CONTEXT: Most labs set the lower limit of normal for testosterone at the 2.5th percentile of values in young or age-matched men, an approach that does not consider the physiologic changes associated with various testosterone concentrations.
OBJECTIVE: To characterize the dose-response relationships between gonadal steroid concentrations and measures regulated by gonadal steroids in older men.
DESIGN, PARTICIPANTS, AND INTERVENTION: 177 men aged 60 to 80 were randomly assigned to receive goserelin acetate plus either 0 (placebo), 1.25, 2.5, 5, or 10 grams of a 1% testosterone gel daily for 16 weeks or placebos for both medications (controls).
PRIMARY OUTCOMES: Changes in serum C-telopeptide (CTX), total body fat by dual energy X-ray absorptiometry, and self-reported sexual desire.
RESULTS: Clear relationships between the testosterone dosage (or the resulting testosterone levels) and a variety of outcome measures were observed. Changes in serum CTX exceeded changes in the controls in men whose testosterone levels were 0 to 99, 100 to 199, 200 to 299, or 300 to 499 ng/dL, whereas increases in total body fat, subcutaneous fat, and thigh fat exceeded controls when testosterone levels were 0 to 99 or 100 to 199 ng/dL. Sexual desire and erectile function were indistinguishable from controls until testosterone levels were <100 ng/dL.
CONCLUSION: Changes in measures of bone resorption, body fat, and sexual function begin at a variety of testosterone concentrations with many outcome measures remaining stable until testosterone levels are well below the stated normal ranges. In light of this variation, novel approaches for establishing the normal range for testosterone are needed.
BACKGROUND: There is intense interest about whether modulating gut microbiota can impact systemic metabolism. We investigated the safety of weekly oral fecal microbiota transplantation (FMT) capsules from healthy lean donors and their ability to alter gut microbiota and improve metabolic outcomes in patients with obesity.
METHODS AND FINDINGS: FMT-TRIM was a 12-week double-blind randomized placebo-controlled pilot trial of oral FMT capsules performed at a single US academic medical center. Between August 2016 and April 2018, we randomized 24 adults with obesity and mild-moderate insulin resistance (homeostatic model assessment of insulin resistance [HOMA-IR] between 2.0 and 8.0) to weekly healthy lean donor FMT versus placebo capsules for 6 weeks. The primary outcome, assessed by intention to treat, was change in insulin sensitivity between 0 and 6 weeks as measured by hyperinsulinemic euglycemic clamps. Additional metabolic parameters were evaluated at 0, 6, and 12 weeks, including HbA1c, body weight, body composition by dual-energy X-ray absorptiometry, and resting energy expenditure by indirect calorimetry. Fecal samples were serially collected and evaluated via 16S V4 rRNA sequencing. Our study population was 71% female, with an average baseline BMI of 38.8 ± 6.7 kg/m2 and 41.3 ± 5.1 kg/m2 in the FMT and placebo groups, respectively. There were no statistically significant improvements in insulin sensitivity in the FMT group compared to the placebo group (+5% ± 12% in FMT group versus -3% ± 32% in placebo group, mean difference 9%, 95% CI -5% to 28%, p = 0.16). There were no statistically significant differences between groups for most of the other secondary metabolic outcomes, including HOMA-IR (mean difference 0.2, 95% CI -0.9 to 0.9, p = 0.96) and body composition (lean mass mean difference -0.1 kg, 95% CI -1.9 to 1.6 kg, p = 0.87; fat mass mean difference 1.2 kg, 95% CI -0.6 to 3.0 kg, p = 0.18), over the 12-week study. We observed variable engraftment of donor bacterial groups among FMT recipients, which persisted throughout the 12-week study. There were no significant differences in adverse events (AEs) (10 versus 5, p = 0.09), and no serious AEs related to FMT. Limitations of this pilot study are the small sample size, inclusion of participants with relatively mild insulin resistance, and lack of concurrent dietary intervention.
CONCLUSIONS: Weekly administration of FMT capsules in adults with obesity results in gut microbiota engraftment in most recipients for at least 12 weeks. Despite engraftment, we did not observe clinically significant metabolic effects during the study.
TRIAL REGISTRATION: ClinicalTrials.gov NCT02530385.
The 20th annual Santa Fe Bone Symposium was held August 9-10, 2019, in Santa Fe, New Mexico, USA. This is an annual meeting devoted to clinical applications of recent advances in skeletal research that impact the care of patients with osteoporosis, metabolic bone diseases, and inherited bone diseases. Participants included practicing and academic physicians, fellows, advanced practice providers, fracture liaison service (FLS) coordinators, clinical researchers, and bone density technologists. The symposium consisted of lectures, case presentations, and panel discussions, with an emphasis on learning through interaction of all attendees. Topics included new approaches in the use of anabolic agents for the treatment osteoporosis, a review of important events in skeletal health over the past year, new and emerging treatments for rare bone diseases, the use of genetic testing for bone diseases in clinical practice, medication-associated causes of osteoporosis, new concepts in the use of estrogen therapy for osteoporosis, new Official Positions of the International Society for Clinical Densitometry, skeletal consequences of bariatric surgery, and update on the progress and potential of Bone Health TeleECHO, a virtual community of practice using videoconferencing technology to link healthcare professionals for advancing the care of osteoporosis worldwide. Sessions on rare bone diseases were developed in collaboration with the Rare Bone Disease Alliance. Symposium premeetings included an FLS workshop by the National Osteoporosis Foundation and others devoted to the use of new therapeutic agents for the care of osteoporosis and related disorders.
AIMS: Studies have suggested relationships between obesity and cardiovascular disease (CVD) morbidity. However, little is known about whether substantial weight reduction affects the risk of CVD-related acute care use in obese patients with CVD. The objective of this study was to determine whether bariatric surgery is associated with decreased risk of CVD-related acute care use.
METHODS AND RESULTS: We performed a self-controlled case series study of obese adults with CVD who underwent bariatric surgery, using population-based emergency department (ED), and inpatient samples in California, Florida, and Nebraska from 2005 to 2011. The primary outcome was ED visit or unplanned hospitalization for CVD. We used conditional logistic regression to compare the risk during sequential 12-month periods, using pre-surgery months 13-24 as the reference period. We identified 11 106 obese adults with CVD who underwent bariatric surgery. During the reference period, 20.6% [95% confidence interval (CI), 19.8-21.3%] of patients had an ED visit or unplanned hospitalization for CVD. The risk did not significantly change in the subsequent 12-month pre-surgery period [adjusted odds ratio (aOR) 0.98; 95% CI, 0.93-1.04; P = 0.42]. By contrast, in the first 12-month period after bariatric surgery, the risk significantly decreased (aOR 0.91; 95% CI, 0.86-0.96; P = 0.002). The risk remained reduced in the subsequent 13-24 months post-bariatric surgery (aOR 0.84; 95% CI, 0.79-0.89; P < 0.001). There was no reduction in the risk in separate obese populations that underwent non-bariatric surgery (i.e. cholecystectomy, hysterectomy). By CVD category, the risk of acute care use for coronary artery disease (CAD), heart failure (HF), and hypertension decreased after bariatric surgery, whereas that of dysrhythmia and venous thromboembolism transiently increased (Bonferroni corrected P < 0.05 for all comparisons).
CONCLUSION: Bariatric surgery is associated with a lower risk of overall CVD-related ED visit or unplanned hospitalization. The decline was mainly driven by reduced risk of acute care use for CAD, HF, and hypertension after bariatric surgery.
OBJECTIVE: Few bone mineral density (BMD) data are available in men with anorexia nervosa (AN), and none in those with atypical AN (ATYP) (AN psychological symptoms without low weight) or avoidant/restrictive food intake disorder (ARFID) (restrictive eating without AN psychological symptoms). We investigated the prevalence and determinants of low BMD and estimated hip strength in men with these disorders.
DESIGN: Cross-sectional: two centres.
PATIENTS: A total of 103 men, 18-63 years: AN (n = 26), ARFID (n = 11), ATYP (n = 18), healthy controls (HC) (n = 48).
MEASUREMENTS: Body composition, BMD and estimated hip strength (section modulus and buckling ratio) by DXA (Hologic). Serum 25OH vitamin D was quantified, as was daily calcium intake in a subset of subjects.
RESULTS: Mean BMI was lowest in AN and ARFID, higher in ATYP and highest in HC (AN 14.7 ± 1.8, ARFID 15.3 ± 1.5, ATYP 20.6 ± 2.0, HC 23.7 ± 3.3 kg/m ) (P < 0.0005). Mean BMD Z-scores at spine and hip were lower in AN and ARFID, but not ATYP, than HC (postero-anterior (PA) spine AN -2.05 ± 1.58, ARFID -1.33 ± 1.21, ATYP -0.59 ± 1.77, HC -0.12 ± 1.17) (P < 0.05). 65% AN, 18% ARFID, 33% ATYP and 6% HC had BMD Z-scores <-2 at ≥1 site (AN and ATYP vs HC, P < 0.01). Mean section modulus Z-scores were lower in AN than HC (P < 0.01). Lower BMI, muscle mass and vitamin D levels (R = 0.33-0.64), as well as longer disease duration (R = -0.51 to -0.58), were associated with lower BMD (P < 0.05).
CONCLUSIONS: Men with AN, ARFID and ATYP are at risk for low BMD. Men with these eating disorders who are low weight, or who have low muscle mass, long illness duration and/or vitamin D deficiency, may be at particularly high risk.
BACKGROUND AND AIMS: Gastric bypass is known to have larger effects on weight and metabolism than gastric banding. However, scarce data exist as to whether the differences are translated into differential risks of cardiovascular disease (CVD)-related morbidities. The objective was to examine whether adults with obesity and CVD who underwent gastric bypass have a lower rate of acute care use (emergency department [ED] visit or unplanned hospitalization) for CVD than those with gastric banding.
METHODS AND RESULTS: We performed a comparative effectiveness study of gastric bypass versus banding among adults with obesity and CVD who underwent either surgery, using population-based [ED] and inpatient samples in California, Florida, and Nebraska from 2005 through 2011. The primary outcome was acute care use for CVD during a two-year postoperative period. We constructed negative binomial regression models to compare the event rate during sequential 6-month periods, using gastric banding group as the reference. We identified 11,229 adults with obesity and CVD who underwent gastric bypass and 3896 adults who had gastric banding. Patients with gastric bypass had significantly lower rate of the outcome compared to those with banding in the 7-12 months postoperative period (adjusted rate ratio [aRR] 0.77; 95% confidence interval [CI], 0.61-0.98; P = 0.03). The significant reduction in the rate persisted during 13-18 months (aRR 0.71; 95% CI, 0.57-0.90; P = 0.005) and 19-24 months (aRR 0.66; 95% CI, 0.52-0.82; P < 0.001) after bariatric surgery.
CONCLUSION: In this population-based comparative effectiveness study of adults with obesity and CVD, the rate of acute care use for CVD was lower after gastric bypass compared to gastric banding.
Importance: Roux-en-Y gastric bypass (RYGB) is associated with significant bone loss and may increase fracture risk, whereas substantial bone loss and increased fracture risk have not been reported after adjustable gastric banding (AGB). Previous studies have had little representation of patients aged 65 years or older, and it is currently unknown how age modifies fracture risk.
Objective: To compare fracture risk after RYGB and AGB procedures in a large, nationally representative cohort enriched for older adults.
Design, Setting, and Participants: This population-based retrospective cohort analysis used Medicare claims data from January 1, 2006, to December 31, 2014, from 42 345 severely obese adults, of whom 29 624 received RYGB and 12 721 received AGB. Data analysis was performed from April 2017 to November 2018.
Main Outcomes and Measures: The primary outcome was incident nonvertebral (ie, wrist, humerus, pelvis, and hip) fractures after RYGB and AGB surgery defined using a combination of International Classification of Diseases, Ninth Edition and Current Procedural Terminology 4 codes.
Results: Of 42 345 participants, 33 254 (78.5%) were women. With a mean (SD) age of 51 (12) years, recipients of RYGB were younger than AGB recipients (55  years). Both groups had similar comorbidities, medication use, and health care utilization in the 365 days before surgery. Over a mean (SD) follow-up of 3.5 (2.1) years, 658 nonvertebral fractures were documented. The fracture incidence rate was 6.6 (95% CI, 6.0-7.2) after RYGB and 4.6 (95% CI, 3.9-5.3) after AGB, which translated to a hazard ratio (HR) of 1.73 (95% CI, 1.45-2.08) after multivariable adjustment. Site-specific analyses demonstrated an increased fracture risk at the hip (HR, 2.81; 95% CI, 1.82-4.49), wrist (HR, 1.70; 95% CI, 1.33-2.14), and pelvis (HR, 1.48; 95% CI, 1.08-2.07) among RYGB recipients. No significant interactions of fracture risk with age, sex, diabetes status, or race were found. In particular, adults 65 years and older showed similar patterns of fracture risk to younger adults. Sensitivity analyses using propensity score matching showed similar results (nonvertebral fracture: HR 1.75; 95% CI, 1.22-2.52).
Conclusions and Relevance: This study of a large, US population-based cohort including a substantial population of older adults found a 73% increased risk of nonvertebral fracture after RYGB compared with AGB, including increased risk of hip, wrist, and pelvis fractures. Fracture risk was consistently increased among RYGB patients vs AGB across different subgroups, and to a similar degree among older and younger adults. Increased fracture risk appears to be an important unintended consequence of RYGB.
High-resolution peripheral quantitative computed tomography (HR-pQCT) is a non-invasive method of measuring volumetric bone mineral density (vBMD) and microarchitecture at the distal radius and tibia. With increasing use of this technology, it is crucial to understand the potential impact of overlying soft tissue on the accuracy of HR-pQCT measures. Thus, we examined the effects of a simulated increase in adiposity (via 6- and 12-mm thick layers of overlying circumferential fat) on HR-pQCT measures of a hydroxyapatite (HA) phantom and in women (n = 20, aged 18-75 years). In the phantom, increasing the amount of overlying fat tissue led to a corresponding decrease in the mean measured density for each HA rod. In women, fat-layering led to a decrease in total vBMD (-2.9 to -3.7%, p < 0.001), cortical vBMD (-1.4% to -5.5%, p < 0.001), and estimated failure load (-1.4 to -5.7%, p = 0.002) at the radius, with similar changes in the tibia. Trabecular microarchitectural measurements were also impacted by simulated adiposity, with fat-layering leading to decreased trabecular thickness and separation and increased trabecular number at the radius (Δ's = 5 to 12%) with more pronounced differences at the tibia (Δ's = 14 to 40%). At the tibia, fat-layering also led to decreased cortical thickness and increased cortical porosity. Altogether, these results demonstrate that overlying adipose tissue can lead to artifacts in bone measurements by HR-pQCT, resulting in an underestimation of vBMD and generally, an overestimation of bone microarchitecture impairment. Therefore, soft tissue artifact should be considered when interpreting HR-pQCT results, particularly in those with high BMI and/or marked changes in adiposity.
Context: Bone health declines in the initial years after Roux-en-Y gastric bypass (RYGB), but long-term skeletal effects are unclear.
Objective: To document longitudinal changes in bone mineral density (BMD) and microarchitecture 5 years after RYGB.
Design, Setting, and Participants: Prospective 5-year observational study of 21 adults with severe obesity receiving RYGB at an academic medical center.
Main Outcome Measures: Spine and hip areal BMD were measured by dual-energy X-ray absorptiometry, and trabecular volumetric BMD (vBMD) of the spine was assessed by quantitative CT (QCT). We measured vBMD and microarchitecture of the distal radius and tibia by high-resolution peripheral QCT in a subset of subjects. Serum type I collagen C-terminal telopeptide (CTX) and procollagen type I N-terminal propeptide (P1NP) were also measured.
Results: Areal BMD declined by -7.8% ± 7.6% at the spine and -15.3% ± 6.3% at the total hip by 5 years after RYGB (P ≤ 0.001), although the rate of bone loss slowed in later years. Trabecular spine vBMD decreased by -12.1% ± 12.3% by 5 years (P ≤ 0.001). At peripheral sites, vBMD continued to decrease steadily throughout 5 years, with parallel declines in cortical and trabecular microarchitecture, leading to decreases in estimated failure load of -20% and -13% at the radius and tibia, respectively (P < 0.001). Five years after RYGB, CTX and P1NP were 150% and 34% above baseline (P < 0.001 and P = 0.017, respectively).
Conclusions: Sustained high-turnover bone loss and bone microarchitectural deterioration occur in the 5 years after RYGB. Adults receiving RYGB warrant assessment of bone health.
CONTEXT: Both acromegaly and adult growth hormone deficiency (GHD) are associated with increased fracture risk. Sufficient data are lacking regarding cortical bone microarchitecture and bone strength, as assessed by microfinite element analysis (µFEA).
OBJECTIVE: To elucidate both cortical and trabecular bone microarchitecture and estimated bone strength in men with active acromegaly or GHD compared to healthy controls.
DESIGN AND SUBJECTS: Cross-sectional study at a clinical research center, including 48 men (16 with acromegaly, 16 with GHD and 16 healthy controls).
OUTCOME MEASURES: Areal bone mineral density (aBMD), cortical and trabecular bone microarchitecture and estimated bone strength (µFEA) at the radius and tibia.
RESULTS: aBMD was not different between the 3 groups at any skeletal site. At the radius, patients with acromegaly had greater cortical area ( < 0.0001), cortical thickness ( = 0.0038), cortical pore volume ( < 0.0001) and cortical porosity ( = 0.0008), but lower trabecular bone density ( = 0.0010) compared to controls. At the tibia, patients with acromegaly had lower trabecular bone density ( = 0.0082), but no differences in cortical bone microstructure. Compressive strength and failure load did not significantly differ between groups. These findings persisted after excluding patients with hypogonadism. Bone microarchitecture was not deficient in patients with GHD.
CONCLUSIONS: Both cortical and trabecular microarchitecture are altered in men with acromegaly. Our data indicate that GH excess is associated with distinct effects in cortical vs trabecular bone compartments. Our observations also affirm the limitations of aBMD testing in the evaluation of patients with acromegaly.
Bariatric surgery is associated with bone loss but skeletal consequences may differ between Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), the two most commonly performed bariatric procedures. Furthermore, severe weight loss is associated with high marrow adipose tissue (MAT); however, MAT is also increased in visceral adiposity. The purpose of our study was to determine the effects of RYGB and SG on BMD and MAT. We hypothesized that both bariatric procedures would lead to a decrease in BMD and MAT. We studied 21 adults with morbid obesity (mean BMI 44.1±5.1kg/m(2)) prior to and 12months after RYGB (n=11) and SG (n=10). All subjects underwent DXA and QCT of the lumbar spine and hip to assess aBMD and vBMD. Visceral (VAT) and subcutaneous (SAT) adipose tissue was quantified at L1-L2. MAT of the lumbar spine and femur was assessed by 1H-MR spectroscopy. Calcitropic hormones and bone turnover markers were determined. At 12months after surgery, mean weight and abdominal fat loss was similar between the RYGB and SG groups. Mean serum calcium, 25(OH)-vitamin D, and PTH levels were unchanged after surgery and within the normal range in both groups. Bone turnover markers P1NP and CTX increased within both groups and P1NP increased to a greater extent in the RYGB group (p=0.03). There were significant declines from baseline in spine aBMD and vBMD within the RYGB and SG groups, although the changes were not significantly different between groups (p=0.3). Total hip and femoral neck aBMD by DXA decreased to a greater extent in the RYGB than the SG group (p<0.04) although the change in femoral vBMD by QCT was not significantly different between groups (p>0.2). MAT content of the lumbar spine and femoral diaphysis did not change from baseline in the RYGB group but increased after SG (p=0.03). Within the SG group, 12-month change in weight and VAT were positively associated with 12-month change in MAT (p<0.04), suggesting that subjects with less weight and VAT loss had higher MAT. In conclusion, RYGB and SG are associated with declines in lumbar spine BMD, however, the changes are not significantly different between the groups. RYGB may be associated with greater decline of aBMD at the total hip and femoral neck compared to SG. MAT content increased after SG and this was associated with lower weight and VAT loss.
Altan Ercan, Wendy M Kohrt, Jing Cui, Kevin D Deane, Marija Pezer, Elaine W Yu, Jonathan S Hausmann, Harry Campbell, Ursula B Kaiser, Pauline M Rudd, Gordan Lauc, James F Wilson, Joel S Finkelstein, and Peter A Nigrovic. 2017. “Estrogens regulate glycosylation of IgG in women and men.” JCI Insight, 2, 4, Pp. e89703.Abstract
The immunologic potency of IgG is modulated by glycosylation, but mechanisms regulating this process are undefined. A role for sex hormones is suggested by differences in IgG glycans between women and men, most prominently with respect to galactose. We therefore assessed IgG galactosylation in 713 healthy adults from 2 cohorts as well as in 159 subjects from 4 randomized controlled studies of endocrine manipulation: postmenopausal women receiving conjugated estrogens, raloxifene, or placebo; premenopausal women deprived of gonadal hormones with leuprolide and treated with estradiol or placebo; men deprived of gonadal hormones with goserelin and given testosterone or placebo; and men deprived of gonadal hormones with goserelin and given testosterone or placebo together with anastrozole to block conversion of testosterone to estradiol. Menopause was associated with an increase in agalactosylated IgG glycans, particularly in the most abundant fucosylated nonbisected (G0F) glycoform. Conjugated estrogens and raloxifene reduced G0F glycans in postmenopausal women, while in premenopausal women leuprolide increased G0F glycans in a manner reversed by estradiol. Among men, goserelin increased G0F glycans, an effect blocked by testosterone through conversion to estradiol. These results establish estrogens as an in vivo modulator of IgG galactosylation in both women and men, defining a pathway by which sex modulates immunity.
A 57-year-old male presented with recurrent falls, bilateral lower-limb paresthesia, and severe neck pain. Imaging revealed a mass compressing his spinal cord. He was admitted for further workup for spinal cord compression. Within 24 hours of admission, he developed upper-extremity weakness while maintaining lower-extremity function. He underwent urgent decompression of his spinal cord. During exposure, a white, creamy odorless substance was noted. This same substance was found under pressure within the spinal canal. The mass was grossly removed, and the patient's weakness improved postoperatively. Based on the clinical picture, intraoperative presentation, and final histological examination, idiopathic tumoral calcinosis-like lesion was considered as the most appropriate diagnosis.