A CT-based Deep Learning Model for Predicting Subsequent Fracture Risk in Patients with Hip Fracture.

Background Patients have the highest risk of subsequent fractures in the first few years after an initial fracture, yet models to predict short-term subsequent risk have not been developed. Purpose To develop and validate a deep learning prediction model for subsequent fracture risk using digitally reconstructed radiographs from hip CT in patients with recent hip fractures. Materials and Methods This retrospective study included adult patients who underwent three-dimensional hip CT due to a fracture from January 2004 to December 2020. Two-dimensional frontal, lateral, and axial digitally reconstructed radiographs were generated and assembled to construct an ensemble model. DenseNet modules were used to calculate risk probability based on extracted image features and fracture-free probability plots were output. Model performance was assessed using the C index and area under the receiver operating characteristic curve (AUC) and compared with other models using the paired t test. Results The training and validation set included 1012 patients (mean age, 74.5 years ± 13.3 [SD]; 706 female, 113 subsequent fracture) and the test set included 468 patients (mean age, 75.9 years ± 14.0; 335 female, 22 subsequent fractures). In the test set, the ensemble model had a higher C index (0.73) for predicting subsequent fractures than that of other image-based models (C index range, 0.59-0.70 for five of six models; P value range, < .001 to < .05). The ensemble model achieved AUCs of 0.74, 0.74, and 0.73 at the 2-, 3-, and 5-year follow-ups, respectively; higher than that of most other image-based models at 2 years (AUC range, 0.57-0.71 for five of six models; P value range, < .001 to < .05) and 3 years (AUC range, 0.55-0.72 for four of six models; P value range, < .001 to < .05). Moreover, the AUCs achieved by the ensemble model were higher than that of a clinical model that included known risk factors (2-, 3-, and 5-year AUCs of 0.58, 0.64, and 0.70, respectively; P < .001 for all). Conclusion In patients with recent hip fractures, the ensemble deep learning model using digital reconstructed radiographs from hip CT showed good performance for predicting subsequent fractures in the short term. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Li and Jaremko in this issue.

A Computed Tomography-Based Fracture Prediction Model With Images of Vertebral Bones and Muscles by Employing Deep Learning: Development and Validation Study.

BACKGROUND: With the progressive increase in aging populations, the use of opportunistic computed tomography (CT) scanning is increasing, which could be a valuable method for acquiring information on both muscles and bones of aging populations. OBJECTIVE: The aim of this study was to develop and externally validate opportunistic CT-based fracture prediction models by using images of vertebral bones and paravertebral muscles. METHODS: The models were developed based on a retrospective longitudinal cohort study of 1214 patients with abdominal CT images between 2010 and 2019. The models were externally validated in 495 patients. The primary outcome of this study was defined as the predictive accuracy for identifying vertebral fracture events within a 5-year follow-up. The image models were developed using an attention convolutional neural network-recurrent neural network model from images of the vertebral bone and paravertebral muscles. RESULTS: The mean ages of the patients in the development and validation sets were 73 years and 68 years, and 69.1% (839/1214) and 78.8% (390/495) of them were females, respectively. The areas under the receiver operator curve (AUROCs) for predicting vertebral fractures were superior in images of the vertebral bone and paravertebral muscles than those in the bone-only images in the external validation cohort (0.827, 95% CI 0.821-0.833 vs 0.815, 95% CI 0.806-0.824, respectively; P<.001). The AUROCs of these image models were higher than those of the fracture risk assessment models (0.810 for major osteoporotic risk, 0.780 for hip fracture risk). For the clinical model using age, sex, BMI, use of steroids, smoking, possible secondary osteoporosis, type 2 diabetes mellitus, HIV, hepatitis C, and renal failure, the AUROC value in the external validation cohort was 0.749 (95% CI 0.736-0.762), which was lower than that of the image model using vertebral bones and muscles (P<.001). CONCLUSIONS: The model using the images of the vertebral bone and paravertebral muscle showed better performance than that using the images of the bone-only or clinical variables. Opportunistic CT screening may contribute to identifying patients with a high fracture risk in the future.

Expression of CYP11B1 and CYP11B2 in adrenal adenoma correlates with clinical characteristics of primary aldosteronism.

OBJECTIVE: Primary aldosteronism (PA) shows histological heterogeneity and clinical variability, including the coexistence of hypercortisolemia. Immunohistochemical analyses of steroidogenic enzymes in adrenal tissues have provided new insights into the pathogenesis of PA. However, a comprehensive analysis of the association between enzyme expression and clinical characteristics of PA has rarely been conducted. We aimed to investigate the correlation between clinical characteristics and steroidogenic enzyme expression in PA. DESIGN: A retrospective case-control study. PATIENTS: Consecutive patients who underwent unilateral adrenalectomy for PA (n = 180). Patients with adrenal Cushing's syndrome (CS) (n = 29) and nonfunctioning adenoma (n = 6) as comparator groups. MEASUREMENTS: A tissue microarray of adrenal adenomas was constructed and immunostained for CYP11B1, CYP11B2 and CYP17A1. The expression of the three enzymes was compared between PA and other adrenal diseases and between PA with and without mild autonomous cortisol excess (MACE). RESULTS: Adrenal adenomas in PA showed lower CYP11B1, higher CYP11B2 and lower CYP17A1 expression than those in adrenal CS (p < .001). Nonfunctioning adenomas showed low expression of the three enzymes. PA with MACE showed higher CYP11B1 expression than PA without MACE. CYP11B1 expression was positively correlated with the severity of hypercortisolemia, and CYP11B2 was positively correlated with that of hyperaldosteronism. The expression of CYP11B1 and CYP11B2 had a negative correlation. Patients with absent clinical improvement after adrenalectomy had lower CYP11B2 expression than those with complete success. CONCLUSIONS: Variable expression of steroidogenic enzymes in adrenal adenoma underlies the clinical heterogeneity of PA and is associated with treatment outcomes.

Indices of ACTH-stimulated adrenal venous sampling as predictors of postsurgical outcomes in primary aldosteronism.

OBJECTIVE: This study aimed to investigate the impact of indices of adrenal venous sampling (AVS) on postsurgical outcomes in patients with primary aldosteronism (PA). DESIGN AND PATIENTS: This retrospective study determined biochemical and clinical outcomes based on ACTH-stimulated AVS parameters (lateralisation index [LI], contralateral ratio [CLR], and ipsilateral ratio [ILR]) in 251 patients with PA at 3 months after surgery. RESULTS: Modified complete biochemical success was achieved in 8 of 12 (66.7%) patients with LI = 3-4, 39 of 47 (83.0%) with LI = 4-10, and 155 of 169 (91.7%) with LI ≥ 10 (p = .004 for trend). Modified complete biochemical success was achieved in 29 of 38 (76.3%) patients with CLR ≥ 1 and ILR ≤ 2, 73 of 86 (84.9%) with CLR = 0.25-1 and ILR > 2, and 100 of 104 (96.2%) with CLR < 0.25 and ILR > 2 (p = .001 for trend). After adjusting for confounders, modified complete biochemical success was associated with an LI ≥ 10 (odds ratio [OR] = 6.32; 95% confidence interval [CI] = 1.33-29.93) using LI = 3-4 as a reference and combined CLR < 0.25 and ILR > 2 (OR = 11.49; 95% confidence interval [CI] = 2.49-53.01) using combined CLR ≥ 1 and ILR ≤ 2 as a reference. Using combined CLR ≥ 1 and ILR ≤ 2 as a reference, complete clinical success was associated with combined CLR < 0.25 and ILR > 2 (OR = 3.10; 95% CI = 1.03-9.28) and combined CLR = 0.25-1 and ILR > 2 (OR = 4.92; 95% CI = 1.64-14.76). CONCLUSION: LI ≥ 10 may be appropriate for achieving biochemical success. With ILR > 2, CLR < 0.25, and CLR < 1 may be appropriate for achieving biochemical and clinical success, respectively.

Reactivation of Bone Lining Cells are Attenuated Over Repeated Anti-sclerostin Antibody Administration.

Reactivation of bone lining cells (BLCs) is a crucial mechanism governing the anabolic action of anti-sclerostin antibody (Scl-Ab) via modeling-based bone formation; however, it remains unclear whether this reactivation can be attenuated after persistent administration of Scl-Ab. Here, we aimed to investigate the reproducibility of persistent Scl-Ab administration for the reactivation of BLCs, and to elucidate the relationship between the activity of BLCs and serum levels of N-terminal procollagen type I (P1NP) during chronic Scl-Ab administration. We conducted an osteoblast lineage tracing study. Briefly, Dmp1-CreERt2(+):Rosa26R mice were injected with 1 mg of 4-hydroxy-tamoxifen weekly from postnatal weeks four to eight. Mice were treated twice with either vehicle or Scl-Ab (25 mg/kg) at weeks 12, 16, and 20, and were euthanized at weeks 8, 12, 13, 16, 17, 20, and 21 (4-6 mice in each group). After euthanization, the number and thickness of X-gal (+) cells on the periosteum of the femoral bones and the serum levels of P1NP were quantified at each time point. Scl-Ab induced a significant increase in the thickness of X-gal (+) cells on periosteal bone surfaces at postnatal weeks 13 (after 1st dose), 17 (after 2nd dose), and 21 (after 3rd dose) compared to that in vehicle-treated mice (all P < 0.001). In the Scl-Ab group, significant increases in the thickness of labeled cells were observed between weeks 16 and 17 and weeks 20 and 21 (both P < 0.001). The percentage increase in X-gal (+) cell thickness was 108.9% from week 12 to week 13, 54.6% from week 16 to week 17, and 49.2% from week 20 to week 21 in the Scl-Ab group. Although Scl-Ab treatment increased the serum levels of P1NP at postnatal weeks 13 and 17 compared with those at week 12 (P = 0.017 and P = 0.038, respectively), the same was not observed at week 21 (P = 0.296). A significant increase in P1NP levels was observed between weeks 16 and 17 and weeks 20 and 21 in the Scl-Ab group (P = 0.005 and P = 0.007, respectively). The percentage increase in P1NP levels was 141.7% from weeks 12 to 13, 114.8% from weeks 16 to 17, and 99.4% from weeks 20 to 21. Serum P1NP levels were positively correlated with X-gal (+) cell thickness (R2 = 0.732, P < 0.001). Reactivation of BLCs is modestly attenuated, but reproducible, during persistent Scl-Ab administration. Serum P1NP levels appear to be an indicator of the impact of Scl-Ab on the conversion of BLCs into mature osteoblasts on periosteal bone surfaces, thus contributing to modeling-based bone formation.

Skeletal effects of combined bisphosphonates treatment and parathyroidectomy in osteoporotic patients with primary hyperparathyroidism.

INTRODUCTION: Bone loss caused by primary hyperparathyroidism (PHPT) is an indication for parathyroidectomy (PTX). However, whether adding bisphosphonates would be superior to PTX alone to increase bone mass remains unclear. We thus aimed to compare the skeletal effects of the combination treatment of bisphosphonates and PTX with PTX alone. MATERIALS AND METHODS: In this retrospective analysis, bone mineral density (BMD) changes after 1 year of combination treatment and PTX alone were compared. We also analyzed the correlation between changes in serum biochemical parameters and BMD after 1 year of treatment in both groups. RESULTS: The baseline characteristics of patients treated with PTX alone (n = 24) and combination treatment (n = 26) were comparable. BMD significantly increased after 1 year of treatment in both groups (all p < 0.001), and the increase in BMD at the femur neck was higher in the PTX alone group than in the combination group (p = 0.011). There was a decreasing trend in serum alkaline phosphatase (ALP) levels in PTX alone compared to the combination treatment group (p = 0.053). In the study cohort, lower BMD and higher ALP levels at baseline were associated with higher 1-year BMD changes at all sites. Interestingly, a significant association was found between changes in ALP and BMD at the femur neck in the PTX alone group (p = 0.003), but abolished in the combination group (p = 0.946). CONCLUSIONS: There is no additional benefit of BMD in combination treatment with bisphosphonates and PTX over PTX alone in osteoporotic patients with PHPT. Combined bisphosphonate treatment might interfere with the increase in bone mass caused by PTX.

Recognition of Targets in SAR Images Based on a WVV Feature Using a Subset of Scattering Centers.

This paper proposes a robust method for feature-based matching with potential for application to synthetic aperture radar (SAR) automatic target recognition (ATR). The scarcity of measured SAR data available for training classification algorithms leads to the replacement of such data with synthetic data. As attributed scattering centers (ASCs) extracted from the SAR image reflect the electromagnetic phenomenon of the SAR target, this is effective for classifying targets when purely synthetic SAR images are used as the template. In the classification stage, following preparation of the extracted template ASC dataset, some of the template ASCs were subsampled by the amplitude and the neighbor matching algorithm to focus on the related points of the test ASCs. Then, the subset of ASCs were reconstructed to the world view vector feature set, considering the point similarity and structure similarity simultaneously. Finally, the matching scores between the two sets were calculated using weighted bipartite graph matching and then combined with several weights for overall similarity. Experiments on synthetic and measured paired labeled experiment datasets, which are publicly available, were conducted to verify the effectiveness and robustness of the proposed method. The proposed method can be used in practical SAR ATR systems trained using simulated images.

Improvement of Statin Utilization in Veterans With Diabetes Through Pharmacy Interventions.

Quality Improvement Success Stories are published by the American Diabetes Association in collaboration with the American College of Physicians and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes an effort aimed at increasing the use of statins among veterans with diabetes at a Veterans Affairs medical center in New Mexico.

Aromatase inhibitors attenuate the effect of alendronate in women with breast cancer.

INTRODUCTION: Aromatase inhibitors are known to accelerate bone loss in patients with breast cancer. However, how much AIs affect the efficacy of antiresorptive agents has not been studied. The study aimed to compare the effect of alendronate on bone mineral density (BMD) between patients with and without AI treatment. MATERIALS AND METHODS: In this retrospective study, 90 postmenopausal women with early breast cancer who were being treated with both AI and alendronate 70 mg weekly (ALN + AI), and 90 age- and body mass index (BMI)-matched patients who were only taking alendronate (ALN-only) were analyzed. BMD and bone turnover markers (BTMs) were assessed at the baseline and 12 months. RESULTS: The mean age was 63 years. At baseline, the ALN-only group had lower lumbar spine (LS), femur neck (FN), and total hip (TH) BMD than ALN + AI group. After 1-year of alendronate treatment, the LS and FN BMD were improved more in the ALN-only group than those in the ALN + AI group after adjustments for age, BMI, baseline BMD, diabetes, hypertension, renal function, and previous fracture history [LS BMD: 6.2% (3.1%; 9.2%) in ALN-only, 3.5% (-0.5%; 6.5%) in ALN + AI, p = 0.001; FN BMD: 2.5% (0.3%; 5.7%) in ALN-only, 0.9% (- 1.8%; 3.6%) in ALD + AI, p = 0.032]. BTMs were significantly decreased in both groups, but the changes between groups were similar. CONCLUSION: The effect of alendronate on the LS and FN BMD was attenuated in postmenopausal women who were taking AI compared to those who were not on AI.

Effect of Endogenous Parathyroid Hormone on Bone Geometry and Skeletal Microarchitecture.

Parathyroid hormone (PTH) has anabolic or catabolic effects on bones; however, the skeletal effect of endogenous PTH on cortical and trabecular bones is not yet clear. Therefore, we aimed to examine the effects of an excess and a deficiency of endogenous PTH on the lumbar spine trabecular bone score (TBS) and bone geometry using dual-energy X-ray absorptiometry. We retrospectively included 70 patients with primary hyperparathyroidism (PHPT), 26 patients with idiopathic or postoperative hypoparathyroidism (HypoPT), and 96 normal controls matched by age, sex, and body mass index. The bone mineral density (BMD) at the lumbar spine, femur neck, and total hip was higher in the HypoPT, followed by the controls and PHPT group (all P < 0.001). The TBS was significantly decreased in the PHPT group compared to the controls (P = 0.021); however, statistical significance disappeared after adjusting for the lumbar BMD (P = 0.653). There were no significant differences in the TBS between the HypoPT group and controls as well as the PHPT and HypoPT group. As for bone geometry parameters, the cross-sectional area, cross-sectional moment of inertia, and section modulus were higher in the HypoPT, followed by the controls and PHPT group (all P < 0.001); statistical significance remained after adjusting for the total hip BMD. We also observed a significantly increased cortical neck width in the HypoPT group compared to the PHPT group (P = 0.009). The buckling ratio was higher in the PHPT than the HypoPT group and controls (P = 0.018 and P = 0.013, respectively). The present study demonstrated that an excess of endogenous PTH had catabolic effects on both cortical and trabecular bones. Under conditions of endogenous PTH deficiency, the effect on cortical bone was pronounced, but that on trabecular bone was modest.

Metabolic characteristics of subjects with spine-femur bone mineral density discordances: the Korean National Health and Nutrition Examination Survey (KNHANES 2008-2011).

The diagnosis of osteoporosis is determined based on the lowest bone mineral density (BMD) T-score at the lumbar spine (LS) and hip. However, there are occasional marked discordances between the T-score of LS and femur neck (FN). We aimed to examine the prevalence and characteristics of individuals with spine-femur BMD discordance using a nationwide survey. A total of 3233 men aged ≥ 50 years and 2915 postmenopausal women were included from the Korean National Health and Nutrition Examination Surveys (2008-2011). The spine-femur discordance was defined as a difference of ≥ 1.5 SD between LS and FN BMD. Subjects were divided into three groups: low LS (LS < FN), low FN (LS > FN), and no discordance. Four-hundred and seventeen men (12.9%) and two hundred and ninety women (10%) exhibited spine-femur BMD discordance. The prevalence of hypertension and diabetes was higher in men and women with low FN BMD than in any other group. Fasting plasma glucose and homeostasis model assessment of insulin resistance was the highest in subjects with low FN BMD among the three groups. Low FN BMD revealed higher serum parathyroid hormone and lower 25-hydroxyvitamin D3 levels compared to any other group in women, but this was not observed in men. Osteoporosis was prevalent in subjects with discordance in both genders, particularly, in those with low LS BMD (31.6% in men and 63.5% in women). Given the high prevalence of spine-femur BMD discordance, low FN BMD may be associated with vitamin D deficiency and insulin resistance, but low LS BMD may present severe osteoporosis.

Amount of smoking, pulmonary function, and bone mineral density in middle-aged Korean men: KNHANES 2008-2011.

Smoking induces bone loss; however, data on the relationship between smoking history and bone mineral density (BMD) are lacking. Age and pulmonary function can affect BMD. We investigated the relationships among pack-years (PYs) of smoking, pulmonary function, and BMD in middle-aged Korean men (50-64 years old). This cross-sectional study used data from the Korean National Health and Nutrition Examination Survey, 2008-2011. All participants underwent BMD measurements using dual energy X-ray absorptiometry and pulmonary function tests using standardized spirometry. In total, 388 never-smokers and 1088 ever-smokers were analyzed. The number of PYs of smoking was negatively correlated with total hip BMD (r = -0.088; P = 0.004) after adjusting for age, height, and weight. Ever-smokers were classified into 3 groups according to PYs of smoking. The highest tertile (n = 482) exhibited significantly lower total hip bone mass than the lowest tertile (n = 214) after adjusting for confounding factors (age, height, weight, forced expiratory volume in 1 s (FEV1), alcohol consumption, physical activity, and vitamin D levels) that could affect bone metabolism (P = 0.003). In conclusion, smoking for >30 PYs was significantly associated with low hip BMD after adjusting for pulmonary function in middle-aged Korean men. Long-term smoking may be a risk factor for bone loss in middle-aged men independent of age, height, weight, and pulmonary function.

The efficacy of medical treatment in patients with acromegaly in clinical practice.

Although somatostatin analogues (SSAs) are recommended as the first-line medical therapy for acromegaly, dopamine agonists (DAs) are also a therapeutic option for treatment. We aimed to assess and compare the efficacies of DAs and SSAs in treating acromegaly in clinical practice. We included 89 patients with acromegaly who took DAs (bromocriptine [BCT], n = 63; cabergoline [CAB], n = 11) or SSAs (n = 15) as a primary medical therapy for more than 3 months in the Seoul National University Hospital. The CAB (45.5%) and SSA (33.3%) groups achieved random GH levels of <2.5 ng/mL and the normal IGF-1 levels were significantly higher than in the BCT group (11.1%) (p = 0.009). We further included all the patients with acromegaly (n = 132) who had taken CAB, BCT, and SSAs as first- or second-line medical therapy. The CAB group showed similar efficacy as the SSA group in terms of the GH and insulin-like growth factor-1 (IGF-1) levels (57.6% for random GH level <2.5 ng/mL, 42.4% for normal IGF-1 levels, 36.4% for both). Logistic regression analysis revealed that medications, age, GH level, or IGF-1 level before medication, hyperprolactinemia, and prior gamma-knife surgery or radiation therapy, did not affect the therapeutic response. High pretreatment GH levels predicted poor treatment outcomes (odds ratio [95% confidence interval] = 0.95 [0.90-0.99]). CAB was effective in treating acromegaly at a relatively lower cost in patients with low pretreatment GH levels.

The natural history and hip geometric changes of primary hyperparathyroidism without parathyroid surgery.

There have been few reports on changes in bone geometry in asymptomatic patients with primary hyperparathyroidism (PHPT) not treated surgically. We reviewed the records concerning biochemical parameters, bone mineral density (BMD), and hip geometry in 119 PHPT patients who did not undergo parathyroidectomy, followed up at one of three hospitals affiliated to Seoul National University from 1997 to 2013. We examined biochemical parameters over 7 years and BMD and hip geometry over 5 years of follow-up. We further compared hip geometry and BMD derived from dual-energy X-ray absorptiometry (DXA) between patients and age- and sex-matched controls. The median follow-up duration of 56 patients for whom surgery was not indicated was 33.9 months (range 11.2-131.2 months), and 19.6 % of these patients had disease progression during follow-up. Serum calcium levels remained stable for 7 years in all 119 patients. From a comparison of the PHPT patients for whom surgery was not indicated with controls, both male and postmenopausal female patients had significantly lower hip axis length (P < 0.001), cross-sectional moment of inertia (P < 0.001), cross-sectional area (P < 0.001), and section modulus (P < 0.001). In addition, cortical thickness was significantly decreased at 5 years compared with individual baseline values (P = 0.003). However, there was no significant change in BMD for the duration of the 5-year follow-up. DXA-derived geometry can detect skeletal change in asymptomatic PHPT patients for whom surgery is not indicated, supporting the concept that even mild PHPT can eventually compromise the cortical bones. Hip geometry is a potential tool for monitoring skeletal complication in asymptomatic PHPT patients.

Outcomes analysis of surgical and medical treatments for patients with primary aldosteronism.

Patients with aldosterone-producing adenomas are treated using surgery, and patients with idiopathic hyperaldosteronism receive medical treatment using mineralocorticoid receptor antagonists (MRAs). However, the outcomes of surgical and medical treatment for primary aldosteronism (PA) remain unclear. Therefore, we compared the outcomes of surgical and medical treatment for PA and aimed to identify a specific subgroup that might benefit from medical treatment. We identified 269 patients who were treated for PA (unilateral excess: 221 cases; bilateral excess: 48 cases) during 2000-2015 at the Seoul National University Hospital and two other tertiary centers. The main outcomes were the amelioration of hypertension and hypokalemia. Treatment improved hypertension in the surgical treatment group (78.2%) and the medical treatment group (55.6%) (p = 0.001). At the last follow-up, hypokalemia was normalized in the surgical treatment group (97.1%) and the medical treatment group (93.7%, p = 0.046). Among patients with unilateral aldosterone excess, surgery provided advantages in resolving hypertension without worsening renal function. Among patients who were >60 years old or had impaired renal function, surgical and medical treatment provided similar amelioration of hypokalemia and hypertension. Three patients developed hyperkalemia after surgery, and no patients developed hyperkalemia after initiating medical treatment. The surgical treatment group exhibited a lower postoperative estimated glomerular filtration rate (eGFR) and higher serum potassium levels, compared to the medical treatment group. Surgical treatment provided better hypertension and hypokalemia outcomes among patients with PA, compared to medical treatment. However, MRAs may be appropriate for elderly patients with impaired renal function.

Intermittent PTH treatment can delay the transformation of mature osteoblasts into lining cells on the periosteal surfaces.

Mature osteoblasts have three fates: as osteocytes, quiescent lining cells, or osteoblasts that undergo apoptosis. However, whether intermittent parathyroid hormone (PTH) can modulate the fate of mature osteoblasts in vivo is uncertain. We performed a lineage-tracing study using an inducible gene system. Dmp1-CreERt2 mice were crossed with Rosa26R reporter mice to obtain targeted mature osteoblasts and their descendants, lining cells or osteocytes, which were detected using X-gal staining. Rosa26R:Dmp1-CreERt2(+) mice were injected with 0.25 mg 4-OH-tamoxifen (4-OHTam) on postnatal days 5, 7, 9, 16, and 23. In a previous study, at 22 days after the last 4-OHTam, most LacZ+ cells on the periosteal surface were inactive lining cells. On day 25 (D25), the mice were challenged with an injection of human PTH (1-34, 80 µg/kg) or vehicle daily for 10 (D36) or 20 days (D46). We evaluated the number and thickness of LacZ+ osteoblast descendants in the calvaria and tibia. In the vehicle group, the number and thickness of LacZ+ osteoblast descendants at both D36 and D46 significantly decreased compared to D25, which was attenuated in the PTH group. In line with these results, PTH inhibited the decrease in the number of LacZ+/osteocalcin-positive cells compared to vehicle at both D36 and D46. As well, the serum levels of sclerostin decreased, as did the protein expression of sclerostin in the cortical bone. These results suggest that intermittent PTH treatment can increase the number of periosteal osteoblasts by preventing mature osteoblasts from transforming into lining cells in vivo.

Sex differences in the prevalence of metabolic syndrome and its components in hypopituitary patients: comparison with an age- and sex-matched nationwide control group.

PURPOSE: Hypopituitary patients have a reduced life expectancy owing to cardiovascular events. We investigated the prevalence of metabolic syndrome in hypopituitary patients for a follow-up period of at least 1 year in comparison with an age- and sex-matched nationwide control group. METHODS: A total of 515 patients with hypopituitarism who visited Seoul National University Hospital between January 2000 and December 2010 were included. Data for an age- and sex-matched control group were obtained from the Korean National Health and Nutrition Examination Surveys (KNHANES) (n = 1545). Metabolic syndrome was defined according to the modified National Cholesterol Education Program (NCEP-ATPIII). RESULTS: The prevalence of metabolic syndrome did not differ significantly between the hypopituitary and control groups for men (34.9 versus 30.3 %), but the risk of metabolic syndrome was higher in hypopituitary women than in controls (39.8 versus 28.5 %). In both sexes, the risks of central obesity and dyslipidemia were higher in the hypopituitary group than in the control group. Men had lower risks of hypertension and hyperglycemia in the hypopituitary group, which attenuated the risk of metabolic syndrome. Age greater than 40 years and obesity (BMI ≥25 kg/m2) contributed to a higher risk of metabolic syndrome. CONCLUSIONS: The metabolic syndrome prevalence was higher in the hypopituitry group than in the control group in Korean women, and this was attributed to an increased risk of central obesity and dyslipidemia. Accordingly, early intervention to reduce metabolic syndrome needed in hypopituitary patients, i.e. women.

Femoral geometry, bone mineral density, and the risk of hip fracture in premenopausal women: a case control study.

BACKGROUND: The purpose of this study was to determine the relationships among hip geometry, bone mineral density, and the risk of hip fracture in premenopausal women. METHODS: The participants in this case-control study were 16 premenopausal women with minimal-trauma hip fractures (fracture group) and 80 age-and BMI-adjusted controls. Subjects underwent dual-energy X-ray absorptiometry (DXA) to assess BMD at the proximal femur and to obtain DXA-derived hip geometry measurements. RESULTS: The fracture group had a lower mean femoral neck and total hip BMD than the control group (0.721 ± 0.123 vs. 0.899 ± 0.115, p <0.001 for the femoral neck BMD and 0.724 ± 0.120 vs. 0.923 ± 0.116, p <0.001 for the total hip BMD). In addition, participants in the fracture group had a longer hip axis length (HAL; p = 0.007), narrower neck shaft angle (NSA; p = 0.008), smaller cross sectional area (CSA; p < 0.001) and higher cross sectional moment of inertia (CSMI; p = 0.004) than those in control group. After adjusting for BMD, the fracture group still had a significantly longer mean HAL (p = 0.020) and narrower NSA (p = 0.006) than the control group. CONCLUSIONS: BMD is an important predictor of hip fracture in premenopausal women. Furthermore, HAL and NSA are BMD-independent predictors of hip fracture in premenopausal women. Hip geometry may be clinically useful for identification of premenopausal women for whom active fracture prevention should be considered.

In vivo deletion of CAR resulted in high bone mass phenotypes in male mice.

Constitutive androstane receptor (CAR) was originally identified as xenobiotic sensor that regulates the expression of cytochrome P450 genes. However, recent studies suggest that this nuclear receptor is also involved in the regulation of energy metabolism including glucose and lipid homeostasis. This study investigated the role of CAR in the regulation of bone mass in vivo using CAR(-/-) mice. Endogenous mRNA expression of CAR was observed in both primary osteoblasts and osteoclast precursors. CAR(-/-) mice have exhibited significant increase in whole body bone mineral density (BMD) by 9.5% (P < 0.01) and 5.5% (P < 0.05) at 10 and 15 weeks of age, respectively, compared with WT mice in males. Microcomputed tomography analysis of proximal tibia demonstrated a significant increase in trabecular bone volume (62.7%), trabecular number (54.1%) in male CAR(-/-) mice compared with WT mice. However, primary culture of calvarial cells exhibited no significant changes in osteogenic differentiation potential between CAR(-/-) and WT. In addition, the number of tartrate-resistant acid-phosphatase positive osteoclasts in the femur and serum level of CTx was not different between CAR(-/-) and WT mice. The higher BMD and microstructural parameters were not observed in female mice. Interestingly, serum level of testosterone in male CAR(-/-) mice was 2.5-fold higher compared with WT mice and the mRNA expressions of Cyp2b9 and 2b10 in the liver, which regulate testosterone metabolism, were significantly down-regulated in male CAR(-/-) mice. Furthermore, the difference in BMD between CAR(-/-) and WT mice disappeared at 8 weeks after performing orchiectomy. CAR(-/-) mice also exhibited significant increase in serum 1,25(OH)2 D3 levels but Cyp 27B1 which converts 25(OH)D3 to 1,25(OH)2 D3 was significantly down-regulated compared to WT mice. These results suggest that in vivo deletion of CAR resulted in higher bone mass, which appears to be a result from reduced metabolism of testosterone due to down-regulation of Cyp2b.

Subtype-specific Body Composition and Metabolic Risk in Patients With Primary Aldosteronism.

BACKGROUND: Primary aldosteronism (PA) is associated with increased metabolic risks. However, controversy exists as to which subtype of PA has a higher metabolic risk between bilateral and lateralized PA. This study aimed to assess the body composition of 2 PA subtypes, bilateral PA and lateralized PA, according to sex and autonomous cortisol secretion (ACS) and their contribution to comorbidities. DESIGN AND METHODS: A total of 400 patients with PA (females, n = 210) and 1:10 age- and sex-matched healthy controls (n = 4000) were enrolled. The skeletal muscle area (SMA), subcutaneous fat area, and visceral fat area (VFA) at the third lumbar spine were calculated using abdominal computed tomography-based body composition analysis. RESULTS: Patients with bilateral PA had higher body mass index (BMI) in both sexes (all P < .05). Hemoglobin A1c level and the prevalence of diabetes were higher in female patients with bilateral PA than in those with lateralized PA (all P < .05). The VFA/BMI ratio was significantly higher in bilateral PA patients than in lateralized PA patients (5.77 ± 2.69 vs 4.56 ± 2.35 in men; 4.03 ± 2.58 vs 2.53 ± 2.05 in women, all P < .001). PA patients with ACS showed decreased SMA compared to those without ACS. Compared with healthy controls, all patients with bilateral PA and female patients with lateralized PA showed significantly higher VFA and VFA/BMI. CONCLUSIONS: Patients with bilateral PA were more obese and had higher VFA levels than those with lateralized PA. Despite a milder form of PA, this metabolically unfavorable visceral fat distribution may lead to a higher metabolic risk in patients with bilateral PA.