescents and young adults with moderate to severe obesity, with Blacks having higher vBMD than Whites, while there were no differences in MAT content. The known inverse association between BMD and MAT was only observed in Whites but not in Blacks, suggesting possible racial differences in stem cell differentiation into the bone and fat lineages.

Marrow adipose tissue in adolescent girls with obesity.

BACKGROUND: Marrow adipose tissue (MAT) is increasingly recognized as an active and dynamic endocrine organ that responds to changes in nutrition and environmental milieu. Compared to normal weight controls, adolescent girls with anorexia nervosa have higher MAT content, which is associated with impaired skeletal integrity, but data are limited regarding MAT content in adolescents with obesity and how this interacts with bone endpoints. OBJECTIVE: To evaluate (i) MAT content in adolescents with obesity compared to normal-weight controls, (ii) the association of MAT with bone endpoints, and (iii) whether these associations of MAT are affected by body weight. METHODS: We assessed MAT, bone endpoints, and body composition in 60 adolescent girls 14-21 years old: 45 with obesity (OB) and 15 normal-weight controls (NW-C). We used (i) DXA to assess areal bone mineral density (aBMD) at the lumbar spine and total hip, and total body fat and lean mass, (ii) proton magnetic resonance spectroscopy (1H-MRS) to assess MAT at the 4th lumbar vertebra and femur, and MRI to assess visceral (VAT) and subcutaneous adipose tissue (SAT), (iii) high resolution peripheral quantitative CT (HR-pQCT) to assess volumetric BMD (vBMD), (iv) individual trabeculae segmentation to evaluate trabecular bone (plate-rod morphology), and (v) finite element analysis to assess stiffness (a strength estimate) at the distal radius and tibia. RESULTS: Groups did not differ for age or height. Weight, BMI, and areal BMD Z-scores at all sites were higher in the OB group (p<0.0001). MAT was lower in OB at the femoral diaphysis (p= <0.0001) and the lumbar spine (p=0.0039). For the whole group, MAT at the lumbar spine and femoral diaphysis was inversely associated with BMI, total fat mass, lean mass, and VAT. Even after controlling for body weight, independent inverse associations were observed of femoral diaphyseal and lumbar MAT with total tibial vBMD, and of lumbar MAT with radial trabecular vBMD. CONCLUSION: Adolescent girls with obesity have lower MAT than normal-weight controls despite having an excess of total body fat. These findings confirm that MAT is regulated uniquely from other adipose depots in obesity. MAT was inversely associated with vBMD, emphasizing an inverse relationship between MAT and bone even in adolescent girls with obesity.

Suboptimal bone microarchitecure in adolescent girls with obesity compared to normal-weight controls and girls with anorexia nervosa.

BACKGROUND: Despite their higher areal bone mineral density (aBMD), adolescents with obesity (OB) have an increase in fracture risk, particularly of the extremities, compared with normal-weight controls. Whereas bone parameters that increase fracture risk are well characterized in anorexia nervosa (AN), the other end of nutritional spectrum, these data are lacking in adolescents with obesity. OBJECTIVE: Our objective was to compare bone parameters in adolescent girls across the nutritional spectrum, to determine whether suboptimal bone adaptation to increased body weight may explain the increased fracture risk in OB. METHODS: We assessed bone endpoints in 153 adolescent girls 14-21 years old: 50 OB, 48 controls and 55 AN. We used (i) DXA to assess aBMD at the lumbar spine, proximal femur and whole body, and body composition, (ii) high resolution peripheral quantitative CT (HRpQCT) to assess bone geometry, microarchitecture and volumetric BMD (vBMD), and (iii) finite element analysis to assess failure load (a strength estimate) at the distal radius and tibia. All aBMD, microarchitecture and FEA analyses were controlled for age and race. RESULTS: Groups did not differ for age or height. Areal BMD Z-scores at all sites were highest in OB, intermediate in controls and lowest in AN (p < 0.0001). At the radius, cortical area and thickness were higher in OB compared to AN and control groups (p = 0.001) while trabecular area did not differ across groups. Compared to controls, OB had higher cortical porosity (p = 0.003), higher trabecular thickness (p = 0.024), and higher total, cortical and trabecular vBMD and rod BV/TV (p < 0.04). Plate BV/TV did not differ in OB vs. controls, but was higher than in AN (p = 0.001). At the tibia, total, cortical, and trabecular area and cortical thickness were higher in OB vs. controls and AN (p < 0.005). OB also had higher cortical porosity (p < 0.007) and lower trabecular thickness (p < 0.02) than the other two groups. Trabecular number, total and trabecular vBMD, and rod BV/TV were higher in OB vs. controls and AN (p < 0.02), while cortical vBMD and plate BV/TV did not differ in OB vs. the other two groups. Finally, failure load (a strength estimate) was higher in OB at the radius and tibia compared to controls and AN (p < 0.004 for all). However, after adjusting for body weight, failure load was lower in OB vs. controls at both sites (p < 0.05), and lower than in AN at the distal tibia. CONCLUSION: Not all bone parameters demonstrate appropriate adaptation to higher body weight. Cortical porosity and plate BV/TV at the radius and tibia, and cortical vBMD and trabecular thickness at the tibia are particularly at risk. These effects may contribute to the higher risk for fracture reported in OB vs. controls.

Impact of Route of Estrogen Administration on Bone Turnover Markers in Oligoamenorrheic Athletes and Its Mediators.

OBJECTIVE: Transdermal, but not oral, estrogen replacement improves bone mineral density (BMD) in athletes with oligoamenorrhea (OA). Our objective was to determine mechanisms that may explain the impact of route of estrogen administration on bone outcomes. METHODS: Seventy-three participants with OA between 14 and 25 years old received (i) a 17ß-estradiol transdermal patch continuously with cyclic oral micronized progesterone (PATCH), (ii) a combined ethinyl estradiol and desogestrel pill (PILL), or (iii) no estrogen/progesterone (NONE) for 12 months. We evaluated morning fasting levels of a marker of bone formation [N-terminal propeptide of type 1 procollagen (P1NP)], a marker of bone resorption (N-telopeptide), IGF-1, insulinlike growth factor binding protein 3, total testosterone, estradiol, SHBG, sclerostin, preadipocyte factor-1 (Pref-1), brain-derived neurotrophic factor (BDNF), calcium, 25(OH) vitamin D, and PTH levels at baseline and 12 months. RESULTS: Groups did not differ for age, weight, exercise activity, or markers of bone formation at baseline. Over 12 months, P1NP decreased the most in the PILL group (P = 0.03) associated with a decrease in IGF-1 levels (r = 0.37; P = 0.003). Sclerostin, Pref-1, and BDNF decreased in the PATCH group over 12 months. PATCH had the greatest increases in estradiol (P ≤ 0.0001), and estradiol increases were associated with increases in bone density. CONCLUSION: Transdermal 17ß-estradiol given over 12 months does not cause the decrease in IGF-1 observed with oral ethinyl estradiol. It also leads to decreases in sclerostin, Pref-1, and BDNF, which may mediate the beneficial effects of estrogen.

Bone Parameters in Anorexia Nervosa and Athletic Amenorrhea: Comparison of Two Hypothalamic Amenorrhea States.

Objective: We have reported low bone mineral density (BMD), impaired bone structure, and increased fracture risk in participants with anorexia nervosa (AN) and normal-weight oligoamenorrheic athletes (OAs). However, data directly comparing compartment-specific bone parameters in participants with AN, OAs, and controls are lacking. Design: A total of 468 female participants 14 to 21.9 years old were included: 269 with AN, 104 OAs, and 95 normal-weight eumenorrheic controls. Dual-energy x-ray absorptiometry was used to assess areal BMD (aBMD) of the whole body less head (WBLH), spine, and hip. High-resolution peripheral quantitative computed tomography was used to assess volumetric BMD (vBMD), bone geometry, and structure at the non-weight-bearing distal radius and weight-bearing distal tibia. Results: Participants with AN had lower WBLH and hip aBMD z scores than OAs and controls (P < 0.0001). Participants with AN and OAs had lower spine aBMD z scores than controls (P < 0.01). At the radius, total and cortical vBMD, percentage cortical area, and thickness were lower in the AN and OA groups than in controls (P ≤ 0.04); trabecular vBMD was lower in participants with AN than controls. At the tibia, participants with AN had lower measures for most parameters compared with OAs and controls (P < 0.05); OAs had lower cortical vBMD than controls (P = 0.002). Participants with AN and OAs had higher fracture rates than controls. Stress fracture prevalence was highest in OAs (P < 0.0001); nonstress fracture prevalence was highest in participants with AN (P < 0.05). Conclusion: AN is deleterious to bone at all sites and both bone compartments. A high stress fracture rate in OAs, who have comparable WBLH and hip aBMD measures to controls, indicates that BMD in these women may need to be even higher to avoid fractures.