Consensus Statement on Vitamin D Status Assessment and Supplementation: Whys, Whens, and Hows.

The 6th International Conference, "Controversies in Vitamin D," was convened to discuss controversial topics, such as vitamin D metabolism, assessment, actions, and supplementation. Novel insights into vitamin D mechanisms of action suggest links with conditions that do not depend only on reduced solar exposure or diet intake and that can be detected with distinctive noncanonical vitamin D metabolites. Optimal 25-hydroxyvitamin D (25(OH)D) levels remain debated. Varying recommendations from different societies arise from evaluating different clinical or public health approaches. The lack of assay standardization also poses challenges in interpreting data from available studies, hindering rational data pooling and meta-analyses. Beyond the well-known skeletal features, interest in vitamin D's extraskeletal effects has led to clinical trials on cancer, cardiovascular risk, respiratory effects, autoimmune diseases, diabetes, and mortality. The initial negative results are likely due to enrollment of vitamin D-replete individuals. Subsequent post hoc analyses have suggested, nevertheless, potential benefits in reducing cancer incidence, autoimmune diseases, cardiovascular events, and diabetes. Oral administration of vitamin D is the preferred route. Parenteral administration is reserved for specific clinical situations. Cholecalciferol is favored due to safety and minimal monitoring requirements. Calcifediol may be used in certain conditions, while calcitriol should be limited to specific disorders in which the active metabolite is not readily produced in vivo. Further studies are needed to investigate vitamin D effects in relation to the different recommended 25(OH)D levels and the efficacy of the different supplementary formulations in achieving biochemical and clinical outcomes within the multifaced skeletal and extraskeletal potential effects of vitamin D.

Alteration in the gut microbiome is associated with changes in bone metabolism after laparoscopic sleeve gastrectomy.

Laparoscopic sleeve gastrectomy (LSG), the most common bariatric surgical procedure, leads to durable weight loss and improves obesity-related comorbidities. However, it induces abnormalities in bone metabolism. One unexplored potential contributor is the gut microbiome, which influences bone metabolism and is altered after surgery. We characterized the relationship between the gut microbiome and skeletal health in severe obesity and after LSG. In a prospective cohort study, 23 adults with severe obesity underwent skeletal health assessment and stool collection preoperatively and 6 mo after LSG. Gut microbial diversity and composition were characterized using 16S rRNA gene sequencing, and fecal concentrations of short-chain fatty acids (SCFA) were measured with LC-MS/MS. Spearman's correlations and PERMANOVA analyses were applied to assess relationships between the gut microbiome and bone health measures including serum bone turnover markers (C-terminal telopeptide of type 1 collagen [CTx] and procollagen type 1 N-terminal propeptide [P1NP]), areal BMD, intestinal calcium absorption, and calciotropic hormones. Six months after LSG, CTx and P1NP increased (by median 188% and 61%, P < .01) and femoral neck BMD decreased (mean -3.3%, P < .01). Concurrently, there was a decrease in relative abundance of the phylum Firmicutes. Although there were no change in overall microbial diversity or fecal SCFA concentrations after LSG, those with greater within-subject change in gut community microbial composition (ß-diversity) postoperatively had greater increases in P1NP level (ρ = 0.48, P = .02) and greater bone loss at the femoral neck (ρ = -0.43, P = .04). In addition, within-participant shifts in microbial richness/evenness (α-diversity) were associated with changes in IGF-1 levels (ρ = 0.56, P < .01). The lower the postoperative fecal butyrate concentration, the lower the IGF-1 level (ρ = 0.43, P = .04). Meanwhile, the larger the decrease in butyrate concentration, the higher the postoperative CTx (ρ = -0.43, P = .04). These findings suggest that LSG-induced gut microbiome alteration may influence skeletal outcomes postoperatively, and microbial influences on butyrate formation and IGF-1 are possible mechanisms.

Laparoscopic sleeve gastrectomy (LSG), the most common bariatric surgical procedure, is a highly effective treatment for obesity because it produces dramatic weight loss and improves obesity-related medical conditions. However, it also results in abnormalities in bone metabolism. It is important to understand how LSG affects the skeleton, so that bone loss after surgery might be prevented. We studied adult men and women before and 6 mo after LSG, and we explored the relationship between the altered gut bacteria and bone metabolism changes. We found that: Those with greater shifts in their gut bacterial composition had more bone loss.Butyrate, a metabolite produced by gut bacteria from fermentation of dietary fiber, was associated with less bone breakdown and higher IGF-1 level (a bone-building hormone). We conclude that changes in the gut bacteria may contribute to the negative skeletal impact of LSG and reduced butyrate production by the gut bacteria leading to lower IGF-1 levels is a possible mechanism.

Microvascular disease not type 2 diabetes is associated with increased cortical porosity: A study of cortical bone microstructure and intracortical vessel characteristics.

Introduction: Fracture risk is elevated in type 2 diabetes (T2D) despite normal or even high bone mineral density (BMD). Microvascular disease (MVD) is a diabetic complication, but also associated with other diseases, for example chronic kidney disease. We hypothesize that increased fracture risk in T2D could be due to increased cortical porosity (Ct.Po) driven by expansion of the vascular network in MVD. The purpose of this study was to investigate associations of T2D and MVD with cortical microstructure and intracortical vessel parameters. Methods: The study group consisted of 75 participants (38 with T2D and 37 without T2D). High-resolution peripheral quantitative CT (HR-pQCT) and dynamic contrast-enhanced MRI (DCE-MRI) of the ultra-distal tibia were performed to assess cortical bone and intracortical vessels (outcomes). MVD was defined as ≥1 manifestation including neuropathy, nephropathy, or retinopathy based on clinical exams in all participants. Adjusted means of outcomes were compared between groups with/without T2D or between participants with/without MVD in both groups using linear regression models adjusting for age, sex, BMI, and T2D as applicable. Results: MVD was found in 21 (55 %) participants with T2D and in 9 (24 %) participants without T2D. In T2D, cortical pore diameter (Ct.Po.Dm) and diameter distribution (Ct.Po.Dm.SD) were significantly higher by 14.6 µm (3.6 %, 95 % confidence interval [CI]: 2.70, 26.5 µm, p = 0.017) and by 8.73 µm (4.8 %, CI: 0.79, 16.7 µm, p = 0.032), respectively. In MVD, but not in T2D, cortical porosity was significantly higher by 2.25 % (relative increase = 12.9 %, CI: 0.53, 3.97 %, p = 0.011) and cortical BMD (Ct.BMD) was significantly lower by -43.6 mg/cm3 (2.6 %, CI: -77.4, -9.81 mg/cm3, p = 0.012). In T2D, vessel volume and vessel diameter were significantly higher by 0.02 mm3 (13.3 %, CI: 0.004, 0.04 mm3, p = 0.017) and 15.4 µm (2.9 %, CI: 0.42, 30.4 µm, p = 0.044), respectively. In MVD, vessel density was significantly higher by 0.11 mm-3 (17.8 %, CI: 0.01, 0.21 mm-3, p = 0.033) and vessel volume and diameter were significantly lower by -0.02 mm3 (13.7 %, CI: -0.04, -0.004 mm3, p = 0.015) and - 14.6 µm (2.8 %, CI: -29.1, -0.11 µm, p = 0.048), respectively. Conclusions: The presence of MVD, rather than T2D, was associated with increased cortical porosity. Increased porosity in MVD was coupled with a larger number of smaller vessels, which could indicate upregulation of neovascularization triggered by ischemia. It is unclear why higher variability and average diameters of pores in T2D were accompanied by larger vessels.

Bone Marrow Adiposity Alterations in Type 2 Diabetes Are Sex-Specific and Associated with Serum Lipid Levels.

Type 2 diabetes (T2D) has negative effects on skeletal health. A proposed mechanism of diabetic bone disease connects hyperlipidemia to increased bone marrow adiposity and decreased bone quality. Previous research on Type 1 diabetes reported positive associations between serum lipid levels and marrow adiposity, but no data exist for T2D. In addition, marrow adiposity is sex-dependent in healthy populations, but sex has not been addressed adequately in previous reports of marrow adiposity in T2D. The purpose of this study was to quantify associations of marrow adiposity and composition with T2D status, serum lipid levels, and sex. T2D patients and normoglycemic controls (n = 39/37) were included. Single-voxel magnetic resonance spectroscopy (MRS) was performed at the spine and tibia. Quantitative MRS outcomes of marrow adiposity and composition were calculated. Linear regression models were used to compare MRS outcomes among groups and to evaluate associations of MRS outcomes with serum lipid levels. All analyses were performed on sex-stratified subgroups. Total, unsaturated, and saturated fat content at the spine were lower in T2D participants compared to controls in age-adjusted models; these differences were significant in men but not in women. In our study cohort, total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were lower in T2D participants compared to controls. Adjustment for LDL, HDL, and statin use attenuated the association of T2D status with unsaturated fat but not saturated fat in men. Further analysis confirmed significant associations between serum lipid levels and MRS outcomes. Specifically, we found a positive association between LDL cholesterol and total marrow fat in the male T2D group and a negative association between HDL and total marrow fat in the female T2D group. In conclusion, our results suggest that marrow adiposity and composition are associated with lipid levels as well as T2D status, and these relationships are sex-specific. © 2023 American Society for Bone and Mineral Research (ASBMR).

Vitamin D status and supplementation before and after Bariatric Surgery: Recommendations based on a systematic review and meta-analysis.

Bariatric surgery is associated with a postoperative reduction of 25(OH) vitamin D levels (25(OH)D) and with skeletal complications. Currently, guidelines for 25(OH)D assessment and vitamin D supplementation in bariatric patients, pre- and post-surgery, are still lacking. The aim of this work is to analyse systematically the published experience on 25(OH)D status and vitamin D supplementation, pre- and post-surgery, and to propose, on this basis, recommendations for management. Preoperatively, 18 studies including 2,869 patients were evaluated. Prevalence of vitamin D insufficiency as defined by 25(OH)D < 30 ng/mL (75 nmol/L) was 85%, whereas when defined by 25(OH)D < 20 ng/mL (50 nmol/L) was 57%. The median preoperative 25(OH)D level was 19.75 ng/mL. After surgery, 39 studies including 5,296 patients were analysed and among those undergoing either malabsorptive or restrictive procedures, a lower rate of vitamin D insufficiency and higher 25(OH)D levels postoperatively were observed in patients treated with high-dose oral vitamin D supplementation, defined as ≥ 2,000 IU/daily (mostly D3-formulation), compared with low-doses (< 2,000 IU/daily). Our recommendations based on this systematic review and meta-analysis should help clinical practice in the assessment and management of vitamin D status before and after bariatric surgery. Assessment of vitamin D should be performed pre- and postoperatively in all patients undergoing bariatric surgery. Regardless of the type of procedure, high-dose supplementation is recommended in patients after bariatric surgery.

Prognostic Value for Mortality of Plasma Bioactive Adrenomedullin in Patients with Pulmonary Arterial Hypertension: A Sub Analysis of the Biomarker Study in the COHARD-PH Registry.

The adrenomedullin level increases in pulmonary arterial hypertension (PAH, and correlates with a high mortality rate. Its active form, bioactive adrenomedullin (bio-ADM), has been recently developed and has significant prognostic applications in acute clinical settings. Aside from idiopathic/hereditary PAH (I/H-PAH), atrial septal defects-associated pulmonary artery hypertension (ASD-PAH) is still prevalent in developing countries and associated with increased mortality. This study aimed to investigate the mortality-wise prognostic value of the plasma bio-ADM level by comparing subjects with ASD-PAH and I/H-PAH with ASD patients without pulmonary hypertension (PH) as a control group. This was a retrospective, observational cohort study. The subjects were Indonesian adult patients who were recruited from the Congenital Heart Disease and Pulmonary Hypertension (COHARD-PH) registry and divided into three groups: (1) ASD without PH (control group), (2) ASD-PAH and (3) I/H-PAH. During right-heart catheterization at the time of diagnosis, a plasma sample was taken and assayed for bio-ADM using a chemiluminescence immunoassay. Follow-up was performed as a part of the COHARD-PH registry protocol in order to evaluate the mortality rate. Among the 120 subjects enrolled: 20 turned out to have ASD without PH, 85 had ASD-PAH and 15 had I/H-PAH. Compared to the control group (5.15 (3.0-7.95 pg/mL)) and ASD-PAH group (7.30 (4.10-13.50 pg/mL)), bio-ADM levels were significantly higher in the I/H-PAH group (median (interquartile range (IQR)): 15.50 (7.50-24.10 pg/mL)). Moreover, plasma bio-ADM levels were significantly higher in subjects who died (n = 21, 17.5%) compared to those who survived (median (IQR): 11.70 (7.20-16.40 pg/mL) vs. 6.90 (4.10-10.20 pg/mL), p = 0.031). There was a tendency toward higher bio-ADM levels in those who died among the PAH subjects, in both ASD-PAH and I/H-PAH groups. In conclusion, the plasma bio-ADM level is elevated in subjects with PAH from both ASD-PAH and I/H-PAH origins, reaching the highest levels in subjects with the I/H-PAH form. A high bio-ADM level tended to be associated with a high mortality rate in all subjects with PAH, indicating a relevant prognostic value for this biomarker. In patients with I/H-PAH, monitoring bio-ADM could represent a valid tool for predicting outcomes, allowing more appropriate therapeutical choices.

Prevalence of osteoporosis in older male veterans receiving hip-containing computed tomography scans: opportunistic use of biomechanical computed tomography analysis (BCT).

Osteoporosis care in men is suboptimal due to low rates of testing and treatment. Applying biomechanical computed tomography (BCT) analysis to existing CT scans, we found a high proportion of men with osteoporosis have never been diagnosed or treated. BCT may improve identification of patients at high risk of fracture. PURPOSE: Osteoporosis care in men is suboptimal due to low rates of DXA testing and treatment. Biomechanical computed tomography analysis (BCT) can be applied "opportunistically" to prior hip-containing CT scans to measure femoral bone strength and hip BMD. METHODS: In this retrospective, cross-sectional study, we used BCT in male veterans with existing CT scans to investigate the prevalence of osteoporosis, defined by hip BMD (T-score ≤ - 2.5) or fragile bone strength (≤ 3500 N). 577 men, age ≥ 65 with abdominal/pelvic CTs performed in 2017-2019, were randomly selected for BCT analysis. Clinical data were collected via electronic health records and used with the femoral neck BMD T-score from BCT to estimate 10-year hip fracture risks by FRAX. RESULTS: Prevalence of osteoporosis by BCT increased with age (13.5% age 65-74; 18.2% age 75-84; 34.3% age ≥ 85), with an estimated overall prevalence of 18.3% for men age ≥ 65. In those with osteoporosis (n = 108/577), only 38.0% (41/108) had a prior DXA and 18.6% (7/108) had received osteoporosis pharmacotherapy. Elevated hip fracture risk by FRAX (≥ 3%) did not fully capture those with fragile bone strength. In a multivariate logistic regression model adjusted for age, BMI, race, and CT location, end stage renal disease (odds ratio 7.4; 95% confidence interval 2.3-23.9), COPD (2.2; 1.2-4.0), and high-dose inhaled corticosteroid use (3.7; 1.2-11.8) were associated with increased odds of having osteoporosis by BCT. CONCLUSION: Opportunistic BCT in male veterans provides an additional avenue to identify patients who are at high risk of fractures.

Intestinal Calcium Absorption Decreases After Laparoscopic Sleeve Gastrectomy Despite Optimization of Vitamin D Status.

CONTEXT: Laparoscopic sleeve gastrectomy (LSG), now the most commonly performed bariatric operation, is a highly effective treatment for obesity. While Roux-en-Y gastric bypass is known to impair intestinal fractional calcium absorption (FCA) and negatively affect bone metabolism, LSG's effects on calcium homeostasis and bone health have not been well characterized. OBJECTIVE: We determined the effect of LSG on FCA, while maintaining robust 25-hydroxyvitamin D (25OHD) levels and recommended calcium intake. DESIGN, SETTING, PARTICIPANTS: Prospective pre-post observational cohort study of 35 women and men with severe obesity undergoing LSG. MAIN OUTCOMES: FCA was measured preoperatively and 6 months postoperatively with a gold-standard dual stable isotope method. Other measures included calciotropic hormones, bone turnover markers, and bone mineral density (BMD) by dual-energy X-ray absorptiometry and quantitative computed tomography. RESULTS: Mean ± SD FCA decreased from 31.4 ± 15.4% preoperatively to 16.1 ± 12.3% postoperatively (P < 0.01), while median (interquartile range) 25OHD levels were 39 (32-46) ng/mL and 36 (30-46) ng/mL, respectively. Concurrently, median 1,25-dihydroxyvitamin D level increased from 60 (50-82) pg/mL to 86 (72-107) pg/mL (P < 0.01), without significant changes in parathyroid hormone or 24-hour urinary calcium levels. Bone turnover marker levels increased substantially, and areal BMD decreased at the proximal femur. Those with lower postoperative FCA had greater areal BMD loss at the total hip (ρ = 0.45, P < 0.01). CONCLUSIONS: FCA decreases after LSG, with a concurrent rise in bone turnover marker levels and decline in BMD, despite robust 25OHD levels and with recommended calcium intake. Decline in FCA could contribute to negative skeletal effects following LSG.

The Bioactive Phenolic Agents Diaryl Ether CVB2-61 and Diarylheptanoid CVB4-57 as Connexin Hemichannel Blockers.

Inflammation mediators enhance the activity of connexin (Cx) hemichannels, especially in the epithelial and endothelial tissues. As potential release routes for injury signals, such as (oligo)nucleotides, Cx hemichannels may contribute to long-lasting inflammation. Specific inhibition of Cx hemichannels may therefore be a mode of prevention and treatment of long-lasting, chronic sterile inflammation. The activity of Cx hemichannels was analysed in N2A and HeLa cells transfected with human Cx26 and Cx46 as well as in Calu-3 cells, using dye uptake as functional assay. Moreover, the possible impacts of the bioactive phenolic agents CVB2-61 and CVB4-57 on the barrier function of epithelial cells was analysed using Calu-3 cells. Both agents inhibited the dye uptake in N2A cells expressing Cx26 (>5 µM) and Cx46 (>20 µM). In Calu-3 cells, CVB2-61 and CVB4-57 reversibly inhibited the dye uptake at concentrations as low as 5 µM, without affecting the gap junction communication and barrier function, even at concentrations of 20 µM. While CVB2-61 or CVB4-57 maintained a reduced dye uptake in Calu-3 cells, an enhancement of the dye uptake in response to the stimulation of adenosine signalling was still observed after removal of the agents. The report shows that CVB2-61 and CVB4-57 reversibly block Cx hemichannels. Deciphering the mechanisms of the interactions of these agents with Cx hemichannels could allow further development of phenolic compounds to target Cx hemichannels for better and safer treatment of pathologies that involve Cx hemichannels.

Bone marrow adipose tissue composition and glycemic improvements after gastric bypass surgery.

Fracture risk is increased in type 2 diabetes, which may in part be due to altered bone marrow adiposity. Cross sectional studies have reported that people with type 2 diabetes have lower unsaturated BMAT lipid levels than people without diabetes, although there are limited data on longitudinal changes. We hypothesized that Roux-en-Y gastric bypass (RYGB), which dramatically improves glycemic status, would have differential effects on BMAT composition, with increases in the unsaturated lipid index in people with diabetes. Given reports that axial BMAT is responsive to metabolic stimuli while appendicular BMAT is stable, we hypothesized that BMAT changes would occur at the spine but not the tibia. We enrolled 30 obese women, stratified by diabetes status, and used magnetic resonance spectroscopy to measure BMAT at the spine in all participants, and the tibia in a subset (n = 19). At baseline, BMAT parameters were similar between those with and without diabetes, except tibial marrow fat content was lower in women with diabetes (97.4 % ± 1.0 % versus 98.2 % ± 0.4 %, p = 0.04). Six months after surgery, both groups experienced similar weight loss of 27 kg ± 7 kg. At the spine, there was a significant interaction between diabetes status and changes in both marrow fat content and the unsaturated lipid index (p = 0.02, p < 0.01 for differences, respectively). Women with diabetes had a trend towards a decline in marrow fat content (-4.3 % ± 8.2 %, p = 0.09) and increase in the unsaturated lipid index (+1.1 % ± 1.5 %, p = 0.02). In contrast, BMAT parameters did not significantly change in women without diabetes. In all women, changes in the unsaturated lipid index inversely correlated with hemoglobin A1c changes (r = -0.47, p = 0.02). At the tibia, there was little BMAT change by diabetes status. Our results suggest that vertebral BMAT composition is responsive to changes in glycemic control after RYGB.

No Evidence of Association Between Undercarboxylated Osteocalcin and Incident Type 2 Diabetes.

Mouse models suggest that undercarboxylated osteocalcin (ucOC), produced by the skeleton, protects against type 2 diabetes development, whereas human studies have been inconclusive. We aimed to determine if ucOC or total OC is associated with incident type 2 diabetes or changes in fasting glucose, insulin resistance (HOMA-IR), or beta-cell function (HOMA-Beta). A subcohort (n = 338; 50% women; 36% black) was identified from participants without diabetes at baseline in the Health, Aging, and Body Composition Study. Cases of incident type 2 diabetes (n = 137) were defined as self-report at an annual follow-up visit, use of diabetes medication, or elevated fasting glucose during 8 years of follow-up. ucOC and total OC were measured in baseline serum. Using a case-cohort design, the association between biomarkers and incident type 2 diabetes was assessed using robust weighted Cox regression. In the subcohort, linear regression models analyzed the associations between biomarkers and changes in fasting glucose, HOMA-IR, and HOMA-Beta over 9 years. Higher levels of ucOC were not statistically associated with increased risk of incident type 2 diabetes (adjusted hazard ratio = 1.06 [95% confidence interval, 0.84-1.34] per 1 standard deviation [SD] increase in ucOC). Results for %ucOC and total OC were similar. Adjusted associations of ucOC, %ucOC, and total OC with changes in fasting glucose, HOMA-IR, and HOMA-Beta were modest and not statistically significant. We did not find evidence of an association of baseline undercarboxylated or total osteocalcin with risk of incident type 2 diabetes or with changes in glucose metabolism in older adults. © 2022 American Society for Bone and Mineral Research (ASBMR).

Saturated and Unsaturated Bone Marrow Lipids Have Distinct Effects on Bone Density and Fracture Risk in Older Adults.

Greater bone marrow adiposity (BMAT) is associated with lower bone mineral density (BMD) and vertebral fractures; less is known about BMAT composition and bone. We studied BMAT composition and bone outcomes in 465 participants from the Age Gene/Environment Susceptibility (AGES)-Reykjavik study. BMAT saturation and unsaturation, measured with magnetic resonance spectroscopy, were defined as the ratio of saturated (1.3 ppm peak) or unsaturated (5.3 ppm peak) lipid to total marrow contents, respectively. At baseline and follow-up visits, spine and hip BMD were assessed with quantitative computed tomography (QCT) and dual-energy X-ray absorptiometry (DXA) and vertebral fractures were identified with DXA. Incident clinical fractures were identified through medical records for up to 8.8 years of follow-up. Associations between BMAT composition and BMD, bone loss, and fractures were evaluated in adjusted regression models. At baseline, mean ± standard deviation (SD) participant age was 81.7 ± 4.3 years, mean BMAT unsaturation was 3.5% ± 1.0%, and mean saturation was 46.3% ± 7.2% in the full cohort (47.7% women). Each SD increase in BMAT saturation was associated with lower trabecular BMD: -23.6% (spine) and -13.0% (total hip) (all p < 0.0001). Conversely, BMAT unsaturation (per SD increase) was associated with higher trabecular BMD: +17.5% (spine) and +11.5% (total hip) (all p < 0.001). BMAT saturation (per SD increase) was associated with greater risk for prevalent (odds ratio [OR] 1.46; 95% confidence interval [CI], 1.11-1.92) and incident (OR 1.55; 95% CI, 1.03-2.34) vertebral fracture. BMAT unsaturation (per SD increase) was associated with lower risk for incident vertebral fracture (OR 0.58; 95% CI, 0.38-0.89). In gender stratified analyses, BMAT saturation and unsaturation had opposite associations with incident clinical fracture among men. In general, saturated marrow lipids were associated with worse skeletal outcomes, whereas unsaturated lipids were associated with better outcomes. We recommend that future studies of marrow fat and skeletal health report measurements of saturated and unsaturated marrow lipids, rather than total marrow fat content alone. © 2022 American Society for Bone and Mineral Research (ASBMR).

Cortical Bone Loss Following Gastric Bypass Surgery Is Not Primarily Endocortical.

Roux-en Y gastric bypass (RYGB) surgery is an effective treatment for obesity; however, it may negatively impact skeletal health by increasing fracture risk. This increase may be the result not only of decreased bone mineral density but also of changes in bone microstructure, for example, increased cortical porosity. Increased tibial and radial cortical porosity of patients undergoing RYGB surgery has been observed as early as 6 months postoperatively; however, local microstructural changes and associated biological mechanisms driving this increase remain unclear. To provide insight, we studied the spatial distribution of cortical porosity in 42 women and men (aged 46 ± 12 years) after RYGB surgery. Distal tibias and radii were evaluated with high-resolution peripheral quantitative computed tomography (HR-pQCT) preoperatively and at 12 months postoperatively. Laminar analysis was used to determine cortical pore number and size within the endosteal, midcortical, and periosteal layers of the cortex. Paired t tests were used to compare baseline versus follow-up porosity parameters in each layer. Mixed models were used to compare longitudinal changes in laminar analysis outcomes between layers. We found that the midcortical (0.927 ± 0.607 mm-2 to 1.069 ± 0.654 mm-2 , p = 0.004; 0.439 ± 0.293 mm-2 to 0.509 ± 0.343 mm-2 , p = 0.03) and periosteal (0.642 ± 0.412 mm-2 to 0.843 ± 0.452 mm-2 , p < 0.0001; 0.171 ± 0.101 mm-2 to 0.230 ± 0.160 mm-2 , p = 0.003) layers underwent the greatest increases in porosity over the 12-month period at the distal tibia and radius, respectively. The endosteal layer, which had the greatest porosity at baseline, did not undergo significant porosity increase over the same period (1.234 ± 0.402 mm-2 to 1.259 ± 0.413 mm-2 , p = 0.49; 0.584 ± 0.290 mm-2 to 0.620 ± 0.299 mm-2 , p = 0.35) at the distal tibia and radius, respectively. An alternative baseline-mapping approach for endosteal boundary definition confirmed that cortical bone loss was not primarily endosteal. These findings indicate that increases in cortical porosity happen in regions distant from the endosteal surface, suggesting that the underlying mechanism driving the increase in cortical porosity is not merely endosteal trabecularization. © 2022 American Society for Bone and Mineral Research (ASBMR).

The Interaction of Acute-Phase Reaction and Efficacy for Osteoporosis After Zoledronic Acid: HORIZON Pivotal Fracture Trial.

Zoledronic acid (ZOL) as a yearly infusion is effective in reducing fracture risk. An acute-phase reaction (APR), consisting of flu-like symptoms within 3 days after infusion, is commonly seen. The objective of this analysis was to investigate whether APR occurrence influences drug efficacy. This analysis uses data from the 3-year randomized clinical trial, Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT). APRs were identified as adverse events within 3 days of first infusion with higher frequency in ZOL than placebo. To compare mean 3-year change in bone mineral density (BMD) in ZOL versus placebo, among women with and without APR, t tests were used. Logistic regression was used to examine the relationship between APR occurrence and odds of incident morphometric vertebral fracture. Cox regression was used to determine the risk of nonvertebral and hip fractures for women with versus without APR. Logistic and Cox models were used to determine the risk of incident fracture in ZOL versus placebo for women with and without an APR. The analysis included 3862 women in the ZOL group and 3852 in placebo, with 42.4% in ZOL versus 11.8% in placebo experiencing an APR. The difference in BMD mean change for ZOL versus placebo was similar for women with and without an APR (all p interaction >0.10). Among ZOL women, those with APR had 51% lower vertebral fracture risk than those without (odds ratio [OR] = 0.49, p < 0.001). A similar but nonsignificant trend was observed for nonvertebral and hip fracture (relative hazard [RH] = 0.82, p = 0.10; RH = 0.70, p = 0.22, respectively). There was a greater treatment-related reduction in vertebral fracture risk among women with APR (OR = 0.19) than those without (OR = 0.38) (p interaction = 0.01). Our results suggest that women starting ZOL who experience an APR will have a larger reduction in vertebral fracture risk with ZOL. © 2021 American Society for Bone and Mineral Research (ASBMR).

Prebiotic to Improve Calcium Absorption in Postmenopausal Women After Gastric Bypass: A Randomized Controlled Trial.

CONTEXT: The adverse skeletal effects of Roux-en-Y gastric bypass (RYGB) are partly caused by intestinal calcium absorption decline. Prebiotics, such as soluble corn fiber (SCF), augment colonic calcium absorption in healthy individuals. OBJECTIVE: We tested the effects of SCF on fractional calcium absorption (FCA), biochemical parameters, and the fecal microbiome in a post-RYGB population. METHODS: Randomized, double-blind, placebo-controlled trial of 20 postmenopausal women with history of RYGB a mean 5 years prior; a 2-month course of 20 g/day SCF or maltodextrin placebo was taken orally. The main outcome measure was between-group difference in absolute change in FCA (primary outcome) and was measured with a gold standard dual stable isotope method. Other measures included tolerability, adherence, serum calciotropic hormones and bone turnover markers, and fecal microbial composition via 16S rRNA gene sequencing. RESULTS: Mean FCA ± SD at baseline was low at 5.5 ± 5.1%. Comparing SCF to placebo, there was no between-group difference in mean (95% CI) change in FCA (+3.4 [-6.7, +13.6]%), nor in calciotropic hormones or bone turnover markers. The SCF group had a wider variation in FCA change than placebo (SD 13.4% vs 7.0%). Those with greater change in microbial composition following SCF treatment had greater increase in FCA (r2 = 0.72, P = 0.05). SCF adherence was high, and gastrointestinal symptoms were similar between groups. CONCLUSION: No between-group differences were observed in changes in FCA or calciotropic hormones, but wide CIs suggest a variable impact of SCF that may be due to the degree of gut microbiome alteration. Daily SCF consumption was well tolerated. Larger and longer-term studies are warranted.

Comparison of the distribution and phenology of Arctic Mountain plants between the early 20th and 21st centuries.

Arctic plants are adapted to climatic variability, but their long-term responses to warming remain unclear. Responses may occur by range shifts, phenological adjustments in growth and reproduction, or both. Here, we compare distribution and phenology of 83 arctic and boreal mountain species, sampled identically in the early 20th (1917-1919) and 21st centuries (2017-2018) from a region of northern Sweden that has warmed significantly. We test two compensatory hypotheses to high-latitude warming-upward shifts in distribution, and earlier or extended growth and reproduction. For distribution, we show dramatic upward migration by 69% of species, averaging 6.1 m per decade, especially boreal woodland taxa whose upward expansion has reduced arctic montane habitat by 30%. Twenty percent of summit species showed distributional shifts but downward, especially moisture-associated snowbed flora. For phenology, we detected wide inter-annual variability in the onset of leafing and flowering in both eras. However, there was no detectable change in growing-season length, relating to two mechanisms. First, plot-level snow melt data starting in 1917 demonstrated that melt date, rather than vernal temperatures, better predicts plant emergence, with snow melt influenced by warmer years having greater snowfall-warmer springs did not always result in earlier emergence because snowbeds can persist longer. Second, the onset of reproductive senescence between eras was similar, even when plant emergence was earlier by a month, possibly due to intensified summer heat stress or hard-wired 'canalization' where senescence occurs regardless of summer temperature. Migrations in this system have possibly buffered arctic species against displacement by boreal expansion and warming, but ongoing temperature increases, woody plant invasion, and a potential lack of flexibility in timing of senescence may foreshadow challenges.

FSH Level and Changes in Bone Mass and Body Composition in Older Women and Men.

CONTEXT: FSH may have independent actions on bone remodeling and body fat regulation. Cross-sectionally, we have shown that serum FSH is associated with bone mineral density (BMD) and body fat in older postmenopausal women, but it remains unknown whether FSH predicts bone and fat changes. OBJECTIVE: We examined whether baseline FSH level is associated with subsequent bone loss or body composition changes in older adults. SETTING, DESIGN, PARTICIPANTS: We studied 162 women and 158 men (mean age 82 ± 4 years) from the Age, Gene/Environment Susceptibility (AGES)-Bone Marrow Adiposity cohort, a substudy of the AGES-Reykjavik Study of community-dwelling older adults. Skeletal health and body composition were characterized at baseline and 3 years later. MAIN OUTCOMES: Annualized change in BMD and body composition by dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT). Models were adjusted for serum estradiol and testosterone levels. RESULTS: There was no evidence for an association between baseline FSH level and change in BMD or body composition by DXA or QCT. For femoral neck areal BMD, adjusted mean difference (95% CI) per SD increase in FSH was 1.3 (-0.7 to 3.3) mg/cm2/y in women, and -0.2 (-2.6 to 2.2) mg/cm2/y in men. For visceral fat, adjusted mean difference (95% CI) per SD increase in FSH was 1.80 (-0.03 to 3.62) cm2/y in women, and -0.33 (-3.73 to 3.06) cm2/y in men. CONCLUSIONS: Although cross-sectional studies and studies in perimenopausal women have demonstrated associations between FSH and BMD and body composition, in older adults, FSH level is not associated with bone mass or body composition changes.