Association of Famine Exposure on the Changing Clinical Phenotypes of Primary Hyperparathyroidism in 20 years.

Background & Aims: Primary hyperparathyroidism(PHPT) has been evolving into a milder asymptomatic disease. No study has assessed the association between famine exposure and such a shift. We aim to explore the effects of China's Great Famine exposure on the changing pattern of PHPT phenotypes. Methods: 750 PHPT patients diagnosed from 2000 to 2019 were studied. The clinical presentations were compared between them in recent 10 years (2010-2019) and previous 10 years (2000-2009). Participants were then categorized into fetal, childhood, adolescent, adult exposure, and unexposed groups. Logistic regression was used to estimate the odds ratios (ORs) and confidence intervals (CIs) of famine exposure as factors contributing to the changes in the clinical presentations of PHPT. Results: Serum levels of PTH, albumin-corrected Ca, tumor size, eGFR, BMDs (all P<0.001), and clinical symptoms became milder in recent 10 years. Famine exposure (72.6% vs 58.4%, P<0.001), especially the adult exposure (18.8% vs 4.1%, P<0.001)was significant less in recent 10 years. The ORs (95%CIs) of having upper 3rd tertile PTH were 2.79(1.34,5.8), 2.07(1.04,4.11), 3.10(1.15,8.38) and 8.85(2.56,30.56) for patients with fetal, childhood, adolescent and adult famine exposure, respectively. The ORs (95%CIs) of upper 3rd tertile albumin-corrected Ca and upper 3rd tertile of tumor size was 4.78(1.39, 16.38) and 4.07(1.12,14.84) for participants with adult famine exposure, respectively. All these associations were independent of age, sex, disease duration and other confounders. Conclusions: The clinical manifestations of PHPT in China continue to be milder. Exposure to famine is associated with PHPT. Less famine exposure might be responsible for the mile form of PHPT in recent years.

Multidisciplinary team efforts to improve the pregnancy outcome of pregnancy complicated with primary hyperparathyroidism: case series from a single hospital.

BACKGROUND: There is no consensus or management algorithm for primary hyperparathyroidism (PHPT) in pregnancy. METHODS: This study comprises a retrospective case series. From August 2014 to December 2020, 9 cases of PHPT in pregnancy were diagnosed by a multidisciplinary team (MDT) consultation center of obstetrics in our hospital. Their clinical manifestations, treatment strategies, and maternal and infant outcomes were analyzed. RESULTS: The median onset age of the patients was 32 (25 ~ 38) years. PHPT was diagnosed in two cases before pregnancy, in six cases during pregnancy and in one case postpartum. The main clinical manifestations were nausea, vomiting, and other nonspecific symptoms, with anemia as the most common maternal complication. Hypercalcemia crisis was developed in one case. The median levels of preoperative serum calcium and parathyroid hormone (PTH) were 3.08 (2.77 ~ 4.21) mmol/L and 300.40 (108.80 ~ 2603.60) pg/ml, respectively. The parathyroid ultrasonography tests were positive in eight cases and negative in one patient who had an ectopic lesion localized by 99mTc-MIBI. Parathyroidectomy was conducted in 7 cases during the 2nd trimester, including 2 patients diagnosed before pregnancy who refused surgery, 1 patient during the 1st trimester, and 1 patient postpartum, with a significant reduction in serum concentrations of calcium and PTH. A management algorithm was developed. CONCLUSION: This case series suggests that pregnant women with PHPT should be managed by MDT according to the algorithm. If PHPT is confirmed in fertile women before pregnancy, parathyroidectomy should be strongly suggested and performed. If PHPT is diagnosed during pregnancy, even in its mild form, surgical treatment, optimally during the 2nd trimester, is effective and safe for pregnancy and neonatal outcome.

Lgr4 promotes aerobic glycolysis and differentiation in osteoblasts via the canonical Wnt/ß-catenin pathway.

Lgr4, a G-protein-coupled receptor, is associated with various physiological and pathological processes including oncogenesis, energy metabolism, and bone remodeling. However, whether Lgr4 is involved in osteoblasts' metabolism is not clear. Here we uncover that in preosteoblast cell line, lacking Lgr4 results in decreased osteogenic function along with reduced glucose consumption, glucose uptake, and lactate production in the presence of abundant oxygen, which is referred to as aerobic glycolysis. Activating canonical Wnt/ß-catenin signaling rescued the glycolytic dysfunction. Lgr4 promotes the expression of pyruvate dehydrogenase kinase 1 (pdk1) and is abolished by interfering canonical Wnt/ß-catenin signaling. Mice lacking Lgr4 specifically in osteoblasts (Lgr4osb-/- ) exhibit decreased bone mass and strength due to reduced bone formation. Additionally, glycolysis of osteoblasts is impaired in Lgr4osb-/- mice. Our study reveals a novel function of Lgr4 in regulating the cellular metabolism of osteoblasts. © 2021 American Society for Bone and Mineral Research (ASBMR).

BMP9 Reduces Bone Loss in Ovariectomized Mice by Dual Regulation of Bone Remodeling.

Bone remodeling is dynamic and is tightly regulated through bone resorption dominated by osteoclasts and bone formation dominated by osteoblasts. Imbalances in this process can cause various pathological conditions, such as osteoporosis. Bone morphogenetic protein 9 (BMP9), a biomolecule produced and secreted by the liver, has many pharmacological effects, including anti-liver fibrosis, antitumor, anti-heart failure, and antidiabetic activities. However, the effects of BMP9 on the regulation of osteoblast and osteoclast functions and the underlying molecular mechanism(s) have not yet been investigated. In this study, BMP9 increased the expression of osteoblastogenic gene markers, such as ALP, Cola1, OCN, RUNX2, and OSX, and ALP activity in MC3T3-E1 cells by upregulating LGR6 and activating the Wnt/ß-catenin pathway. BMP9 also suppressed receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast differentiation of bone marrow macrophages (BMMs) by inhibiting the Akt-NF-κB-NFATc1 pathway. More importantly, in an ovariectomy (OVX) mouse model, BMP9 attenuated bone loss and improved bone biomechanical properties in vivo by increasing bone-forming activity and suppressing bone resorption activity. Accordingly, our current work highlights the dual regulatory effects that BMP9 exerts on bone remodeling by promoting bone anabolic activity and inhibiting osteoclast differentiation in OVX mice. © 2020 American Society for Bone and Mineral Research.

PITUITARY STALK THICKENING IN A LARGE COHORT: TOWARD MORE ACCURATE PREDICTORS OF PITUITARY DYSFUNCTION AND ETIOLOGY.

Objective: To summarize the characteristics of patients with pituitary stalk thickening, analyze the association between pituitary stalk width and hypopituitarism, and develop a diagnostic model to differentiate neoplastic and inflammatory origins. Methods: A total of 325 patients with pituitary stalk thickening in a tertiary teaching hospital between January 2012 and February 2018 were enrolled. Basic characteristics and hormonal status were evaluated. Indicators to predict etiology in patients with histologic diagnoses were analyzed. Results: Of the 325 patients, 62.5% were female. Deficiency in gonadotropin was most common, followed by corticotropin, growth hormone, and thyrotropin. The increase in pituitary stalk width was associated with a risk of central diabetes insipidus (odds ratio [OR], 3.57; P<.001) and with a combination of central diabetes insipidus and anterior pituitary deficiency (OR, 2.28; P = .029). The cut-off pituitary stalk width of 4.75 mm had a sensitivity of 69.2% and a specificity of 71.4% for the presence of central diabetes insipidus together with anterior pituitary deficiency. Six indicators (central diabetes insipidus, pattern of pituitary stalk thickening, pituitary stalk width, neutrophilic granulocyte percentage, serum sodium level, and gender) were used to develop a model having an accuracy of 95.7% to differentiate neoplastic from inflammatory causes. Conclusion: Pituitary stalk width could indicate the presence of anterior pituitary dysfunction, especially in central diabetes insipidus patients. With the use of a diagnostic model, the neoplastic and inflammatory causes of pituitary stalk thickening could be preliminarily differentiated. Abbreviations: APD = anterior pituitary dysfunction; AUC = area under the curve; CDI = central diabetes insipidus; GH = growth hormone; MRI = magnetic resonance imaging; OR = odd ratio; PHBS = posterior hypophyseal bright spots; PST = pituitary stalk thickening; PSW = pituitary stalk width.

The browning of white adipose tissue and body weight loss in primary hyperparathyroidism.

BACKGROUND: Parathyroid hormone related protein (PTHrP) triggers white adipose tissue (WAT) browning and cachexia in lung cancer mouse models. It remains unknown whether excessive PTH secretion affects WAT browning and to what extent it contributes to body weight change in primary hyperparathyroidism (PHPT). METHODS: Using the adeno-associated virus injection, Pth gene over-expressed mice mimicking PHPT were firstly established to observe their WAT browning and body weight alteration. The association between PTH and body weight was investigated in 496 PHPT patients. The adipose browning activities of 20 PHPT and 60 control subjects were measured with PET/CT scanning. FINDINGS: Elevated plasma PTH triggered adipose tissue browning, leading to increased energy expenditure, reduced fat content, and finally decreased body weight in PHPT mice. Higher circulating PTH levels were associated with lower body weight (ß = -0.048, P = .0003) independent of renal function, serum calcium, phosphorus,and albumin levels in PHPT patients. PHPT patients exhibited both higher prevalence of detectable brown/beige adipose tissue (20% vs 3.3%, P = .03) and increased browning activities (SUV in cervical adipose was 0.77 vs 0.49,P = .02) compared with control subjects. INTERPRETATION: Elevated serum PTH drove WAT browning program, which contributed in part to body weight loss in both PHPT mice and patients. These results give insights into the novel pathological effect of PTH and are of importance in understanding the metabolic changes of PHPT. FUND: This research is supported by the National Key Research and Development Program of China and National Natural Science Foundation of China.

The relationship among serum lipocalin 2, bone turnover markers, and bone mineral density in outpatient women.

PURPOSE: We aimed to investigate associations among serum levels of LCN2, bone resorption marker carboxy-terminal cross-linking telopeptide of type-1 collagen (CTx), bone formation marker osteocalcin (OCN), and bone mineral densities (BMDs) in ambulatory healthy women. METHODS: This cross-sectional study analyzed 1012 previously enrolled outpatient Han Chinese women. BMDs of the lumbar spine and femoral neck were measured using dual energy X-ray absorptiometry. Serum levels of LCN2, CTx, OCN, and creatinine (Scr) were measured. RESULTS: Circulating LCN2 was inversely correlated with BMDs at the lumbar spine and femoral neck (Spearman's r = -0.08, P = 0.010 and r = -0.14, P < 0.001; respectively). A significant positive correlation between LCN2 and CTx (r = 0.11, P < 0.001), OCN (r = 0.06, P = 0.047), age (r = 0.21, P < 0.001), and Scr (r = 0.24, P < 0.001) was also observed. After adjusting for age and Scr, the correlation among LCN2, BMDs and OCN disappeared, but LCN2 was still positively associated with CTx (r = 0.08, P = 0.010). The circulating concentration of LCN2 showed no significant difference between subjects with and without osteoporotic fractures (43.63 (35.29, 53.66) vs. 42.25 (34.43, 51.46) ng/ml, respectively, P = 0.111). Serum CTx concentrations rose with serum LCN2 increasing from the lowest to the highest quartile (P for trend = 0.005), even after adjusting for age and Scr (P for trend = 0.040). In multivariate regression analysis, LCN2 was one of the main determinants for changes in serum CTx (standard ß = 0.061, P = 0.005). CONCLUSIONS: In ambulatory healthy women, the relationships among serum LCN2 level, BMDs, and OCN were confounded by age and Scr. Although LCN2 was positively related with CTx, the correlation was very weak and may not be physiologically relevant.

Rictor/mTORC2 loss in osteoblasts impairs bone mass and strength.

Mammalian target of rapamycin (mTOR) is a Ser/Thr kinase conserved through evolution that coordinates extra cellular signals associated with cell growth. Main functions of mTOR present in the form of two complexes, namely mTORC1 and mTORC2, which are distinct in their unique components, raptor and rictor. In the current study, using a Cre/loxp system, we found an anabolic effect of mTORC2 signaling on skeleton. Osteoblast differentiation was reduced, with down-regulation of mTORC2 signaling activity in primary cultures of osteoblasts that did not contain rictor. Mice with a specific deletion of rictor in mature osteoblasts showed a significant reduction in lean mass and bone mineral density by dual energy x-ray absorptiometry analysis. Micro-computed tomography, histomorphometric, and molecular biological analyses revealed a marked impairment of the cortical bone mass and microarchitecture, as well as minor changes in trabecular bone, of the Rictorob(-/-) mice. Cortical bone mass and thickness of the femoral mid-shaft were dramatically reduced, with unusual increases in porosity and marrow area in Rictorob(-/-) mice. Thinner trabeculae were found in the L4 vertebrae with relatively normal structural indices of trabecular numbers and separation. A lower rate of bone turnover was observed, as the consequence of the decreased individual osteoblast activity and bone resorption. Furthermore, these changes were associated with significantly decreased bone biomechanical properties. In conclusion, expression of rictor in osteoblasts is essential for the maintenance of normal bone remodeling and microarchitecture, especially for the maintenance of the cortical bone.

The bone-preserving effects of exendin-4 in ovariectomized rats.

Exendin-4 was found to be beneficial to the skeleton in diabetic rodents. In this study, we assessed the changes of bone mineral densities (BMDs) and quality in non-diabetic ovariectomized (OVX) rats after treatment with exendin-4. The regulatory role of exendin-4 on osteoblastogenesis and adipogenesis in rat bone marrow stromal cells (BMSCs) was also explored. Three months after sham surgery or OVX, 18 5-month-old female Wistar rats were divided into three groups and received the following treatment for 8 weeks: (1) Sham + vehicle; (2) OVX + vehicle; and (3) OVX + exendin-4 20 µg/kg/day. Micro-CT and three-point bending test were used to evaluate the BMDs, bone morphometric parameters, and biomechanical properties. Real-time PCR and Western blot were performed to measure gene and protein expression after exendin-4 treatment in adipogenesis and osteoblastogenesis of rat BMSCs. Exendin-4 could improve trabecular volume, thickness, and number, increase BMD, and reduce trabecular spacing in the lumbar spine and femur of OVX rats. Exendin-4 had little impact on the mechanical resistance of femurs to fracture. When rat BMSCs were treated with exendin-4, the mRNA expression levels of runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and collagen α1 (Coll-1) were increased, while those of peroxisome proliferators activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein (C/EBPα) decreased. Exendin-4 treatment also resulted in increased expression levels of p38, p42/44, and ß-catenin proteins. Exendin-4 was anabolic to bone in OVX rats possibly by facilitating osteoblastogenesis while repressing adipogenesis during BMSC lineage differentiation.

Positive association between serum levels of bone resorption marker CTX and HbA1c in women with normal glucose tolerance.

CONTEXT: The bone formation marker osteocalcin (OCN) has a beneficial effect on glucose metabolism. In mice, the OCN bioactivity is induced by bone resorption. But in humans, the role of bone resorption in modulating glucose homeostasis is not clear. OBJECTIVE: Our study aimed to examine the relationship between bone resorption and glucose homeostasis in humans. DESIGN AND SETTING: This was a cross-sectional study conducted in a university teaching hospital. SUBJECTS: A total of 195 women with normal glucose tolerance (NGT) were analyzed. MAIN OUTCOME MEASURES: Serum OCN, cross-linked C-telopeptide of type I collagen (CTX), fasting plasma glucose, and 2h post-challenge glucose levels during oral glucose tolerance test, fasting insulin, glycated hemoglobin A1c (HbA1c), hepatic and renal functions, electrolytes, and bone mineral densities (BMDs) at lumbar-spine and proximal femur, and anthropometric parameters were measured. RESULTS: CTX was positively associated with HbA1c after adjustments for multiple confounding factors (r = 0.269, P = .006). OCN (ß = 0.015, P = .000), lumbar-spine 2-4 (L2-4) BMD (ß = -0.128, P = .003) and HbA1c (ß = 0.051, P = .01) were the major determinants of the variations of CTX (adjusted R(2) for the model = 0.608, P = .01) based on multivariate regression analysis. Compared with those in the lowest HbA1c tertile, individuals in the highest tertile had significantly higher CTX concentrations (0.37 ± 0.15 ng/ml vs 0.26 ± 0.11 ng/ml, P = .000), even when multiple confounders were adjusted (P for trend = .015). CONCLUSIONS: Bone resorption marker serum CTX was independently associated HbA1c in NGT women. Whether the increased CTX level in NGT subjects is an early marker predicting the subtle impairment of glucose homeostasis and the risk of occurrence of diabetes requires additional study.

Copy number variation in CCND1 gene is implicated in the pathogenesis of sporadic parathyroid carcinoma.

BACKGROUND: The molecular bases for parathyroid carcinomas present in conjunction with sporadic primary hyperparathyroidism are not fully elucidated. Gene copy number variations (CNVs) play an important role in tumorigenesis. The aim of the current study was to explore whether the CNVs of specific tumor-associated genes are involved in parathyroid carcinogenesis. METHODS: A multiplex ligation-dependent probe amplification method was used to compare differences in copy number in 39 common tumor-associated genes among 7 patients with parathyroid carcinoma and 14 age- and sex-matched subjects with parathyroid adenoma. RESULTS: It was shown that amplification of CCND1, a gene encoding cyclin D1, was more prevalent in parathyroid carcinomas than in adenomas (71 vs. 21 %, p = 0.056). This result was confirmed quantitatively by real-time polymerase chain reaction. Expression of CCND1 mRNA level was significantly higher in carcinomas than in adenomas (p = 0.003). Western blot and immunohistochemical analysis also demonstrated higher expression of CCND1 in carcinoma specimens than in adenoma samples. CONCLUSIONS: It is thus inferred that gain in copy number of CCND1 is implicated in the molecular pathogenesis of parathyroid carcinoma.

An independent positive relationship between the serum total osteocalcin level and fat-free mass in healthy premenopausal women.

CONTEXT: It is widely reported that osteocalcin is negatively associated with fat mass. However, there are few reports describing its correlation with fat-free mass, particularly in women. OBJECTIVES: The objective of the current study was to investigate the possible relationship between osteocalcin and fat-free mass in healthy, nonobese women. DESIGN AND SETTING: This study was performed in a tertiary university teaching hospital. SUBJECTS: A total of 504 healthy women aged 20-75 years were enrolled. MAIN OUTCOME MEASURES: Body composition was measured using a bioelectronics impedance analyzer. The serum concentrations of total osteocalcin, estradiol, leptin, osteoprotegerin, the receptor activator of nuclear factor-κB ligand, IGF-I, fasting plasma glucose, and urinary N-terminal telopeptide of type I collagen were tested. The bone mineral densities (BMDs) at the lumbar spine and proximal femoral neck were measured by dual-energy X-ray absorptiometry. RESULTS: The serum total osteocalcin level had a significant positive association with fat-free mass (r = 0.168, P = .007) after adjusting for age, fat mass, menopausal status, estradiol, fasting glucose, leptin, osteoprotegerin, receptor activator of nuclear factor-κB ligand, IGF-I, N-terminal telopeptide of type I collagen, BMDs, and waist and hip circumference. Analysis in pre- and postmenopausal women demonstrated that this association was only present in premenopausal women (r = 0.190, P = .005). The multiple stepwise regression analysis revealed that hip circumference, femoral neck-BMD, fat mass, leptin, osteocalcin, and age are the contributors to the changes in fat-free mass in premenopausal women (adjusted R(2) = 0.521, P < .001). CONCLUSION: The serum level of total osteocalcin was positively associated with fat-free mass independent of age, fat mass, leptin, and other confounders in premenopausal women.

The changing clinical patterns of primary hyperparathyroidism in Chinese patients: data from 2000 to 2010 in a single clinical center.

CONTEXT: In Western countries, most patients with primary hyperparathyroidism (PHPT) are asymptomatic. The incidence of parathyroid cancer is as low as 1% but is trending upward. The clinical outlook for Chinese patients with PHPT is unclear. OBJECTIVE: Our objective was to describe the changing clinical patterns of benign and malignant PHPT in Chinese patients from 2000 to 2010. DESIGN AND SETTING: This was a cross-sectional study. SUBJECTS: A total of 249 patients with PHPT were studied. MAIN OUTCOME MEASURES: The clinical manifestations and biochemical abnormalities of PHPT were analyzed. RESULTS: Of our patients with PHPT, 61.4% were symptomatic, but asymptomatic PHPT has increased from <21% in 2000-2006 to 42.4% to 52.5% in 2007-2010. Of asymptomatic patients, 48.9% came to our center because of elevation of serum calcium levels, and another 46.9% came because of parathyroid nodule(s) incidentally discovered by thyroid ultrasonography, with a steady increase from 18.3% before 2007 to 35.7% in 2007-2008 and 61.5% in 2009-2010. Serum calcium and PTH concentrations greater than 2.77 mmol/L (area under the curve, 0.995; P < .001) and 316.3 pg/dL (area under the curve, 0.842; P < .001), respectively, are responsible for symptom development. The occurrence of parathyroid carcinoma was as high as 5.96%, but a trend downward from 10.53% to 4.44% was observed. CONCLUSIONS: The overall clinical and biochemical features of PHPT in Chinese patients are still classic, but the disease is now evolving into a more asymptomatic type. The incidental parathyroid lesion captured by routine neck ultrasonography was the leading cause for such a dramatic change. The high incidence of parathyroid carcinoma is now decreasing.

The influence of the genetic and non-genetic factors on bone mineral density and osteoporotic fractures in Chinese women.

To investigate the effects of genetic and non-genetic factors on bone mineral densities (BMDs) and osteoporotic fractures. This was a cross-sectional study to investigate the relationships between 18 SNPs and non-genetic factors with BMDs and osteoporotic fractures in 1012 Chinese Han women. Five SNPs in genes GPR177, CTNNB1, MEF2C, SOX6, and TNFRSF11B were associated with L1-4 or total hip BMDs. rs11898505 in SPTBN1 gene was associated with osteoporotic fractures. Subjects carrying the largest number of risk alleles (highest 10 %) not only had lower BMD values as compared to those carrying the least number of risk alleles (lowest 10 %), they also had a higher risk of fracture [P = 0.002, OR = 2.252, 95 %CI (1.136, 4.463)]. Results from multivariate stepwise regression analysis revealed that age [P < 0.001, OR = 1.038, 95 % CI (1.018, 1.058)], number of falls in a year [P < 0.001, OR = 2.347, 95 % CI (1.459, 3.774)], the G risk allele in rs11898505 [P = 0.023, OR = 1.559, 95 % CI (1.062, 2.290)], and the L1-4 BMD [P = 0.017, OR = 0.286, 95 % CI (0.102, 0.798)] were associated with the occurrence of osteoporotic fractures. Genetic (rs11898505) and non-genetic factors (age, number of falls in a year and L1-4 BMD) could work in concert to contribute to the risk of osteoporotic fractures.

A lower value for quantitative ultrasound at radius is an additional indicator of metabolic syndrome and cardiovascular disease risk.

BACKGROUND: The relationships between quantitative ultrasound (QUS) values, metabolic syndrome (MetS) and cardiovascular disease (CVD) risk are unclear. Objective The objective was to determine the relationships between QUS and MetS as well as CVD risk. DESIGN: This was a cross-sectional study conducted in Shanghai, China. PATIENTS: One-thousand four hundred and thirty-nine Chinese women and men with or without MetS were studied. MEASUREMENTS: Speed of sound (SOS) at radius, phalanx and tibia and their relationships with MetS and Framingham's 10-year cardiovascular disease risk scores were investigated. RESULTS: Premenopausal women with MetS had significant lower SOS at radius than those without MetS after adjusting for age, BMI and fat mass percentage (P = 0·02). The radius SOS was negatively associated with waist circumference (r = -0·109, P = 0·025), waist-to-hip ratio (r = -0·124, P = 0·01) and 2 h postprandial glucose level (r = -0·125, P = 0·012) in premenopausal women. Waist circumference, waist-to-hip ratio and 2 h postprandial glucose level increased with the decreasing tertiles of radius SOS after adjustment of age (P = 0·003, 0·002 and 0·008, respectively). The CVD risk increased with decreasing tertiles of radius SOS in postmenopausal women even after the adjustment of age, years since menopause, MetS components, smoking and alcohol habits (P < 0·001), but not in premenopausal women and men. CONCLUSIONS: Lower radius SOS is associated with greater risks of MetS and CVD in premenopausal and postmenopausal women, respectively. The QUS value derived from non-weight-bearing site, such as radius, may represent an additional indicator of MetS and CVD risk in women.

The effects of bisphenol A (BPA) exposure on fat mass and serum leptin concentrations have no impact on bone mineral densities in non-obese premenopausal women.

OBJECTIVES: Bisphenol A (BPA) exposure may promote obesity, but its effect on bone mineral density (BMD) has not been reported in humans. We aimed to examine the relationships between BPA exposure, body composition, serum estradiol, leptin, osteocalcin levels and BMDs in healthy premenopausal women. DESIGN AND METHODS: In this cross-sectional study, a total of 246 healthy premenopausal women aged 20 years and older with regular menstrual cycles were investigated. Body mass index (BMI), fat mass, fat-free mass and BMDs were measured by DXA. Serum estradiol, leptin, osteocalcin, urinary BPA and NTx levels were also tested. RESULTS: Urinary BPA levels were positively associated with fat mass (r=0.193, p=0.006) and leptin (r=0.236, p=0.001) but not with fat-free mass after adjusting for age and BMI. BPA was not associated with serum estradiol levels, BMDs, or bone resorption marker NTx and bone formation parameter osteocalcin, either. A multivariate stepwise regression analysis confirmed that serum leptin levels were positively influenced by fat mass (ß=0.746, p<0.001) and BPA (ß=0.127, p=0.01) but negatively correlated with fat-free mass (ß=-0.196, p<0.001). However, the changes of BMDs at the lumbar spine (ß=0.298, p<0.001) and femoral neck (ß=0.305, p<0.001) were primarily explained by fat-free mass, and were irrelevant of the fat mass, leptin or BPA exposure. CONCLUSIONS: Although BPA exposure is related with increased amount of fat mass and elevated serum leptin levels, it has neutral effect on BMDs in premenopausal women, possibly due to the exclusive role of fat-free mass, which is unrelated to BPA in determining BMDs.

A population-based study examining calcaneus quantitative ultrasound and its optimal cut-points to discriminate osteoporotic fractures among 9352 Chinese women and men.

CONTEXT: No generally accepted thresholds for quantitative ultrasound (QUS) parameters to screen individuals at high risk of osteoporotic fractures have been defined. OBJECTIVE: We sought to define appropriate cutoff points for osteoporotic fractures of calcaneus ultrasound according to participants' prevalent osteoporotic fractures. DESIGN AND SETTING: This was a cross-sectional, population-based study conducted in Shanghai, China. PARTICIPANTS: A total of 9352 Chinese women and men aged 40 and older were studied. MAIN OUTCOME MEASURES: We measured calcaneus QUS (Achilles Express, GE Lunar) values and their relationships with osteoporotic fractures. RESULTS: A prevalence of 14.9 and 12.2% of osteoporotic fractures was found in the women and men (P<0.001), respectively. Subjects with osteoporotic fractures had significantly lower QUS values than those without (P<0.001). One sd decline in the stiffness index (SI)-derived T-score was associated with a high risk of nonvertebral fracture [odds ratio (OR)=1.50; 95% confidence interval (CI), 1.39-1.62; P<0.001], clinical vertebral fracture (OR=1.49; 95% CI, 1.18-1.90; P<0.01), and multi-fractures (OR=1.98; 95% CI, 1.63-2.40; P<0.001). The receiver operating characteristic analysis showed that QUS could differentiate osteoporotic fractures in postmenopausal women and men, but not in premenopausal women. The optimal cutoff points for the SI-derived T-score to detect a high risk of nonvertebral fractures, clinical vertebral fractures, and multi-fractures were -1.25, -1.55, and -1.80 in postmenopausal women, respectively, and -1.30, -1.90, and -2.00 in males, respectively. CONCLUSIONS: As a screening tool, the SI-derived T-score obtained from the Achilles QUS device for a postmenopausal woman or man that is less than -1.25 and -1.30, respectively, may indicate an increased risk of osteoporotic fractures and should be further evaluated by central DXA.

Interactions of osteoporosis candidate genes for age at menarche, age at natural menopause, and maximal height in Han Chinese women.

OBJECTIVE: Age at menarche (AAM), age at natural menopause (ANM), and maximal height are closely related to bone mineral densities and osteoporosis. It is still unclear whether osteoporosis susceptibility genes are also associated with AAM, ANM, and maximal height in Chinese women. METHODS: In this relatively large cross-sectional sample of 722 Han Chinese postmenopausal women, 22 single nucleotide polymorphisms (SNPs) within 12 osteoporosis candidate genes that were identified from genome-wide association studies and replicated in our previous study were studied. The effects of a single gene on the AAM, ANM, and maximal height were investigated by linear regression analysis, whereas the gene-gene interactions were determined by a generalized multifactor dimensionality reduction method. RESULTS: It was revealed that the major histocompatibility complex (MHC) gene (rs3130340) was associated with ANM even after Bonferroni correction (P = 0.001). A significant gene-gene interaction for ANM involving rs3130340 in MHC, rs1038304 and rs4870044 in estrogen receptor-α gene (ESR1), and a significant three-SNP interaction model (SNP rs2273061 in jagged1, SNP rs6929137 in ESR1, and SNP rs2306033 in low-density lipoprotein receptor-related protein 4) for maximal height were identified. No single or combined effect of tested SNPs on AAM was discovered. CONCLUSIONS: Our study indicates that osteoporosis susceptibility SNPs, such as ESR1 (rs1038304, rs4870044, rs6929137), MHC (rs3130340), low-density lipoprotein receptor-related protein 4 (rs2306033), and jagged1 (rs2273061), might independently and/or in an interactive manner influence ANM and maximal height. All the SNPs tested had no association with AAM.

Two unusual cases of intractable hyperthyroidism responsive to octreotide: Munchausen syndrome or not?

BACKGROUND: The effective treatment for patients with resistant hyperthyroidism is difficult. METHODS: In this case report with 4-year follow-up data, we present 2 unusual cases of hyperthyroidism that were unresponsive to almost all antithyroid treatments including total thyroidectomy, but both were controlled with octreotide. RESULTS: Cases 1 and 2 were both middle-aged women. They presented thyrotoxicosis with a low serum concentration of TSH and thyroidal radioactive iodine uptake (RAIU). The underlying causes, such as thyroiditis, metastatic thyroid cancer and struma ovarii were explored. Iodine-induced hyperthyroidism, particularly factitious hyperthyroidism was highly suspected, but there was no direct evidence to establish these diagnoses. In spite of good compliance, their thyrotoxicosis could not be controlled with large doses of PTU or MMI. ß-blocker, methylprednisolone, radio-iodine therapy and even thyroidectomy were all attempted and failed. Short-acting octreotide was first administered to case 1 and then to case 2. Thyroid function improved greatly within 3 days in both cases. The doses of octreotide were tapered down to twice a week with consistent efficacy. During the follow-up periods, case 1 required octreotide 0.1mg twice per week and case 2 is on thyroid replacement therapy due to hypothyroidism. The recurrences of hyperthyroidism in both cases were again rapidly controlled with the increased dose of octreotide in case 1 and re-started the usage of octreotide in case 2. CONCLUSIONS: The etiology of thyrotoxicosis in these 2 cases is not clear. In the absence of struma ovarii or wide-spread follicular thyroid cancer, factitious hyperthyroidism due to Munchausen syndrome should be considered first. The efficacy of the off-label use of octreotide in hyperthyroidism was highly effective (only) in these 2 cases.

Analysis of recently identified osteoporosis susceptibility genes in Han Chinese women.

BACKGROUND: In Europeans and populations of European origin, several osteoporosis susceptibility genes, including ZBTB40, RANK, RANKL, OPG, MHC, and ESR1, were recently identified. However, none of these has been fully investigated in Han Chinese populations. OBJECTIVE AND DESIGN: In this relatively large cross-sectional sample of 1012 Han Chinese women, 21 single-nucleotide polymorphisms (SNPs) within 11 candidate genes that were newly identified in Europeans were tested, and their associations with bone mineral densities (BMDs) and osteoporotic fracture were investigated. RESULTS: A total of 21 SNPs were genotyped. Five SNPs in four genes [ZBTB40 (rs7524102, rs6696981), ESR1 (rs9479055), OPG (rs6469804), and RANK (rs3018362)] were found to be associated with lumbar spine BMD. Seven SNPs in five genes [ZBTB40 (rs7524102, rs6696981), OPG (rs6993813, rs6469804), RANK (rs3018362), LRP5 (rs3736228), and SOST (rs1513670)] were found to be associated with total hip BMD. SPTBN1 (rs11898505) and SOST (rs1107748) were associated with osteoporotic fracture. A significant gene-gene interaction for osteoporotic fracture involving rs1107748 in SOST and rs6469804 in OPG gene was identified from generalized multifactor dimensionality reduction analysis. CONCLUSIONS: Our study provides an independent replication of the associations between several SNPs in ZBTB40, ESR1, OPG, RANK, LRP5, and SOST with lumbar spine and/or total hip BMDs in a large sample of Han Chinese women. The results of this study further support the significant associations found between osteoporotic fracture and SNPs in SPTBN1 and SOST. Our results suggest that these variants represent osteoporosis susceptibility genes in both Han Chinese and European populations.