Update on Pediatric Anti-obesity Medications-Current Landscape and Approach to Prescribing.

PURPOSE OF REVIEW: To review the current medical therapies available for treatment of obesity in children and adolescents less than 18 years old in the United States and outline the approach to their use. RECENT FINDINGS: Obesity is a chronic disease with increasing prevalence in children and adolescents in the United States. Over the past few years, more FDA-approved medical treatments for obesity, such as GLP-1 receptor agonists, have emerged for patients less than 18 years old. Furthermore, there are medications with weight loss effects that can be used off-label for obesity in pediatric patients. However, access to many of these medications is limited due to age restrictions, insurance coverage, and cost. Medical options are improving to provide treatment for obesity in pediatric populations. FDA and off-label medications should be considered when appropriate to treat children and adolescents with obesity. However, further studies are needed to evaluate the efficacy and long-term safety of FDA-approved and off-label medications for obesity treatment in pediatric patients.

Two-Year Study on the Impact of Sleeve Gastrectomy on Depressive and Anxiety Symptoms in Adolescents and Young Adults with Moderate to Severe Obesity.

PURPOSE: Sleeve gastrectomy (SG), the most commonly performed weight loss surgery in adolescents and young adults with moderate to severe obesity, is highly effective for weight loss. Current literature regarding depressive and anxiety symptomatology following SG in youth is sparse and conflicting. We evaluated changes in depressive and anxiety symptoms in adolescents and young adults with moderate to severe obesity 2 years following SG compared with non-surgical controls (NS) followed for a similar duration. MATERIALS AND METHODS: Forty-six youth 13-25 years old with moderate-severe obesity (33 female) were followed for 2 years; 21 underwent SG, and 25 were NS. Subjects underwent anthropometric measurements and completed self-report questionnaires. Beck Depression Inventory-II (BDI-II) was used to assess depressive symptoms and the State-Trait Anxiety Inventory (STAI)-X2 for anxiety symptoms. RESULTS: Groups did not differ for age (18.4 ± 0.4 vs. 17.8 ± 0.5 years, p = 0.456). The SG group had a higher mean BMI vs. NS (47.5 (42.1, 52.4) vs. 41.6 (37.8, 46.5) kg/m2; p = 0.011). At 2-year follow-up, SG had greater reductions in weight and BMI vs. NS (p < 0.0001). Groups did not differ for changes in BDI-II and STAI scores (BDI-II: - 1.0 (- 6.0, 10.0) in SG vs. - 1.0 (- 6.0, 3.5) in NS, p = 0.37; STAI: 3.1 ± 3.2 in SG vs. - 1.1 ± 1.5 in NS, p = 0.24). CONCLUSION: No change was found in depressive and anxiety symptomatology following surgery despite marked weight reduction over a 2-year period, underscoring the need to better evaluate psychopathology in youth undergoing SG to develop supportive therapeutic strategies. GOV IDENTIFIER: NCT02557438 https://clinicaltrials.gov/ct2/show/NCT02557438?id=NCT02557438&draw=2&rank=1 ; The study was registered on 23 September 2015.

Regional Variations in Pediatric Metabolic and Bariatric Surgeon Availability: A Call for Action.

INTRODUCTION: Obesity is a significant public health concern in children. The American Academy of Pediatrics recommends the use of metabolic and bariatric surgery (MBS) in children with severe obesity, however; MBS remains underutilized in part due to lack of access. This study aims to characterize the prevalence of pediatric obesity and compare this to regional pediatric MBS provider availability. METHODS: State-specific prevalence rates of childhood obesity in children aged 10-17 were obtained from the National Survey of Children's Health. The member directory provided by the American Society for Metabolic and Bariatric Surgeons was used to identify all pediatric MBS providers and used to calculate the prevalence of MBS providers by state. RESULTS: The five states with the highest prevalence rates of childhood obesity were Kentucky, Mississippi, Louisiana, West Virginia, and Alabama. The five states with the highest prevalence (per 100,000 children with obesity) of MBS providers doing pediatric cases were North Dakota, New Jersey, Kansas, New York, and Utah. Notably, there was a negative correlation between the states with the lowest prevalence of pediatric MBS providers and states with the highest prevalence of childhood obesity (r -0.40, ∗P = 0.002). CONCLUSIONS: Our study demonstrates significant state-to-state variation in the prevalence of pediatric obesity and MBS provider availability by state as a proxy for access to surgical care for pediatric obesity. Further work to establish accessible multidisciplinary pediatric weight loss centers is needed to ensure that children and adolescents with obesity receive thorough evaluation and have access to MBS.

Risk of wrist fracture, estimated by the load-to-strength ratio, declines following sleeve gastrectomy in adolescents and young adults.

To understand whether the bone loss which occurs after vertical sleeve gastrectomy increases the risk of fracture, we used an engineering model to estimate risk in participants before and after surgery. We found that estimated risk decreased 1 year after surgery and remained lower, though had rebounded, at year 2. PURPOSE: Vertical sleeve gastrectomy (VSG) improves metabolic health in young people with obesity but is accompanied by substantial loss of bone mass and estimated bone strength. We thus estimated fracture risk following VSG using the load-to-strength ratio (LSR), which integrates bone strength estimates with the predicted force of a fall. METHODS: Prospective 2-year study of youth ages 13-24 years with obesity undergoing VSG (n = 24) or lifestyle therapy (n = 34). We performed high-resolution peripheral quantitative computed tomography of the distal radius and microfinite element analysis to estimate bone strength and calculated LSR. RESULTS: VSG participants lost 26.4 ± 8.1% weight at year 1 (p < 0.001), which was sustained at year 2, while control participants gained weight at year 2 (4.5 ± 8.3%, p = 0.009). The predicted impact force decreased at years 1 and 2 following VSG (p < 0.001) but increased at year 2 among controls (p = 0.011). Estimated bone strength was unchanged at year 1 but decreased (p < 0.001) at year 2 following VSG, while bone strength did not change in controls. At year 1, the LSR decreased among VSG participants (p < 0.001), implying a lower risk of fracture. At year 2, the LSR was lower than baseline (p < 0.001), but higher compared to year 1 (p = 0.001). LSR did not change in the control group. CONCLUSIONS: Short-term estimated fracture risk at the radius following VSG decreases. However, ongoing bone loss despite stable weight between years 1 and 2 leads to a concerning rise in estimated fracture risk. Longer follow-up will be critical to evaluate the trajectory of fracture risk. (ClinicalTrials.gov NCT02557438, registered 9/23/2015).

Changes in Branched-Chain Amino Acids One Year after Sleeve Gastrectomy in Youth with Obesity and Their Association with Changes in Insulin Resistance.

Adults with obesity have a reduction in branched-chain amino acid (BCAA) levels following metabolic and bariatric surgery (MBS), which is hypothesized to contribute to the metabolic advantages of MBS. We examined this relationship in 62 youth 13-24 years old with severe obesity (47 female) over 12 months. Thirty had sleeve gastrectomy (SG) and 32 were non-surgical controls (NS). We measured fasting insulin, glucose, glycated hemoglobin (HbA1c), isoleucine, leucine, and valine concentrations, and post-prandial insulin and glucose, following a mixed meal tolerance test. Twenty-four-hour food recalls were collected. At baseline, groups did not differ in the intake or the serum levels of BCAAs, HbA1C, HOMA-IR, Matsuda index, insulinogenic index, or oral Disposition index (oDI). Over 12 months, SG vs. NS had greater reductions in serum BCAAs, and SG had significant reductions in BCAA intake. SG vs. NS had greater reductions in HbA1c and HOMA-IR, with increases in the Matsuda index and oDI. In SG, baseline leucine and total BCAA concentrations were negatively correlated with the baseline Matsuda index. Reductions in serum leucine were positively associated with the reductions in HOMA-IR over 12 months. These associations suggest a potential role of BCAA in regulating metabolic health. Reducing dietary intake and serum BCAA concentrations may reduce insulin resistance.

Bone Density, Geometry, Structure and Strength Estimates in Adolescent and Young Adult Women with Atypical Anorexia Nervosa versus Typical Anorexia Nervosa and Normal-Weight Healthy Controls.

Our objective was to characterize bone outcomes in adolescent and young adult women with atypical anorexia nervosa (AAN) compared to typical AN and normal-weight healthy controls (HC) based on DSM-5 criteria. Four hundred thirty-two participants (141 AN, 131 AAN and 160 HC), ages 12-21 years, underwent dual-energy X-ray absorptiometry for areal BMD, and a subset had high-resolution peripheral quantitative CT assessment of the distal radius and tibia for volumetric BMD (vBMD), bone geometry and microarchitecture, and microfinite element analysis for estimated strength. The groups did not differ for age, pubertal stage, menarcheal age or physical activity. BMI and bone outcomes overall were intermediate in AAN compared with AN and HC. This applied to spine, total hip and femoral neck BMD measures and many distal tibial measures. However, the mean whole-body less head BMD Z-score did not differ between AAN and AN, and it was lower in both vs. HC. Similarly, many distal radius measures did not differ between AAN vs. AN or HC but were lower in AN than HC. Lower BMI, lean mass and bone age, older menarcheal age and longer illness duration correlated with greater impairment of bone outcomes. These data indicate that individuals with AAN overall have bone outcomes that are intermediate between AN and HC.

Bone changes post-sleeve gastrectomy in relation to body mass and hormonal changes.

OBJECTIVE: To determine mechanisms contributing to impaired bone health in youth 24 months following sleeve gastrectomy (SG). DESIGN: Twenty-four-month longitudinal observational study. METHODS: Participants included 23 youth undergoing SG and 30 non-surgical controls (NS) 13-25 years old with moderate-to-severe obesity. Subjects underwent fasting labs for bone turnover markers (N-terminal propeptide of type 1 procollagen, C-telopeptide (CTX)), sex hormones, sex hormone binding globulin (SHBG), and enteric peptides, DXA for areal bone mineral density (aBMD) and body composition, high-resolution peripheral quantitative CT for volumetric BMD (vBMD) at the distal radius and tibia, and microfinite element analysis for strength estimates. RESULTS: Groups did not differ for mean age or BMI z-scores. Over 24 months, compared to NS, SG had greater reductions in BMI z-scores, and spine, hip, and femoral neck aBMD Z-scores (P ≤ .012), greater increases in serum CTX and SHBG (P ≤ .039), and greater decreases in estrone and ghrelin (P ≤ .021). Among females, estrone and free androgen index (FAI) decreased (P ≤ .022) in SG vs NS groups. After controlling for age and sex, decreases in BMI and lean mass were associated with decreases in total hip and femoral neck aBMD Z-scores, and decreases in radial total and trabecular vBMD and failure load, and tibial total and trabecular vBMD. Among females, after controlling for age, decreases in estrone were associated with decreases in spine aBMD Z-scores and radial total and trabecular vBMD, and decrease in FAI with decreases in radial failure load. CONCLUSION: Reductions in BMI, lean mass, and sex steroids over 24 months post-SG are associated with bone loss and could be targeted for preventative or therapeutic interventions. Clinical trial registration number: The study is registered in ClinicalTrials.gov (NCT02557438).

Trajectory of Gonadal Hormones in Adolescent Males up to 2 Years After Sleeve Gastrectomy.

Sleeve gastrectomy (SG) has many metabolic benefits and leads to improvements in testosterone levels, which means improvement in the Leydig cell function of the testis. However, data about the effects of SG on Sertoli cell function (as assessed by inhibin B) are not available. In this preliminary study, we evaluate, for the first time, the effect of SG in adolescents after SG. We evaluate 16 adolescent and young adult males, six of whom underwent SG and followed them for 2 years. We report that Leydig cell function (as assessed by testosterone levels) improved and was associated with degree of weight loss. Sertoli cell function improved only slightly in SG group and did not change compared to the nonsurgical controls, and these changes were not associated with degree of weight loss. Thus, we conclude that larger and long-term follow-up studies are required to evaluate the changes in Sertoli cell function after SG as that is integral to male fertility.Clinical Trial Registration: NCT02557438.

Changes in Hepatic Fat Content by CT 1 Year After Sleeve Gastrectomy in Adolescents and Young Adults With Obesity.

CONTEXT: Obesity is associated with nonalcoholic fatty liver disease (NAFLD). Sleeve gastrectomy (SG) is an effective means of weight loss and improvement of NAFLD in adults; however, data regarding the efficacy of SG in the early stages of pediatric NAFLD are sparse. OBJECTIVE: To assess the impact of SG on hepatic fat content 1 year after SG in youth with obesity compared with nonsurgical controls with obesity (NS). DESIGN: A 12-month prospective study in 52 participants (mean age, 18.2 ± .36 years) with obesity, comprising 25 subjects who underwent SG (84% female; median body mass index [BMI], 44.6 [42.1-47.9] kg/m2) and 27 who were NS (70% female; median BMI, 42.2 [38.7-47.0] kg/m2). MAIN OUTCOME MEASURES: Hepatic fat content by computed tomography (liver/spleen ratio), abdominal fat by magnetic resonance imaging. RESULTS: Mean 12-month decrease in BMI was greater in SG vs NS (-12.5 ± .8 vs -.2 ± .5 kg/m2, P < .0001). There was a within-group increase in the liver-to-spleen (L/S) ratio in SG (.13 ± .05, P = .014) but not NS with a trend for a difference between groups (P = .055). All SG participants with an L/S ratio <1.0 (threshold for the diagnosis of NAFLD) before surgery had a ratio of >1.0 a year after surgery, consistent with resolution of NAFLD. Within SG, the 12-month change in L/S ratio was negatively associated with 12-month change in visceral fat (ρ = -.51 P = .016). CONCLUSIONS: Hepatic fat content as assessed by noncontrast computed tomography improved after SG over 1 year in youth with obesity with resolution of NAFLD in all subjects. This was associated with decreases in visceral adiposity.

Two-year Skeletal Effects of Sleeve Gastrectomy in Adolescents with Obesity Assessed with Quantitative CT and MR Spectroscopy.

Background Sleeve gastrectomy (SG) is effective in the treatment of cardiometabolic complications of obesity but is associated with bone loss. Purpose To determine the long-term effects of SG on vertebral bone strength, density, and bone marrow adipose tissue (BMAT) in adolescents and young adults with obesity. Materials and Methods This 2-year prospective nonrandomized longitudinal study enrolled adolescents and young adults with obesity who underwent either SG (SG group) or dietary and exercise counseling without surgery (control group) at an academic medical center from 2015 to 2020. Participants underwent quantitative CT of the lumbar spine (L1 and L2 levels) to assess bone density and strength, proton MR spectroscopy to assess BMAT (L1 and L2 levels), and MRI of the abdomen and thigh to assess body composition. Student t and Wilcoxon signed-rank tests were used to compare 24-month changes between and within groups. Regression analysis was performed to evaluate associations between body composition, vertebral bone density, strength, and BMAT. Results A total of 25 participants underwent SG (mean age, 18 years ± 2 [SD], 20 female), and 29 underwent dietary and exercise counseling without surgery (mean age, 18 years ± 3, 21 female). Body mass index (BMI) decreased by a mean of 11.9 kg/m2 ± 5.21 [SD] after 24 months in the SG group (P < .001), while it increased in the control group (mean increase, 1.49 kg/m2 ± 3.10; P = .02). Mean bone strength of the lumbar spine decreased after surgery compared with that in control subjects (mean decrease, -728 N ± 691 vs -7.24 N ± 775; P < .001). BMAT of the lumbar spine increased after SG (mean lipid-to-water ratio increase, 0.10 ± 0.13; P = .001). Changes in vertebral density and strength correlated positively with changes in BMI and body composition (R = 0.34 to R = 0.65, P = .02 to P < .001) and inversely with vertebral BMAT (R = -0.33 to R = -0.47, P = .03 to P = .001). Conclusion SG in adolescents and young adults reduced vertebral bone strength and density and increased BMAT compared with those in control participants. Clinical trial registration no. NCT02557438 © RSNA, 2023 See also the editorial by Link and Schafer in this issue.

Serum Oxytocin Levels Decrease 12 Months Following Sleeve Gastrectomy and Are Associated with Decreases in Lean Mass.

Oxytocin (OXT), an anorexigenic hormone, is also bone anabolic. Further, OXT administration results in increases in lean mass (LM) in adults with sarcopenic obesity. We examine, for the first time, associations of OXT with body composition and bone endpoints in 25 youth 13-25 years old with severe obesity who underwent sleeve gastrectomy (SG) and 27 non-surgical controls (NS). Forty participants were female. Subjects underwent fasting blood tests for serum OXT and DXA for areal bone mineral density (aBMD) and body composition. At baseline, SG vs. NS had higher median body mass index (BMI) but did not differ for age or OXT levels. Over 12 months, SG vs. NS had greater reductions in BMI, LM, and fat mass (FM). OXT decreased in SG vs. NS 12 months post-SG. While baseline OXT predicted a 12-month BMI change in SG, decreases in OXT levels 12 months post-SG were not associated with decreases in weight or BMI. In SG, decreases in OXT were positively associated with decreases in LM but not with decreases in FM or aBMD. Loss of LM, a strong predictor of BMD, after bariatric surgery may reduce functional and muscular capacity. OXT pathways may be targeted to prevent LM loss following SG.

The Neurobiology of Eating Behavior in Obesity: Mechanisms and Therapeutic Targets: A Report from the 23rd Annual Harvard Nutrition Obesity Symposium.

Obesity is increasing at an alarming rate. The effectiveness of currently available strategies for the treatment of obesity (including pharmacologic, surgical, and behavioral interventions) is limited. Understanding the neurobiology of appetite and the important drivers of energy intake (EI) can lead to the development of more effective strategies for the prevention and treatment of obesity. Appetite regulation is complex and is influenced by genetic, social, and environmental factors. It is intricately regulated by a complex interplay of endocrine, gastrointestinal, and neural systems. Hormonal and neural signals generated in response to the energy state of the organism and the quality of food eaten are communicated by paracrine, endocrine, and gastrointestinal signals to the nervous system. The central nervous system integrates homeostatic and hedonic signals to regulate appetite. Although there has been an enormous amount of research over many decades regarding the regulation of EI and body weight, research is only now yielding potentially effective treatment strategies for obesity. The purpose of this article is to summarize the key findings presented in June 2022 at the 23rd annual Harvard Nutrition Obesity Symposium entitled "The Neurobiology of Eating Behavior in Obesity: Mechanisms and Therapeutic Targets." Findings presented at the symposium, sponsored by NIH P30 Nutrition Obesity Research Center at Harvard, enhance our current understanding of appetite biology, including innovative techniques used to assess and systematically manipulate critical hedonic processes, which will shape future research and the development of therapeutics for obesity prevention and treatment.

Biomechanical CT to Assess Bone After Sleeve Gastrectomy in Adolescents With Obesity: A Prospective Longitudinal Study.

Sleeve gastrectomy (SG) is effective in treating cardiometabolic complications of obesity but is associated with bone loss. Our aim was to determine the effect of SG on the lumbar spine by biomechanical CT analysis in adolescents/young adults with obesity. We hypothesized that SG would lead to a decrease in strength and bone mineral density (BMD) compared with nonsurgical controls. In a 12-month prospective nonrandomized study, adolescents/young adults with obesity underwent SG (n = 29, 18.0 ± 2.1 years, 23 female) or were followed without surgery (controls, n = 30, 17.95 ± 3.0 years, 22 female). At baseline and 12 months, participants underwent quantitative computed tomography (QCT) of L1 and L2 for biomechanical assessment and MRI of the abdomen and mid-thigh for body composition assessment. Twelve-month changes between groups and within groups were assessed. Analyses were controlled for baseline and 12-month changes in body mass index (BMI) by multivariable analyses. Regression analysis was performed to evaluate the effect of body composition on bone parameters. Our institutional review board (IRB) approved the study, and informed consent/assent was obtained. Participants in the SG group had a higher baseline BMI than controls (p = 0.01) and lost an average of 34.3 ± 13.6 kg 12 months after surgery, whereas weight was unchanged in controls (p < 0.001). There were significant reductions in abdominal adipose tissue and thigh muscle area in the SG group compared with controls (p < 0.001). Bone strength, bending stiffness, and average and trabecular volumetric BMD decreased in the SG group compared with controls (p < 0.001). After controlling for change in BMI, a 12-month reduction in cortical BMD was significant in the SG group compared with controls (p = 0.02). Reductions in strength and trabecular BMD were associated with reductions in BMI, visceral adipose tissue, and muscle (p ≤ 0.03). In conclusion, SG in adolescents decreased strength and volumetric BMD of the lumbar spine compared with nonsurgical controls. These changes were associated with decreases in visceral fat and muscle mass. © 2023 American Society for Bone and Mineral Research (ASBMR).

Differences in bone accrual over one year in young girls with obesity compared to Normal weight controls.

Despite higher bone mineral density (BMD), women with obesity are at an increased risk of fracture compared to normal-weight women. Optimal adolescent bone accrual is critical for normal peak bone mass acquisition and future bone health. Whereas several studies have examined the impact of low body weight on bone accrual in youth, data are lacking regarding the impact of obesity on bone accrual. We examined bone accrual over one year in young women with moderate to severe obesity (OB) (n = 21) versus normal-weight controls (NWC) (n = 50). Participants were 13-25 years old. We used dual-energy X-ray absorptiometry to assess areal BMD (aBMD) and high resolution peripheral quantitative computed tomography (distal radius and tibia) to assess volumetric BMD (vBMD), bone geometry, and microarchitecture. Analyses were controlled for age and race. The mean age was 18.7 ± 2.7 years. OB and NWC were similar for age, race, height, and physical activity. OB had a higher BMI (p < 0.0001) and younger menarchal age (p = 0.022) than NWC. Over one year, OB did not demonstrate the increase in total hip BMD observed in NWC (p = 0.03). Increases in percent cortical area and cortical thickness, and cortical and total vBMD at the radius were lower in OB than in NWC (p ≤ 0.037). Groups did not differ for tibial bone accrual. We demonstrate that longitudinal bone accrual is impaired at the total hip and radial cortex in young women with obesity, raising concerns regarding their future bone health.

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.

Denosumab increases spine bone density in women with anorexia nervosa: a randomized clinical trial.

Objective: Anorexia nervosa is complicated by high bone resorption, low bone mineral density (BMD), and increased fracture risk. We investigated whether off-label antiresorptive therapy with denosumab increases BMD in women with anorexia nervosa. Design: Twelve-month, randomized, double-blind, placebo-controlled study. Methods: Thirty ambulatory women with anorexia nervosa and areal BMD (aBMD) T-score <-1.0 at ≥1 sites were randomized to 12 months of denosumab (60 mg subcutaneously q6 months)(n = 20) or placebo (n = 10). Primary end point was postero-anterior (PA) lumbar spine aBMD by dual-energy x-ray absorptiometry. Secondary end points included femoral neck aBMD, tibia and radius volumetric BMD and bone microarchitecture by high-resolution peripheral quantitative CT, tibia and radius failure load by finite element analysis (FEA), and markers of bone turnover. Results: Baseline mean (±s.d.) age (29 ± 8 (denosumab) vs 29 ± 7 years (placebo)), BMI (19.0 ± 1.7 vs 18.0 ± 2.0 kg/m2), and aBMD (PA spine Z-score -1.6±1.1 vs -1.7±1.4) were similar between groups. PA lumbar spine aBMD increased in the denosumab vs placebo group over 12 months (P = 0.009). The mean (95% CI) increase in PA lumbar spine aBMD was 5.5 (3.8-7.2)% in the denosumab group and 2.2 (-0.3-4.7)% in the placebo group. The change in femoral neck aBMD was similar between groups. Radial trabecular number increased, radial trabecular separation decreased, and tibial cortical porosity decreased in the denosumab vs placebo group (P ≤ 0.006). Serum C-terminal telopeptide of type I collagen and procollagen type I N-terminal propeptide decreased in the denosumab vs placebo group (P < 0.0001). Denosumab was well tolerated. Conclusions: Twelve months of antiresorptive therapy with denosumab reduced bone turnover and increased spine aBMD, the skeletal site most severely affected in women with anorexia nervosa.

Load-to-strength ratio at the radius is higher in adolescent and young adult females with obesity compared to normal-weight controls.

BACKGROUND: Among adolescents with extremity fractures, individuals with obesity have greater representation compared with individuals of normal-weight, despite having higher areal and volumetric bone mineral density (aBMD, vBMD) than their normal-weight counterparts. The relative increase in BMD in individuals with obesity may thus be insufficient to support the greater force generated upon falling. The load-to-strength ratio is a biomechanical approach for assessing the risk of fracture by comparing applied force to bone strength, with higher load-to-strength ratios indicating higher fracture risk. OBJECTIVE: To assess the load-to-strength ratio at the distal radius in adolescent and young adult females with severe obesity (OB) compared with normal-weight healthy controls (HC). We hypothesized that OB have a higher load-to-strength ratio compared to HC. METHODS: We examined bone parameters in 65 girls 14-21 years old: 33 OB and 32 HC. We used dual-energy X-ray absorptiometry (DXA) to assess body composition, high resolution peripheral quantitative CT (HR-pQCT) to estimate vBMD, and microfinite element analysis (µFEA) to assess bone strength at the distal radius. To quantify fracture risk, we computed the load-to-strength ratio, where the numerator is defined as the load applied to the outstretched hand during a forward fall and the denominator is the bone strength, as estimated by µFEA. RESULTS: Although OB had higher total vBMD than HC (368.3 vs. 319.9 mgHA/cm3, p = 0.002), load-to-strength ratio at the radius was greater in OB than HC after controlling for age and race (0.66 vs. 0.54, p < 0.0001). In OB, impact force and load-to-strength ratio were associated negatively with % lean mass (r = -0.49; p = 0.003 and r = -0.65; p < 0.0001 respectively) and positively with visceral fat (r = 0.65; p < 0.0001 and r = 0.36; p = 0.04 respectively). CONCLUSIONS: Adolescent and young adult females with obesity have higher load-to-strength ratio at the distal radius due to higher forces applied to bone in a fall combined with incomplete adaptation of bone to increasing body weight. This is differentially affected by lean mass, fat mass, and visceral fat mass.

One-Year Self-Reported Appetite Is Similar in Adolescents with Obesity Who Do or Do Not Undergo Sleeve Gastrectomy.

BACKGROUND: With the growing prevalence of severe obesity in adolescents, sleeve gastrectomy (SG), a type of metabolic bariatric surgery (MBS), is increasingly being performed at a younger age. Data regarding changes in homeostatic and hedonic appetite following SG are conflicting in adults, with some studies showing no change and others showing a decrease in appetite. Data evaluating the effect of SG on appetite during adolescence, when appetite is more plastic, are currently lacking. OBJECTIVE: To evaluate appetite changes one year after SG in adolescents with obesity vs. in non-surgical controls (NS). METHODS: Thirty-nine subjects 13-21 years old with severe obesity were followed for a year; 19 underwent SG, and 20 were followed without surgery. Subjects had fasting blood tests for appetite-regulating hormones and completed a visual analog scale for appetite assessment (VAS). RESULTS: The SG group had a decrease in body mass index (BMI) at one-year (baseline: 48.2 ± 1.7 kg/m2; one-year follow-up: 42.6 ± 1.0 kg/m2 (p ≤ 0.0001)). No within- or between-group differences were noted in the one-year change in appetite in the SG and NS groups. After SG, fasting ghrelin decreased (p ≤ 0.0001); however, no changes were noted in peptide YY (PYY) levels. Changes in one homeostatic appetite measure following SG were inversely associated with changes in fasting PYY (r = -0.583, p = 0.011). Appetite changes were not associated with weight loss or final BMI. CONCLUSIONS: There were no changes in appetite measures one-year after SG from pre-surgery levels in adolescents with obesity, and appetite changes were not associated with changes in BMI. It is important to evaluate the impact of long-term appetite changes, if any, on weight loss after SG.

Physiologic Transdermal Estradiol Replacement Mimics Effects of Endogenous Estrogen on Bone Outcomes in Hypoestrogenic Women with Anorexia Nervosa.

Background: While physiologic estrogen replacement results in increases in areal bone mineral density (aBMD) in hypoestrogenic adolescent girls and young adult women with AN, data are lacking regarding its impact on measures of volumetric BMD (vBMD), bone geometry, and structure. Methods: 23 young women with anorexia nervosa (AN) and 27 normal-weight healthy controls (HC) between 14−25 years old were followed for 12 months. AN participants received transdermal 17ß-estradiol (continuously) with 10 days of cyclic oral progesterone (100 mg daily) every month for the study duration (AN-E+). DXA was used to measure aBMD and body composition, high resolution peripheral quantitative CT (HRpQCT) to assess vBMD, bone geometry and structure at the distal radius and tibia, and microfinite element analysis to estimate strength. Results: Groups did not differ for age. Median baseline BMI z-scores were −1.13 (−1.58, −0.38) in AN-E+ vs. 0.08 (−0.40, 0.84) in HC (p < 0.0001). For most HRpQCT parameters and strength estimates, young women with AN receiving physiologic estrogen replacement demonstrated similar changes over 12 months as did normoestrogenic HC. Additionally, radial cortical tissue mineral density, cortical vBMD, and failure load increased (p = 0.01; p = 0.02; p = 0.004 respectively) over 12 months in AN-E+ compared to HC. Conclusions: With physiologic estrogen replacement, bone accrual improved in AN to approximate changes observed in normoestrogenic controls followed without any intervention, with additional benefits observed for cortical tissue mineral density, cortical vBMD, and failure load at the radius in AN vs. controls. Thus, this strategy for estrogen replacement effectively mimics the effects of endogenous estrogen on bone structure and estimated strength.

Changes in Sex Steroids and Enteric Peptides After Sleeve Gastrectomy in Youth in Relation to Changes in Bone Parameters.

CONTEXT: Sleeve gastrectomy (SG) improves metabolic endpoints but is associated with impaired bone outcomes. OBJECTIVE: To determine mechanisms contributing to impaired bone health in youth following SG. METHODS: 12-month longitudinal observational study in a multidisciplinary tertiary-care hospital, including 64 youth 13-25 years old with moderate-to-severe obesity (51 females); 30 underwent SG and 34 were nonsurgical (NS) controls. SG was undertaken after a combined decision-making process between treatment team and patient. The main outcome measures were fasting blood for enteric peptides, sex steroids, sclerostin, and bone turnover markers (N-terminal propeptide of type 1 procollagen [P1NP] and C-terminal cross-linking telopeptide [CTX]); dual-energy X-ray absorptiometry measures of areal bone mineral density (aBMD) and body composition; high resolution peripheral quantitative computed tomography; measures of volumetric BMD (vBMD); microfinite element analysis of strength estimates (distal radius and tibia). RESULTS: SG had greater reductions in body mass index (BMI) z-scores, serum estrone, and the free androgen index (FAI) (P ≤ .046), and greater increases in sclerostin, P1NP, and CTX (P ≤ .010) than NS controls. Fasting ghrelin decreased in SG vs NS (P < .0001); fasting peptide YY did not change. Most changes were driven by female SG participants. Among females (the majority of study participants), after controlling for baseline age and race, reductions in total hip aBMD Z-scores were positively associated with changes in BMI, lean mass, estrone, FAI, and ghrelin, and inversely with changes in sclerostin.. Decreases in total vBMD of the radius and tibia were associated positively with decreases in BMI. Increases in CTX were associated with decreases in BMI, lean mass, and ghrelin, and increases in sclerostin. CONCLUSION: Bone loss after SG in youth is associated with changes in body composition, sex steroids, sclerostin, and enteric peptides. These are potential targets for future preventative or therapeutic strategies.