Search

In the first case, a 60-year-old man who was using continuous subcutaneous insulin infusion (CSII), developed recurrent hypoglycemia due to insulin antibodies. This is the first report of such a case using CSII. In the second case, a 70-year-old man was follow-up case who developed hypoglycemia while using human insulin. In both cases, the hypoglycemia subsided after switching to multiple daily insulin injection and/or insulin preparation. The results of Scatchard analyses of the two cases were similar to those of cases of insulin autoimmune syndrome (IAS) that improved after recovery from hypoglycemia.The clinical characteristics and Scatchard analysis data were essentially the same as those for IAS, except for the presence of insulin administration.

Purpose Dehydroepiandrosterone sulfate (DHEAS) from the adrenal cortex substantially decreases with age, which may accelerate osteoporosis. However, the association of DHEAS with bone mineral density (BMD) and fracture is inconclusive. We conducted a Mendelian randomization (MR) analysis to investigate the role of DHEAS in age-related changes in BMD and fracture risk. Methods Single nucleotide polymorphisms (SNPs) associated with serum DHEAS concentrations were used as instrumental variables (4 SNPs for main analysis; 4 SNPs for men and 5 SNPs for women in sex-related analysis). Summary statistics were obtained from relevant genome-wide association studies. Results A log-transformed unit (µmol/L) increase in serum DHEAS concentrations was associated with an SD increase in estimated BMD at the heel (estimate, 0.120; 95% CI, 0.081-0.158; P = 9 × 10−10), and decreased fracture (odds ratio, 0.989; 95% CI, 0.981-0.996; P = 0.005), consistent with dual-energy X-ray absorptiometry–derived BMD at the femoral neck and lumbar spine. Their associations remained even after adjusting for height, body mass index, testosterone, estradiol, sex hormone-binding globulin, and insulin-like growth factor 1. The association of DHEAS with fracture remained after adjusting for falls, grip strength, and physical activity but was attenuated after adjusting for BMD. The MR-Bayesian model averaging analysis showed BMD was the top mediating factor for association of DHEAS with fracture. The association between DHEAS and BMD was observed in men but not in women. Conclusion DHEAS was associated with increased BMD and decreased fracture. DHEAS may play a protective role in decreasing fracture risk, mainly by increasing bone mass.

Context Primary aldosteronism (PA) is known to increase vertebral fracture (VF), although the detailed mechanism remains to be elucidated. We hypothesized that the PA subtype is associated with VF. Objective To evaluate whether unilateral PA is associated with the prevalence of VF. Design This was a retrospective cross-sectional study in a single referral centre. Patients We identified 210 hypertensive patients whose clinical data were available for case-detection results. One hundred and fifty-two patients were diagnosed with PA using captopril challenge tests. Measurements We measured the prevalence of VF, according to PA subtype. Results One hundred thirteen patients with PA were subtype classified by adrenal vein sampling. Of these, 37 patients had unilateral PA, 76 patients had bilateral PA, 58 patients had non-PA; 39 patients with PA were not subtype-classified. Patients with PA had a higher prevalence of VF (29%, 44/152) than those with non-PA (12%, 7/58; P = .011). Moreover, unilateral PA had a higher prevalence of VF (46%, 17/37) than bilateral PA (20%, 15/76; P = .021). There was no significant difference in the prevalence of VF between bilateral PA and non-PA. Unilateral PA was an independent risk factor for VF after adjusting for age and sex (OR: 3.16, 95% confidence interval: 1.12-8.92; P = .017). Among patients with unilateral PA, serum cortisol concentrations after 1-mg dexamethasone suppression test were higher in those with VF (1.32 ± 0.67 g/dL) than those without (0.96 ± 0.33 g/dL; P = .048). Conclusions Unilateral PA is an independent risk factor for VF.

Context Prolonged exposure to pathological cortisol, as in Cushing’s syndrome causes various age-related disorders, including sarcopenia. However, it is unclear whether mild cortisol excess, for example, accelerates sarcopenia due to aging or chronic stress. Objective We used Mendelian randomization (MR) analysis to assess whether cortisol was causally associated with muscle strength and mass. Methods Three single-nucleotide polymorphisms associated with plasma cortisol concentrations in the CORtisol NETwork consortium (n = 12 597) were used as instrumental variables. Summary statistics with traits of interest were obtained from relevant genome-wide association studies. For the primary analysis, we used the fixed-effects inverse-variance weighted analysis accounting for genetic correlations between variants. Results One SD increase in cortisol was associated with SD reduction in grip strength (estimate, −0.032; 95% CI −0.044 to −0.020; P = 3e-04), whole-body lean mass (estimate, −0.032; 95% CI, −0.046 to −0.017; P = 0.004), and appendicular lean mass (estimate, −0.031; 95% CI, −0.049 to −0.012; P = 0.001). The results were supported by the weighted-median analysis, with no evidence of pleiotropy in the MR-Egger analysis. The association of cortisol with grip strength and lean mass was observed in women but not in men. The association was attenuated after adjusting for fasting glucose in the multivariable MR analysis, which was the top mediator for the association in the MR Bayesian model averaging analysis. Conclusion This MR study provides evidence for the association of cortisol with reduced muscle strength and mass, suggesting the impact of cortisol on the development of sarcopenia.

Objective Glucose-lowering drug-induced hypoglycemia is a serious complication and there have been a few reports of seasonal variations in hypoglycemia in patients with type 2 diabetes. The aim of the present study was to examine the association between severe drug-induced hypoglycemia and seasonal variations, and to elucidate the contributing factors. Methods This retrospective, single center clinical study, analyzed the cases of 125 patients who required emergency hospitalization for severe drug-induced hypoglycemia between January 1, 2001 and December 31, 2014. The period from November to April was defined as the cold season. Results Severe hypoglycemia occurred more often in the cold season than in the warm season. In the cold season, 62 of 9,981 (0.6%) emergency department visits involved patients who required hospitalization for drug-induced hypoglycemia. In contrast, in the warm season, 27 of 8,649 (0.3%) visits involved patients who required hospitalization for drug-induced hypoglycemia (p=0.002). The proportion of patients treated with sulfonylurea (SU) in the cold season was higher than that in the warm season. Even the use of low-dose SU caused hypoglycemia in the cold season. In the SU-treated group, the proportion of patients with white blood cell and/or C-reactive protein elevation was higher in the cold season than in the warm season (p=0.04). Conclusion Severe glucose-lowering drug-induced hypoglycemia occured more frequently in the cold season than in the warm season, and was associated with an inflammatory state in patients treated with SU.

Primary aldosteronism (PA) is associated with an increased risk of cardiometabolic diseases, especially in unilateral subtype. Despite its high prevalence, the case detection rate of PA is limited, partly because of no clinical models available in general practice to identify patients highly suspicious of unilateral subtype of PA, who should be referred to specialized centers. The aim of this retrospective cross-sectional study was to develop a predictive model for subtype diagnosis of PA based on machine learning methods using clinical data available in general practice. Overall, 91 patients with unilateral and 138 patients with bilateral PA were randomly assigned to the training and test cohorts. Four supervised machine learning classifiers; logistic regression, support vector machines, random forests (RF), and gradient boosting decision trees, were used to develop predictive models from 21 clinical variables. The accuracy and the area under the receiver operating characteristic curve (AUC) for predicting of subtype diagnosis of PA in the test cohort were compared among the optimized classifiers. Of the four classifiers, the accuracy and AUC were highest in RF, with 95.7% and 0.990, respectively. Serum potassium, plasma aldosterone, and serum sodium levels were highlighted as important variables in this model. For feature-selected RF with the three variables, the accuracy and AUC were 89.1% and 0.950, respectively. With an independent external PA cohort, we confirmed a similar accuracy for feature-selected RF (accuracy: 85.1%). Machine learning models developed using blood test can help predict subtype diagnosis of PA in general practice.

Context Current clinical guidelines recommend confirmation of a positive result in at least one confirmatory test in the diagnosis of primary aldosteronism (PA). Clinical implication of multiple confirmatory tests has not been established, especially when patients show discordant results. Objective The aim of the present study was to explore the role of 2 confirmatory tests in subtype diagnosis of PA. Design and Setting A retrospective cross-sectional study was conducted at two referral centers. Participants and Methods We identified 360 hypertensive patients who underwent both a captopril challenge test (CCT) and a saline infusion test (SIT) and exhibited at least one positive result. Among them, we studied 193 patients with PA whose data were available for subtype diagnosis based on adrenal vein sampling (AVS). Main Outcome Measure The prevalence of bilateral subtype on AVS according to the results of the confirmatory tests was measured. Results Of patients studied, 127 were positive for both CCT and SIT (double-positive), whereas 66 were positive for either CCT or SIT (single-positive) (n = 34 and n = 32, respectively). Altogether, 135 were diagnosed with bilateral subtype on AVS. The single-positive patients had milder clinical features of PA than the double-positive patients. The prevalence of bilateral subtype on AVS was significantly higher in the single-positive patients than in the double-positive patients. (63/66 [95.5%] vs 72/127 [56.7%], P Conclusion Patients with discordant results between CCT and SIT have a high probability of bilateral subtype of PA on AVS.

CONTEXT The success rate of cannulation of the right adrenal vein is limited. The aldosterone gradient within the same adrenal vein branch is specific for aldosterone-producing adenoma. OBJECTIVE This study was performed to investigate whether the absolute aldosterone gradient within the left adrenal vein (left-AV absolute aldosterone gradient) indicates unilateral excess aldosterone. DESIGN AND SETTING A retrospective cross-sectional study in a single referral centre. PATIENTS AND METHODS In total, 123 consecutive patients with primary aldosteronism who had successful adrenal vein sampling (AVS) data were examined. The left-AV absolute aldosterone gradient was considered significant when a gradient of >4:1 in the aldosterone-to-cortisol ratio between the common trunk vein and central vein was found. MAIN OUTCOME MEASURE The prevalence of the unilateral subtype in patients with a significant left-AV absolute aldosterone gradient. RESULTS The prevalence of the unilateral subtype was higher in patients with than without a significant left-AV absolute aldosterone gradient (88.2% [15/17] vs 21.7% [23/106], P

Context: Many endocrine diseases are known to cause secondary osteoporosis, which is potentially reversible by treatment of the underlying disease itself. Pheochromocytoma (PHEO) and paraganglioma (PGL) (PHEO and PGL: PPGLs) are the rare catecholamine-producing neuroendocrine tumors, which are associated with low bone mineral density (BMD). However, PPGLs have not been recognized as a cause of secondary osteoporosis. Indeed, even the prevalence of osteoporotic fracture in patients with PPGLs is currently unknown. Furthermore, whether surgical resection contributes to the improvement of BMD has never been addressed. Objective: This study was designed to evaluate 1) whether PPGLs increase the risk of vertebral fracture (VF), which is the most common type of osteoporotic fracture and 2) whether surgical resection of PPGLs contributes to the improvement of BMD. Design and Settings: A retrospective cross-sectional study in a single referral center. Participants: Among 443 patients with adrenal tumor (AT), we included 62 patients with histologically confirmed PPGLs and 61 patients with non-functional AT. Intervention: The prevalence of VF was examined in 49 out of 62 patients with PPGLs and 61 patients with non-functional AT. In 23 out of 62 patients with PPGLs, BMD was evaluated at baseline and after surgery. Results: PPGLs had a higher prevalence of VF (43% [21/49]) than non-functional AT (16% [10/61]; p = 0.002). PPGLs were an independent risk factor for VF after adjusting for age and sex (odds ratio, 4.47; 95% confidence interval, 1.76–11.3; p = 0.001). In PPGLs, BMD expressed as Z score at the lumbar spine was significantly improved at follow-up (before -0.5±1.0, after -0.2±0.9; p = 0.005). Conclusion: This study demonstrates that PPGLs are an independent risk factor for VF and that their surgical resection contributes to the improvement of BMD in the trabecular bone. These observations support the notion that PPGLs are an emerging cause of secondary osteoporosis.

Context: Primary aldosteronism (PA) is known to increase vertebral fracture (VF), although the detailed mechanism remains to be elucidated. PA consists of two subtypes: the unilateral and bilateral subtype. Patients with unilateral PA, who usually have a higher plasma aldosterone concentration than those with bilateral PA, exhibit a more severe clinical phenotype. We hypothesized that PA subtype affects the prevalence of VF. Objective: To evaluate whether unilateral PA is associated with the prevalence of VF. Design: Cross-sectional study in a single referral center. Patients: We identified 210 hypertensive patients whose clinical data were available for case-detection results. One hundred and fifty-two patients were diagnosed with PA using captopril challenge tests. Measurements: The prevalence of VF according to PA subtype. Results: We included 113 patients with PA who were subtype classified according to adrenal vein sampling, of whom 37 patients had unilateral PA and 76 patients had bilateral PA, whereas 58 patients had non-PA. We excluded 39 patients with PA who were not subtype classified. Patients with PA had a higher prevalence of VF (28% [32/113]) than those with non-PA (12% [7/58]; p = 0.020). Moreover, unilateral PA had a higher prevalence of VF (46% [17/37]) than bilateral PA (20% [15/76]; p = 0.021). There was no significant difference between bilateral PA and non-PA. Unilateral PA was an independent risk factor for VF after adjusting for age and sex (odds ratio, 3.16; 95% confidence interval, 1.12-8.92; p = 0.017). Among patients with unilateral PA, serum cortisol concentrations after 1 mg dexamethasone suppression test were higher in those with VF (1.32 ± 0.67 g/dl) than those without (0.96 ± 0.33 g/dl; p = 0.048). Conclusions: Unilateral PA is an independent risk factor for VF, which is associated with autonomous cortisol secretion. Thus, careful management is required to prevent the development of VF in patients with unilateral PA.

Context: Adrenal vein sampling (AVS) is the standard method for subtype diagnosis in primary aldosteronism (PA), while success rate of its procedures, especially in right adrenal vein (AV), has limited. However, unilateral subtype of PA can be completely cured by surgical treatment and hence diagnostic approach for PA should be established especially when patients with apparent adrenal disease on computed tomography (CT) lack complete AVS result. In recent years, segmental AVS demonstrates that apparent aldosterone gradient in each adrenal vein branch is specific finding in aldosterone producing adenoma. Since we have reported that plasma aldosterone concentrations different in the proximal and distal regions of the left AV in some of the patients with PA, we hypothesized that solo finding of adrenal aldosterone gradient in the left AV (left AV gradient) should be the clue for unilateral subtype of PA. Objective: The aim was to investigate whether left AV gradient indicate the left unilateral subtype of PA. Design and Setting This study was a part of the Kyushu Adrenal Network Database for Advanced medicine (Q-AND-A) study, a cross-sectional and retrospective study in a single referral center. Participants and AVS procedure: Of 194 PA patients who underwent AVS with cosyntropin stimulation between January 2007 and April 2019, 111 patients had available and successful AVS data. Blood samples in left adrenal veins were obtained from following two positions; the common trunk and the central adrenal vein. We calculated left AV gradient by the ratio of aldosterone-to-cortisol ratio on the higher position in left AV to that on the lower position. We determined the presence of left AV gradient if it was greater than four. Main outcome measures: Prevalence of unilateral subtype in patients with left AV gradient who had unilateral disease on CT. Results: Of 111 patients with complete AVS data, 43 who had left unilateral disease on CT were analyzed in present study. Twenty-nine patients were diagnosed as left unilateral subtype on AVS and 14 were bilateral subtype. Aldosterone gradient was observed only in patients with unilateral subtype (41% [12/29]), not in patients with bilateral subtype (0% [0/14]). Of 29 patients with unilateral subtype on AVS, clinical parameters, including plasma aldosterone concentrations, plasma renin activity, and serum potassium levels, were not different in those with and without left AV gradient. The receiver operative curve analysis for the diagnosis of unilateral subtype on AVS showed that the optimal cutoff value of left AV gradient was 3.3 with a sensitivity of 45% and specificity of 100%. Conclusion: The presence of left AV gradient is the reliable finding for the diagnosis of left unilateral subtype in patients with PA who have unilateral disease on CT. However, further study in a larger number of cases is required to validate this finding.

Osteoporosis and atherosclerosis frequently coexist in patients with pheochromocytoma. The presence of osteoporosis may predict that of atherosclerosis and vice versa in patients with PHEO. These findings have implications for the long-term management of the pheochromocytoma and its potential chronic complications. Pheochromocytoma (PHEO), a catecholamine-producing tumor, is often found incidentally, and it may be present for years before it is diagnosed. However, long-term exposure to catecholamines excess may induce chronic complications, such as osteoporosis and atherosclerosis. We aimed to evaluate concomitant osteoporosis and atherosclerosis in patients with PHEO. Fifty-one patients with PHEO and 51 patients with a non-functional adrenal tumor were compared radiographically for the prevalence of vertebral fracture (VF), a typical osteoporotic fracture, and abdominal aortic calcification (AAC). In patients with PHEO, the prevalence of AAC was higher in those with VF (58%) than in those without (6%, p

Objectives The aim of this study was to investigate the impact of adrenal venous sampling (AVS) lateralization cutoffs on surgical outcomes. Patients and Methods Cosyntropin-stimulated AVS was used to guide surgical management of 377 patients with primary aldosteronism (PA) who were evaluated 6 months after surgery. Main Outcome Measures The proportion of patients that achieved clinical benefit and complete biochemical success based on the AVS aldosterone lateralization index (LI) was determined. Results Clinical benefit was achieved in 29 of 47 patients with an LI between 2 and 4, in 66 of 101 with an LI between 4 and 10, and in 158 of 203 with an LI > 10 (P < 0.01 for trend). Complete biochemical success was achieved in 27 of 42 with an LI between 2 and 4, in 60 of 76 with an LI between 4 and 10, and in 127 of 155 with an LI > 10 (P = 0.024 for trend). After adjustment for confounders and using those patients with an LI between 2 and 4 as a reference, a clinical benefit was associated only with those with an LI > 10 (OR, 2.30; 95% CI, 1.03 to 5.16), whereas complete biochemical success was associated with those with an LI between 4 and 10 (OR, 2.83; 95% CI, 1.14 to 7.01) or LI > 10 (OR, 3.55; 95% CI, 1.47 to 8.55). Conclusions Difference of clinical outcome was relatively small when strict LI diagnostic threshold was used; biochemical cure was sufficiently achieved when an LI > 4 was used. Our study by standardized outcome measures validated that an LI > 4 may be appropriate for determining unilateral disease in PA., We investigated the impact of AVS lateralization cutoffs on surgical outcome by standardized measures and validated that an LI > 4 is appropriate to determine unilateral disease in PA.

Context: Primary aldosteronism (PA) is a common cause of secondary hypertension and is associated with an increased risk of cardiometabolic diseases, especially in unilateral subtype. Despite its high prevalence, the case detection rate of PA is limited, partly because of no clinical models available in general practice to identify patients highly suspicious of unilateral subtype of PA, who can be cured by unilateral adrenalectomy and should be referred to specialized centers. The use of machine learning has been introduced in some fields of clinical prediction. Combining machine learning with clinical data could lead to the development of new models for predicting unilateral subtype of PA. Objective: The aim of this study was to develop a predictive model of subtype diagnosis of PA based on machine learning methods using clinical data available in general practice. Design and setting: This was a retrospective cross-sectional study in referral centers. Patients: We retrospectively analyzed 91 patients with unilateral and 138 patients with bilateral subtype of PA diagnosed according to adrenal venous sampling findings, and stratified randomly split to the training (80%) and test cohorts (20%). Four supervised machine learning classifiers; logistic regression, support vector machines, random forests (RF), and gradient boosting decision trees, were used to develop prediction models from 21 clinical variables. Classifiers were trained using stratified 10 fold cross-validation of the training cohort and hyperparameters of each classifier were adjusted using grid search to optimize the accuracy in the training cohort. Main Outcome Measures: The accuracy and the area under the receiver operating characteristic curve (AUC) for subtype prediction in the test cohort were compared among the optimized classifiers. Results: Of the four classifiers, the accuracy and AUC were highest in RF, with 95.7% and 0.990, respectively. Serum potassium levels, plasma aldosterone concentrations, and serum sodium levels were highlighted as important variables in this model. For feature-selected RF with the three variables, the accuracy and AUC were 89.1% and 0.950, respectively. With an independent external PA cohort, we confirmed a similar accuracy for feature-selected RF. Conclusions: Machine learning models developed using blood test can help predict subtype diagnosis of PA in general practice.

Advanced glycation end products (AGEs) cause bone fragility due to deterioration in bone quality. We previously reported that AGE3 induced apoptosis and inhibited differentiation via increased transforming growth factor (TGF)-β signaling in osteoblastic cells. Additionally, we demonstrated that AGE3 increased apoptosis and sclerostin expression and decreased receptor activator of nuclear factor-κB ligand (RANKL) expression in osteocyte-like cells. However, it remains unclear whether TGF-β signaling is involved in the effects of AGEs on apoptosis and the expression of sclerostin and RANKL in osteocytes. Effects of AGE3 on apoptosis of mouse osteocyte-like MLO-Y4-A2 cells were examined by DNA fragmentation ELISA. Expression of TGF-β, sclerostin, and RANKL was evaluated using real-time PCR, Western blotting, and ELISA kits. To block TGF-β signaling, we used SD208, a TGF-β type I receptor kinase inhibitor. AGE3 (200 µg/mL) significantly increased apoptosis and mRNA expression of Sost, the gene encoding sclerostin, and decreased Rankl mRNA expression in MLO-Y4-A2 cells. AGE3 significantly increased the expression of TGF-β. Co-incubation of SD208 with AGE3 significantly rescued AGE3-induced apoptosis in a dose-dependent manner. Moreover, SD208 restored AGE3-increased mRNA and protein expression of sclerostin. In contrast, SD208 did not affect AGE3-decreased mRNA and protein expression of RANKL. These findings suggest that AGE3 increases apoptosis and sclerostin expression through increasing TGF-β expression in osteocytes, and that AGE3 decreases RANKL expression independent of TGF-β signaling.

Context The current clinical guidelines suggest that confirmatory tests for primary aldosteronism (PA) may be excluded in some of patients who have elevated plasma aldosterone concentration (PAC) under plasma renin suppression. However, this has low-priority evidence and is under debate in use of serum potassium. Objective This study aimed to investigate an appropriate setting for sparing confirmatory tests in PA. Design and Setting A retrospective cross-sectional study in a single referral center. Participants This study included 327 patients who had hypertension under plasma renin suppression and underwent the captopril challenge test (CCT) between January 2007 and April 2019. CCT results were used to diagnose PA. Main Outcome Measure Diagnostic value of PAC and serum potassium in confirmation of PA. Results Of the studied patients, 252 of 327 (77%) were diagnosed with PA. All 61 patients with PAC > 30 ng/dL were diagnosed with PA. In patients with PAC between 20 and 30 ng/dL, 44 of 55 (80%) were diagnosed with PA, while all 26 with PAC between 20 to 30 ng/dL who had spontaneous hypokalemia were diagnosed with PA. The proportion of unilateral PA determined by adrenal vein sampling (AVS) was higher in patients who had PAC > 30 ng/dL or those with spontaneous hypokalemia who had PAC between 20 and 30 ng/dL than those who did not meet the criteria (76% vs. 17%, P < .001). Conclusion Confirmatory tests in PA could be spared in patients who have typical features of PA and these patients had a high probability of unilateral PA on AVS.

Pathological excess of fibroblast growth factor 23 (FGF23) causes mineral and bone disorders. However, the causality of FGF23 in the development of osteoporosis remains unknown. Whether FGF23 has systemic effects on cardio-metabolic disorders beyond regulating mineral metabolism is also controversial. In this study, we evaluated the causal effect of FGF23 on osteoporosis and cardiometabolic disorders using Mendelian randomization (MR) analysis. Summary statistics for single-nucleotide polymorphisms with traits of interest were obtained from the relevant genome-wide association studies. As a result, FGF23 was found to be inversely associated with femoral neck-BMD (odds ratio [OR] 0.682, 95% confidence interval [CI] 0.546–0.853, p = 8e-04) and heel estimated BMD (eBMD) (OR 0.898, 95%CI 0.820–0.985, p = 0.022) in the inverse-variance-weighted analysis, but not lumbar spine-BMD and fractures. The results were supported by the weighted-median analysis, and there was no evidence of pleiotropy in the MR-Egger analysis. FGF23 was directly associated with FN-BMD and eBMD after adjustment for estimated glomerular filtration rate, height, and body mass index in multivariable MR analysis. On the other hand, there was no association between FGF23 and cardiometabolic traits including cardio artery disease, brachial-ankle pulse wave velocity, intima-media thickness of carotid arteries, systolic and diastolic blood pressure, fasting glucose, high and low-density lipoprotein cholesterol, and triglycerides. Therefore, FGF23 has been causally associated with bone loss. In contrast, FGF23 has not been causally associated with cardiometabolic disorders. The data of this study provides important insights into the role of FGF23 in the pathogenesis of osteoporosis and cardiometabolic disorders.

Pathological excess of fibroblast growth factor 23 (FGF23) causes mineral and bone disorders. However, the causality of FGF23 in the development of osteoporosis remains unknown. Whether FGF23 has systemic effects on cardiometabolic disorders beyond regulating mineral metabolism is also controversial. In this study, we investigated the causal effect of FGF23 on osteoporosis and cardiometabolic disorders using Mendelian randomization (MR) analysis. Summary statistics for single-nucleotide polymorphisms with traits of interest were obtained from the relevant genome-wide association studies. As a result, FGF23 was found to be inversely associated with femoral neck-BMD (odds ratio [OR] 0.682, 95% confidence interval [CI] 0.546–0.853, p = 8e-04) and heel estimated BMD (eBMD) (OR 0.898, 95%CI 0.820–0.985, p = 0.022) in the inverse-variance-weighted analysis, but not lumbar spine-BMD and fractures. The results were supported by the weighted-median analysis, and there was no evidence of pleiotropy in the MR-Egger analysis. FGF23 was associated with FN-BMD and eBMD after adjustment for estimated glomerular filtration rate, height, and body mass index in multivariable MR analysis. On the other hand, there was no association between FGF23 and cardiometabolic traits including cardio artery disease, brachial-ankle pulse wave velocity, intima-media thickness of carotid arteries, systolic and diastolic blood pressure, fasting glucose, high and low-density lipoprotein cholesterol, and triglycerides. Therefore, this MR study established that FGF23 was involved in bone loss and, in contrast, was not involved in cardiometabolic disorders. Our findings provide important insights into the role of FGF23 in the pathogenesis of osteoporosis and cardiometabolic disorders.

Context Pheochromocytoma (PHEO) and paraganglioma (PGL) (PHEO and PGL: PPGLs), catecholamine-producing tumors, represent an emerging cause of secondary osteoporosis. However, despite decreased bone mineral density (BMD), vertebral fracture (VF) is not associated with BMD in PPGLs. Objective To evaluate whether deteriorated bone quality is involved in the development of osteoporosis in PPGLs. Participants Trabecular bone score (TBS), used to assess trabecular bone quality, was examined in 56 patients with PPGLs and 52 with non-functional adrenal tumors (AT). Radiograph of the spine was carried out in 35 patients with PPGLs, and TBS was analyzed in 18 patients with PPGLs at follow-up. Main outcome measure TBS and BMD at the lumbar spine in patients with PPGLs with and without VF. Results PPGLs had a lower TBS (n = 56, 1.338 [1.294–1.420]) than non-functional AT (n = 52, 1.394 [1.342–1.444]; p = 0.033). Among those with PPGLs, patients with VF (n = 14, 1.314 [1.289–1.346]) had a lower TBS than those without VF (n = 21, 1.383 [1.324–1.426]; p = 0.046), despite no significant difference in BMD at the lumbar spine between the two groups (p = 0.501). An optimal cut-off level of TBS for diagnosing VF in PPGLs was 1.323, and its area under the curve was 0.702. The severity of catecholamine excess and maximal size of tumor were associated with decreased TBS in PPGLs patients (p = 0.016 and p = 0.020, respectively). Surgical resection of PPGLs improved TBS at follow-up, with 2.5% increase (p = 0.007). Conclusions This study provides evidence for the importance of deteriorated bone quality rather than decreased bone mass in the development of VF in PPGLs.

Background: AMP-activated protein kinase (AMPK) plays important roles in bone metabolism; however, little is known about its role in osteocytes. This study investigated the effects of AMPK activation on the expression of receptor activator of NF-κB ligand (RANKL) and sclerostin in osteocytes., Results: Real-time PCR showed that AMPK activation by 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) significantly decreased the expression of Rankl in a dose- and time-dependent manner and significantly increased the expression of Sost, the gene encoding sclerostin, in osteocytic MLO-Y4 cells. Western blotting confirmed that AICAR decreased RANKL protein levels and increased sclerostin levels. In addition, suppression of AMPKα1 by siRNA significantly increased the expression of Rankl on 4 days after the transfection of siRNA, while Sost expression was not changed. Simvastatin, an inhibitor of HMG-CoA reductase, significantly decreased Rankl expression and increased Sost expression in MLO-Y4 cells. Supplementation with mevalonate or geranylgeranyl pyrophosphate, which are downstream metabolites of HMG-CoA reductase, significantly reversed the effects of AICAR., Conclusion: These findings indicated that AMPK regulated RANKL and sclerostin expression through the mevalonate pathway in osteocytes.

Clinical studies have shown that hyperhomocysteinemia is associated with bone fragility. Homocysteine (Hcy) induces apoptosis of osteoblastic cell lineage by increasing oxidative stress, which may contribute to Hcy-induced bone fragility. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, ameliorate oxidative stress by regulating oxidant and anti-oxidant enzymes. However, the effects of statins on Hcy-induced apoptosis of osteocytes are unknown. This study was thus aimed to investigate whether or not statins prevent Hcy-induced apoptosis of osteocytic MLO-Y4 cells and regulate NADPH oxidase (Nox) expression. TUNEL staining showed that 5 mM Hcy induced apoptosis of MLO-Y4 cells, and that co-incubation of 10(-9) or 10(-8) M simvastatin significantly suppressed the apoptotic effect. Moreover, we confirmed the beneficial effect of simvastatin against Hcy's apoptotic effect by using a DNA fragment ELISA assay. However, TUNEL staining showed no significant effects of pravastatin, a hydrophilic statin, on the Hcy-induced apoptosis. Real-time PCR showed that Hcy increased the mRNA expressions of Nox1 and Nox2, whereas simvastatin inhibited the stimulation of Nox1 and Nox2 expressions by Hcy. In contrast, neither Hcy nor simvastatin had any effect on Nox4 expression. These findings indicate that simvastatin prevents the detrimental effects of Hcy on the apoptosis of osteocytes by regulating the expressions of Nox1 and Nox2, suggesting that statins may be beneficial for preventing Hcy-induced osteocyte apoptosis and the resulting bone fragility.

Context Pheochromocytoma (PHEO) and paraganglioma (PGL) (PHEO and PGL: PPGLs) are catecholamine-producing neuroendocrine tumors, which are known to be associated with low bone mineral density (BMD). However, it remains unknown whether PPGLs are associated with high prevalence of osteoporotic fracture and if so, whether their surgical resection improves BMD has been addressed. Objective To evaluate the risk of vertebral fracture (VF) in PPGLs and the improvement of BMD after surgery. Design and settings A retrospective cross-sectional study in a single referral center. Participants This study included the following patients: 1) 49 patients with PPGLs and 61 patients with non-functional AT who were examined radiograph of the spine, 2) 23 patients with PPGLs who were examined BMD at follow-up. Intervention 1) The prevalence of VF was evaluated between PPGLs and non-functional AT. 2) In PPGLs, BMD was evaluated at baseline and after surgery. Results PPGLs had a higher prevalence of VF (43% [21/49]) than non-functional AT (16% [10/61]; p = 0.002). PPGLs were associated with VF after adjusting for age and sex (odds ratio, 4.47; 95% confidence interval, 1.76–11.3; p = 0.001). In PPGLs, BMD at the lumber spine was improved (before: 0.855 ± 0.198 g/cm2, after: 0.888 ± 0.169 g/cm2, mean of the difference: 0.032 g/cm2, p = 0.026), with 3.8% increase. Conclusion This study demonstrates that PPGLs was associated with VF and that their surgical resection contributes to the improvement of BMD in the trabecular bone. These observations support the notion that PPGLs are an emerging cause of secondary osteoporosis.

Diabetes mellitus is associated with an increased risk of falls, which increases the incidence of osteoporotic fractures and accordingly decreases quality of life. However, the association between fall risk and diabetic complications is not completely understood. Therefore, the aim of this study was to examine the association between fall risk and osteoporotic fractures in patients with type 2 diabetes mellitus (T2DM). We enrolled 194 Japanese patients with T2DM and assessed their fall risk using a brief interview form that included five items covering physical and social aspects of functioning and environmental factors. We examined the associations between fall risk and the presence of diabetic complications, such as neuropathy, retinopathy, nephropathy, cardiovascular disease, cerebrovascular disease, peripheral artery disease (PAD), and osteoporotic fractures (including any fracture and vertebral fractures only). In the multivariate logistic regression analysis, a longer history of T2DM, the presence of neuropathy and PAD, and a history of any fractures were significantly and positively associated with the risk of falls. On the other hand, a lower body mass index, the presence of neuropathy, and the risk of falls were independently and positively associated with the risk of any fracture. When fractures were limited to vertebral fractures only, the association with the risk of falls remained significant. We found that the risk of falls and osteoporotic fractures were associated in patients with T2DM and that a brief screening test of the risk of falls was useful for assessing the risk of osteoporotic fractures.