United States

Cardiovascular morbidity and mortality are high in persons with severe mental illness. Psychotropic medications, particularly second-generation antipsychotics (SGA), and also adverse health behaviors are mediators of adverse cardiometabolic health outcomes in persons with severe mental illness. Identifying and addressing specific risk factors early and aggressively is key to improving health outcomes in these patients; yet studies addressing the above problems are limited. We therefore evaluated 39 patients with schizophrenia, schizoaffective, or bipolar disorder on SGA in a comprehensive cardiometabolic, lifestyle, and mental health screening program. Data were analyzed using SPSS version 24. As previously reported, the majority of screened patients had prediabetes (PD) or diabetes mellitus (DM), 74% per oral Glucose Tolerance Testing (oGTT), 56% per HbA1c criteria. Pulse rates, insulin resistance indices (Homeostatic Model Assessment of Insulin Resistance, HOMA IR, and Matsuda) were significantly different between patients classified as normal or with PD/DM, using either oGTT or HbA1c criteria. However, patients with PD/DM per HbA1c, but not oGTT criterium, also had higher waist/hip ratios (p=0.01), triglyceride (p=0.01) and hsCRP levels (p=0.04) as well as lower HDL levels (p=0.04). We then determined whether dietary habits (by UK Diabetes and Diet Questionnaire, UKDDQ), mood (by Patient Health Questionnaire, PHQ-9) and/or physical activity (average daily step count) were associated with unfavorable, and potentially modifiable cardiometabolic biomarkers (fasting, 2h-oGTT plasma glucose, serum insulin, triglycerides, HDL, LDL, HbA1c, hsCRP and adiponectin). We find that fasting plasma glucose and triglyceride levels significantly correlated with UKDDQ scores (fasting plasma glucose: r=0.34, p=0.03, fasting triglyceride levels: r=0.37, p=0.02); a trend was observed for higher insulin resistance indices (HOMA IR) being associated with higher UKDDQ scores (r=0.31, p=0.06). We also confirm a strong negative correlation of the average daily step count with hsCRP levels (r=-0.62, p&lt;0.0001). PHQ-9 scores negatively correlated with adiponectin levels (r=-0.475, p&lt;0.005). Altogether, in our patient population with severe mental illness on SGA, unhealthy diet habits, low physical activity, and symptoms of depression were associated with higher fasting glucose and triglycerides, higher hsCRP and lower adiponectin levels, all of which may potentially contribute to adverse cardiometabolic outcomes. Future studies should assess the impact of specifically tailored individual lifestyle counseling and medical management interventions in this high-risk patient population.

ENDO 2022

Poor Diet Habits, Depression and Low Physical Activity Correlate with Cardiometabolic Risk Markers in Persons with Severe Mental Illness on Second-Generation Antipsychotic Medications.

**Program**
ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

**What Programming Is Included in My Virtual Meeting Registration?**
As you build your schedule during the conference, you can select the sessions that are tagged with 'Livestreamed', so you can view virtually. These sessions are being livestreamed, so they are available in real time to our virtual audience. In addition, our in-person and livestreamed sessions will be recorded, so you can access them on demand after 72 hours. We will have over 200 hours available on demand for Standard and Premium pass registrants.

Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

Cardiovascular morbidity and mortality are high in persons with severe mental illness. Psychotropic medications, particularly second-generation antipsychotics (SGA), and also adverse health behaviors are mediators of adverse cardiometabolic health outcomes in persons with severe mental illness. Identifying and addressing specific risk factors early and aggressively is key to improving health outcomes in these patients; yet studies addressing the above problems are limited. We therefore evaluated 39 patients with schizophrenia, schizoaffective, or bipolar disorder on SGA in a comprehensive cardiometabolic, lifestyle, and mental health screening program. Data were analyzed using SPSS version 24. As previously reported, the majority of screened patients had prediabetes (PD) or diabetes mellitus (DM), 74% per oral Glucose Tolerance Testing (oGTT), 56% per HbA1c criteria. Pulse rates, insulin resistance indices (Homeostatic Model Assessment of Insulin Resistance, HOMA IR, and Matsuda) were significantly different between patients classified as normal or with PD/DM, using either oGTT or HbA1c criteria. However, patients with PD/DM per HbA1c, but not oGTT criterium, also had higher waist/hip ratios (p=0.01), triglyceride (p=0.01) and hsCRP levels (p=0.04) as well as lower HDL levels (p=0.04). We then determined whether dietary habits (by UK Diabetes and Diet Questionnaire, UKDDQ), mood (by Patient Health Questionnaire, PHQ-9) and/or physical activity (average daily step count) were associated with unfavorable, and potentially modifiable cardiometabolic biomarkers (fasting, 2h-oGTT plasma glucose, serum insulin, triglycerides, HDL, LDL, HbA1c, hsCRP and adiponectin). We find that fasting plasma glucose and triglyceride levels significantly correlated with UKDDQ scores (fasting plasma glucose: r=0.34, p=0.03, fasting triglyceride levels: r=0.37, p=0.02); a trend was observed for higher insulin resistance indices (HOMA IR) being associated with higher UKDDQ scores (r=0.31, p=0.06). We also confirm a strong negative correlation of the average daily step count with hsCRP levels (r=-0.62, p<0.0001). PHQ-9 scores negatively correlated with adiponectin levels (r=-0.475, p<0.005). Altogether, in our patient population with severe mental illness on SGA, unhealthy diet habits, low physical activity, and symptoms of depression were associated with higher fasting glucose and triglycerides, higher hsCRP and lower adiponectin levels, all of which may potentially contribute to adverse cardiometabolic outcomes. Future studies should assess the impact of specifically tailored individual lifestyle counseling and medical management interventions in this high-risk patient population.

technical paper

Aims: Nephrolithiasis is a common disease, estimated to affect 10% of the US population. In addition to pain, often severe, it can lead to urinary tract infections and acute kidney injury, while contributing to health care costs from emergency room visits and follow-up interventions necessary to relieve stone burden. Type 2 diabetes (T2D) is a well-known risk factor for nephrolithiasis. Recently in an observational study of patients with T2D, use of sodium-glucose transport protein 2 (SGLT2) inhibitors as glucose lowering agents was associated with a 49% lower risk of nephrolithiasis when compared with use of glucagon like peptide 1 (GLP-1) receptor agonists. We examined, prospectively, the association between renal stone disease and the use of the SGLT2 inhibitor empagliflozin, using existing data from randomized clinical trials.
Methods: Pooled data from 15,081 patients with T2D treated with empagliflozin (10,177) or placebo (4,904) from 20 phase I-IV randomized, placebo-controlled trials including the large cardiovascular outcome trial, EMPA-REG OUTCOME, were included in this analysis. Incident urinary tract stone events were captured using a pre-defined collection of MedDRA terms: nephrolithiasis, renal colic, ureterolithiasis, calculus bladder, calculus urinary, calculus urethral, and nephrocalcinosis (MedDRA version 22.1). A sensitivity analysis used a narrower definition by excluding the terms renal colic and nephrocalcinosis. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were calculated using the relative risk estimate stratified by study.
Results: The median exposure to study drug was 543 (placebo) and 549 (empagliflozin 10 or 25 mg) days We found that a total of 183 patients experienced an incident urolithiasis during follow-up (79 in placebo, 104 in pooled empagliflozin) yielding annual incidence rates of 1.01 versus 0.63 events per 100 patient years in placebo and empagliflozin, respectively. All but one event occurred in patients with no prior history of urinary tract stones. The IRR was 0.64 (95% CI 0.48, 0.86), in favor of empagliflozin. In the sensitivity analysis, now restricted to nephrolithiasis, ureterolithiasis, calculus bladder, calculus urinary, and calculus urethral, the results were similar (IRR, empagliflozin vs. placebo, 0.62 [95% CI 0.45, 0.85]).
Conclusion: As compared to placebo, use of empagliflozin was associated with an approximate 40% reduction in the risk of urolithiasis in patients with T2D. Alterations in lithogenic profile of the urine (including dilutional effects) of potential stone formers after SGLT2 inhibition may explain this finding. Based on these initial observations, mechanistic studies to elucidate the mediator(s) of this seemingly protective effect and dedicated randomized prospective clinical trials appear warranted in patients with renal stone disease. As with follow-up SGLT2 inhibitor investigations conducted in patients with heart failure and chronic kidney disease, such trials should include individuals who do not have T2D.

Empagliflozin and the risk of nephrolithiasis

Background: Patients with gestational diabetes mellitus (GDM) have an increased risk of developing type 2 diabetes mellitus (T2DM) after delivery and are encouraged to practice behaviors, such as healthy nutrition, physical activity and weight loss to attenuate future risk of T2DM. GDM has been shown to significantly increase the risk for post-partum depressive symptoms, which can impair a woman's ability to engage in and adhere to diabetes prevention efforts. To further inform the development and adapation of lifestyle interventions to prevent T2DM, we sought to identify factors associated with depressive symptoms in the early postpartum period among women with recent GDM.
Methods: Participants are from the baseline cohort of the Balance after Baby Intervention study, a two-year randomized clinical trial of a lifestyle intervention for women with recent history GDM conducted in Boston, MA and Denver, CO between 2016-2019. Prior to randomization, a study visit was scheduled at approximately 6 weeks post-partum. At this visit, weight and height were measured for determination of BMI. We administered the Edinburgh Postpartum Depression Scale (EPDS) and Perceived Stress Scale (PSS-10). We used an EPDS score of ≥9 as depressive symptoms and a PSS score of ≥14 as moderate to high perceived stress. We collected self-reported pre-pregnancy weight, and reviewed medical records to obtain medical history, including GDM diagnosis, mode of delivery, gestational weight gain and insulin use during pregnancy. We conducted bivariate analyses to identify predictors of postpartum depressive symptoms, then modeled the odds of post-partum depressive symptoms using multivariate logistic regression.
Results: Our study included 181 women (mean age, SD 32.6 ± 5.3 years, 51.4% White/14.4% Black/33.7% Latinx, mean pre-pregnancy BMI 29.8 ± 6.0 kg/m²). 19% of women scored ≥9 on EPDS and 53% of women scored ≥14 on PSS at the post-partum visit. Variables included in the bivariate analysis were age, Black/Latinx-identifying, college completion, perceived stress, primiparity, having a partner, pre-pregnancy BMI, gestational weight gain, C-section, insulin use during pregnancy, breastfeeding, 1st GDM pregnancy, exceeding IOM weight gain guidelines and income level. Of those variables, the best fit multivariate model with the lowest Akaike information criterion (AIC) included perceived stress, C-section and 1st GDM pregnancy. Using this model, the regression analysis showed that only perceived stress (4.5 OR, 95% CI [2.6-7.7], p was predictive of post-partum depressive symptoms. Conclusion: Perceived stress was predictive of post-partum depressive symptoms in women with recent GDM. Addressing perceived stress in the early post-partum period may be an important target for development or adaptations of future lifestyle interventions to prevent T2DM in women with recent GDM.

Predictors of Postpartum Depressive Symptoms in Women with Recent GDM

Central estrogen signaling in the medial basal hypothalamus (MBH) coordinates energy expenditure, food intake, and reproduction, as well as skeletal homeostasis. Prior work from our lab found that estrogen signaling via Estrogen Receptor alpha (ERa) in the arcuate (ARC) nucleus normally restrains bone formation in female mice only. We asked if the high bone mass in the Esr1Nkx2-1Cre mouse model, which ablates ERa in the MBH, is maintained or deteriorates with chronic overnutrition, as this is known to increase bone frailty in humans. To carry out this study, Esr1Nkx2-1Cre mutant female mice were fed HFD (Research Diets, D12492, 60% fat) or chow (SCD, 5058; LabDiet, 4% fat) for 17 weeks beginning at 10 weeks of age and housed at 22C. Although neither cohort gained significant weight on HFD nor exhibited marked changes in other metabolic parameters (%fat, GTT, ITT, etc.), this dietary challenge reversed and normalized the high bone mass in mutant females. Specifically, the ratio of BV/TV in the distal femur decreased dramatically from 36% to 6%, as measured by 3D-microcomputed tomography (micro-CT); cortical bone also decreased similarly. For comparison, control females fed HFD showed a non-significant decrease in bone mass (4.9% to 3.9% BV/TV). Unexpectedly, the large drop in bone mass in Ers1Nkx2-1Cre females fed HFD was uncoupled from an increase in bone marrow adipose tissue (BMAT). In contrast, control cohorts showed a marked 9-fold increase in BMAT following HFD. Thus, the high bone mass in mutant Ers1Nkx2-1Cre females, which persists in aged and estrogen-depleted females, quickly disintegrates with a dietary challenge. Recent RNA-Seq data from microdissected ARC tissue reveals several secreted factors that are dramatically elevated in mutant females but drop 10-20-fold after HFD. Current studies are underway to ask if these candidate factors from the ARC impact bone mass or the osteogenic capacity of skeletal stem cells. Our findings are in stark contrast to the notion that dietary excess reduces bone health by increasing bone fat at the expense of osteogenesis. Instead, based on our model, we posit that dietary excess directly determines dynamic bone remodeling by acting on the brain.

Brain Determinants of Dynamic Bone Remodeling in Females

Female athletes with low energy availability are at risk for impaired bone microarchitecture and strength associated with hypogonadism. Data are lacking for bone outcomes in male athletes. We studied 31 men 16-30 years (n=15 runners with mean (±SD) mileage 43±4 miles/week, n=16 non-athlete controls). We assessed distal tibia and radius volumetric BMD (vBMD) and microarchitecture by high resolution peripheral quantitative CT (HRpQCT), estimated bone strength by microfinite element analysis and body composition by DXA. Testosterone, estradiol (by LC-MS) and leptin (by electrochemiluminescence) were measured. Groups did not differ for mean age (24.5±3.6y), BMI (22.2±2.6 kg/m²), lean mass, or testosterone or estradiol levels. Mean tibial cortical vBMD was lower and porosity higher in athletes than controls (p<0.01). In contrast, mean tibial trabecular vBMD and number were higher, and separation lower, in athletes (p<0.02). Athletes with BMI ≤ 21 kg/m² had lower tibial failure load (bone strength estimate) than those with BMI >21 kg/m² (p=0.007). Lean mass (R=0.85, p<0.0001), serum leptin (R=0.59, p=0.046) and estradiol (R=0.66, p=0.007), but not testosterone, were associated with tibial failure load in athletes. Athlete and control groups did not differ for HRpQCT variables at the radius. Despite weight-bearing activity, male runners have impaired tibial cortical BMD and microarchitecture, which may increase their risk for bone stress injuries. Lower leptin (reflecting lower fat mass) and estradiol (converted from testosterone in adipose tissue), as well as lean mass, are determinants of lower tibial strength in these athletes, suggesting that low energy availability is a risk factor for impaired bone strength in male runners.

Male Runners Have Impaired Tibial Cortical Bone Integrity and Strength Compared to Non-athletes

Background: Primary hyperparathyroidism (PHPT) is one of the known causes of secondary osteoporosis. PHPT is associated with increased bone turnover, low bone density and quality; but there have been conflicting results on the risk of fractures. There is limited information on the effects of age, gender, and ethnicity on fracture risk in PHPT.
Objective: To determine the prevalence of vertebral fractures (VFx) and associated risk factors in patients with PHPT
Design: Retrospective cross-sectional study
Setting: Academic medical center in a community setting
Main outcome measured: 1) Bone mineral density (BMD), and T- and Z-scores of the lumbar spine (LS). 2) Vertebral morphometry was assessed using the Genant method to identify asymptomatic vertebral fractures (VFx) on CT spine images. 3) Biochemical measurements included serum PTH, Creatinine (Cr) and Calcium (Ca).
Results: In this retrospective study of consecutive 560 PHPT patients verified by surgery [447 women with a median age of 62y; 362 Caucasians (65%), 142 African Americans (AA, 25%) and 22 unspecified race (10%)] were included. Prevalence of VFx was 13% (n=75), other sites 15% (n=84), wrist fractures 3% (n=16) and hip fractures 1% (n=6). Fracture prevalence at all sites was higher in women, but significant only for VFx (71% vs 29%, p=0.04). In subgroup analysis by age (above or below 50y) and gender, there was no significant difference in LS BMD, T- or Z-score values, serum PTH, Ca and Cr in patients with and without VFx. In subgroup analysis by ethnicity: i) prevalence of all fractures was higher in Caucasians compared to AA and others ii) mean serum PTH (±SD) level was significantly higher in AA vs Caucasian patients with VFx (190 ± 124 vs 121 ± 57 pg/mL, p=0.03) and iii) no significant differences were noted in LS BMD, T-or Z-scores, serum Ca and Cr in patients with VFx.
In multivariate analysis (age, serum Ca, PTH >100, and LS BMD) to predict risk of VFx in all patients, only age [OR 1.07, CI 1.03-1.11) and serum Ca [OR 1.7, CI 1.03 – 2.79] were significant factors. In women, multivariate analysis identified increasing age to be the only significant risk factor to predict risk of VFx. [OR 1.107, CI 1.03-1.12].
Conclusion: Vertebral fractures (VFx) is more prevalent in comparison to wrist and hip fractures in patients with PHPT. Serum PTH is significantly higher in African American PHPT patients with VFx. Increasing age and serum calcium ≥11.1 mg/dL are significant predictors of VFx in PHPT patients.

Effect of Age, Gender, & Ethnicity on the Prevalence of Vertebral fractures in Patients with Primary Hyperparathyroidism

Introduction: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder of progressive heterotopic ossification, resulting in cumulative loss of joint function and severe disability. We present results from an international, cross-sectional FOP Burden of Illness Survey (NCT04665323) demonstrating the impact of loss of joint function on quality of life (QoL) for patients and their family members. Methods: Individuals with FOP (survey proxy-completed for patients aged <13 years), their primary caregivers, and other family members (aged ≥18 years) were eligible to participate. Family members who acted as a proxy could also participate themselves, as a family member. The survey was available online from 18Jan21–30Apr21 in 15 countries and 11 languages. The Patient­-Reported Mobility Assessment (PRMA) evaluated range of motion across 12 joints and 3 body regions (total scores range from 0–30; higher scores reflect more severe limitations). PRMA total scores were categorized into four Levels: Level 1, 0–6; Level 2, 7–12; Level 3, 13–18; Level 4, ≥19. To assess the impact of FOP on QoL, patients ≥13 years and their family members completed the EuroQoL health-related QoL questionnaire (EQ-5D-5L; index ranges from <0 [worst health] to 1 [full health]). Descriptive analyses of EQ-5D-5L index scores were performed for each population and by patients' PRMA Level. Linear regression analyses (adjusted for geographic region) were used to evaluate the relationship between patients' degree of joint impairment (PRMA total score) and patient or family member EQ-5D-5L index score. Results: 463 survey responses were received from 405 individuals: patient/proxy population, n=219 (patients ≥13 years, n=161; proxies for patients <13 years, n=58); family member population, n=244, of whom 163 identified as primary caregivers. Mean (standard deviation [SD]) EQ-5D-5L index score was 0.24 (0.36) for patients ≥13 years, 0.83 (0.22) for primary caregivers, and 0.85 (0.21) across all family members. For the patient population, mean (SD) EQ-5D-5L index score decreased as PRMA Level increased: Level 1, 0.61 (0.26); Level 2, 0.46 (0.34); Level 3, 0.21 (0.30); Level 4, 0.05 (0.26). There was a significant negative association between PRMA total score and EQ­-5D-5L index score for patients, such that for every 1-unit increase in the PRMA total score of the patient, there was a mean (standard error [SE]) decrease of 0.029 (0.003; p<0.0001) in EQ-5D-5L adjusted for geographic region. For all family members, there was no significant association between EQ-5D-5L and the PRMA total score of the patient (p=0.6737). Conclusion: Loss of joint function (as represented by PRMA Level) has a significant, detrimental impact on QoL for patients with FOP. These findings increase understanding of the impact of FOP on patients and their family members, and may help to improve quality of care and access to support for the FOP community. Funding: Sponsored by Ipsen.

Joint Function and Quality of Life in Fibrodysplasia Ossificans Progressiva: Results from an International Burden of Illness Survey of Patients and Family Members

Background: Hypercalcemia during pregnancy is rare. The true incidence, however, is difficult to estimate as routine calcium screening is not recommended. Hypercalcemia is linked with various maternal and fetal outcomes but overall, the literature is conflicting.
Aims: Aim of this study is to determine the frequency of hypercalcemia in pregnancy and to determine association with early maternal and fetal outcomes.
Methods: This retrospective cohort study included all confirmed gestations with expected date of delivery (EDD) between 2017-2019 at a large tertiary maternity unit. Baseline demographic, biochemical, and clinical data collected as part of a clinical-administrative dataset was retrieved. Maternal and fetal outcomes studied were incidence of fetal loss (miscarriage/stillbirth), pre-term delivery, emergency C-section, hypertension, blood loss during delivery, neonatal intensive care unit (NICU) admission, and fetal birth weight (for term deliveries).
Results: Total number of gestations and livebirths recorded between 2017-2019 were 33,118 and 20,969, respectively, with median age of 30.1 [IQR 25.6-34.3] years. Two-thirds of pregnancies were in Caucasian women (65.9%) followed by Asians (9.6%), Afro-Caribbean (5%), and others (19.5%). 15.7% (n=5195) of all gestations had calcium tested in the preceding ten months of EDD. Of these, the hypercalcemia and hypocalcemia were noted in 42 (0.81%) and 499 gestations (9.61%) respectively. The median adjusted calcium in the hypercalcemic group was 2.75 mmol/L [IQR 2.65-2.88] and underlying diagnoses were primary hyperparathyroidism (n=17), transient hypercalcemia (n=12), suspected familial hypocalciuric hypercalcemia (n=2), sarcoidosis (n=1), and unknown (n=10). Of maternal and fetal outcomes, the incidence of pre-term delivery (20.0% v 9.2%; P=0.042), emergency C-section (42.4% v 21.4%; P=0.021), neonatal intensive care unit (NICU) admission (19.4% v 8.2%; P=0.024), and blood loss during delivery (1252 v 526 mL; P<0.001) was higher in the hypercalcemic group. The incidence of fetal loss (22.5% v 18.9%; P=0.560) and hypertension (0% v 1%; P =0.561) was not different between hyper and normocalcemic groups. Interestingly, the hypocalcemic group also demonstrated higher incidence of pre-term delivery (24.2% v 9.2%; P=<0.001), emergency C-section (28.6% v 21.4%; P=0.025), NICU admission (15.9% v 8.2%; P<0.001), and blood loss (627 v 526 mL; P<0.001), but not of fetal loss (21.0% v 18.9%; P=0.281) or hypertension (2.2% v 1.0%; P =0.054) compared to the eucalcemic group.
Conclusion: The incidence of hypercalcemia in pregnancy is low (0.81%). However, abnormal calcium levels are associated with worse maternal and fetal outcomes. Research needs to focus on whether routine calcium estimations are necessary and if treatment of these conditions improves maternal and fetal outcomes. We recommend that calcium testing should be considered in women who are at risk of worse outcomes during current or previous pregnancies.

Hypercalcemia and hypocalcemia during pregnancy are associated with worse maternal and fetal outcomes

Introduction
We used a machine-learning algorithm (gradient boosting) to test the association of genetic risk for 11 glycemic traits with osteoporosis and fractures in the UK Biobank population.
Methods
The study was performed with 409,633 caucasian participants in the UKBIobank. We identified 4626 SNPs associated with 11 glycemic traits from the NGHRI catalogue for GWAS studies. Weighted genetic risk scores (wGRS) were calculated using the effect estimates from the GWAS studies. We used a gradient-boosting machine-learning (GBM) model to identify the relative influence (RI) of baseline variables and wGRS of the glycemic traits on osteoporosis and all-cause fractures in the UK Biobank population. We split the data into training (2/3) and testing set (1/3) and calculated the discriminatory power of the models using the area under the curve (AUC) with the testing model.
Results
The study consisted of 409,633 individuals (53% females) with a median age of 58 (51-63) years and a median BMI of 26.7 (24.1-29.8) kg/m². The study population had 41954 (10.2%) all-cause fractures and 4995 (1.2%) participants with osteoporosis. In the GBM model, top wGRS associated with all-cause fractures were wGRS for Type 1 diabetes (RI=4.49) and fasting glucose (4.17). In contrast, the top wGRS associated with osteoporosis were wGRS for acute insulin response to glucose (RI=6.74) and Type 1 diabetes (RI=5.62). Both models showed low to moderate discriminatory power with the area under the AUC of 0.57(CI: 0.56-0.57) for fractures and 0.75(CI: 0.74-0.76) for osteoporosis.
Conclusion
We showed a differential effect of wGRS for various glycemic traits on the risk of fractures and osteoporosis in the UK Biobank population. However, the machine-learning model with wGRS for glycemic traits demonstrated limited capacity to predict fractures and osteoporosis in the general population.

Estimating the relative influence (RI) of genetic risk of 11 glycemic traits on osteoporosis and fractures in 409633 participants in the UK Biobank using Machine learning

Purpose: Metabolic syndrome (MetS) comprises a constellation of risk factors for cardiovascular disease, which are thought to be derived from truncal obesity. Adipose tissue can have positive effects on bone density through mechanical stimulation on weight bearing sites and can have hormonal influences which affect bone cells, however in obesity this relationship is inversed as the deleterious effects of excess fat mass predominate. It is unclear how MetS and the regional distribution of fat relate with bone density and bone quality in lean individuals who do not benefit from increased weight bearing.
Methods: We performed a cross sectional analysis of adults who underwent bone density and body composition by dual energy x-ray absorptiometry (DXA) at a university health system bone clinic, and had laboratory and demographic data available in the electronic medical record. We included adults with BMI below 24.9 kg/m2 in the analysis. Individuals were classified as being metabolically unhealthy lean (MUL) when they fulfilled at least 2 of the following criteria: blood pressure > 130/85, triglyceride >150 mg/dL, HDL < 50 mg/dL for women and < 40 mg/dL for men, fasting plasma glucose >100mg/dL (or HbA1c >=5.7), and metabolically healthy lean (MHL) when they did not fit the criteria. Linear regression was used to evaluate the association of body composition fat parameters with trabecular bone score (TBS), and bone mineral density (BMD) at the total hip (TH).
Results: Among the 119 (100%) lean adults, 50 (42%) were classified as being MUL. Mean age was 62 ±14 years old and mean BMI was 22 ±1.9kg/m2. The population was mostly white 105 (88%) and 70 (41%) were Hispanics. Additionally, 43 subjects (40%) had a history of a previous fracture. Total body fat was similar between the two groups (mean,%) MHL 33.5, MUL 34.1 (p=0.32), as were age (mean, years) MHL 62.3 vs MUL 62.5 (p=0.48), BMI (mean, kg/m2) MHL 22.2, MUH 22.2 (p=0.49), TH BMD (mean, g/cm2) MHL 0.74, MUL 0.72 (p=0.140) and TBS (mean, unitless) MHL 1.34, MUL 1.33 (p=0.308). However, visceral adipose tissue area (VAT) (mean, cm2) was statistically significantly different between the groups (MHL 69.0, MUL 86.7, p=0.004). In linear regression analyses total body fat had negative association with TBS (B=-0.44, p<0.001) and TH BMD (B= -0.37, p<0.001) while VAT had negative association with TBS (B=-0.26, p=0.02) but not TH BMD (B=-0.17, p=0.08).
Conclusion: In our sample of older lean individuals body fat distribution varied by classification of metabolic health. Total body fat amount was associated with decreasing bone density and quality, while higher truncal fat as measured by VAT area was associated with decreasing bone quality. Our findings suggest that excess body fat may have deleterious effects on bone health even in lean individuals

Bone Quality in Lean Adults with Metabolic Syndrome

While anorexia nervosa is associated with impaired skeletal integrity, less is known about the skeletal effects of atypical anorexia nervosa, in which psychological criteria for anorexia nervosa are met, but affected individuals are not low weight. Mean bone mineral density (BMD) is higher in atypical anorexia nervosa than in low-weight anorexia nervosa but lower than in healthy controls. However, it is unknown whether bone microarchitecture and strength are affected. We hypothesized that bone microarchitecture and estimated strength would be impaired in women with atypical anorexia nervosa.
This was a cross-sectional study of women ages 21-46 years (n=55): n=28 with atypical anorexia nervosa (body mass index (BMI) >18.5 kg/m²), n=27 healthy, normal weight, eumenorrheic controls. Exclusion criteria included use of oral contraceptives. Areal BMD (aBMD) was assessed by DXA. Volumetric BMD (vBMD), microarchitecture, and failure load (a bone strength estimate) at the distal tibia and radius were assessed by high-resolution peripheral quantitative CT.
Median(IQR) BMI was lower [19.4(18.6,20.2) vs 22.2(21.5,23.0), p<0.0001] and median serum 25OH vitamin D level was higher [31(24,39) vs 22(17,25), p=0.0001] in atypical anorexia nervosa than healthy controls. In the atypical anorexia nervosa group, 89% had a history of low weight, 21% had a history of overweight/obesity, 31% had current amenorrhea, and 88% had a history of amenorrhea; median duration of anorexia nervosa was 11(5,14) years.
Median lateral spine, total hip, femoral neck, and total radius aBMD Z-scores were lower in atypical anorexia nervosa than healthy controls [lateral spine: -1.1(-2.0,-0.1) vs -0.4(-0.7,0.4), total hip: -0.8(-1.3,0.2) vs 0.2(-0.4,0.7), femoral neck: -0.9(-1.4,0.1) vs -0.1(-0.9,0.6), radius: -0.2(-0.9,0.3) vs 0.1(-0.4,0.6); p≤0.04 for all]. At the tibia, median total, cortical, and trabecular vBMD; cortical thickness; trabecular bone volume fraction; and failure load were lower in atypical anorexia nervosa than healthy controls (p<0.05). At the radius, median trabecular number was lower and trabecular separation was higher in atypical anorexia nervosa than healthy controls (p≤0.04), but there was no difference in failure load between the groups. After controlling for baseline BMI, differences at the radius but not tibia remained significant. At the tibia and radius, median total vBMD, cortical vBMD, and cortical thickness were lower in atypical anorexia nervosa subjects with amenorrhea compared to healthy controls and to atypical anorexia nervosa subjects with eumenorrhea (p≤0.04).
Conclusions: We demonstrate that, despite normal weight, women with atypical anorexia nervosa have impaired vBMD, microarchitecture, and estimated strength compared to healthy controls, with differences more pronounced at the weight-bearing tibia vs non-weight-bearing radius. Individuals with amenorrhea had additional impairments in the non-weight-bearing radius, suggesting an effect of systemic estrogen deficiency. Our data suggest that current normal weight is not protective against impaired bone structure and strength in atypical anorexia nervosa.

Poor Diet Habits, Depression and Low Physical Activity Correlate with Cardiometabolic Risk Markers in Persons with Severe Mental Illness on Second-Generation Antipsychotic Medications.

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