Validation of the clinical consensus recommendations on the management of fracture risk in postmenopausal women with type 2 diabetes.

BACKGROUND AND AIMS: Bone fragility is recognized as a complication of type 2 diabetes (T2D). However, the fracture risk in T2D is underestimated using the classical assessment tools. An expert panel suggested the diagnostic approaches for the detection of T2D patients worthy of bone-active treatment. The aim of the study was to apply these algorithms to a cohort of T2D women to validate them in clinical practice. METHODS AND RESULTS: The presence of T2D-specific fracture risk factors (T2D ≥ 10 years, ≥1 T2D complications, insulin or thiazolidinedione use, poor glycaemic control) was assessed at baseline in 107 postmenopausal T2D women. In all patients at baseline and in 34 patients after a median follow-up of 60.2 months we retrospectively evaluated bone mineral density and clinical and morphometric vertebral fractures. No patient was treated with bone-active drug. Following the protocols, 34 (31.8%) and 73 (68.2%) patients would have been pharmacologically and conservatively treated, respectively. Among 49 patients without both clinical fractures and major T2D-related risk factors, who would have been, therefore, conservatively followed-up without vertebral fracture assessment, only one showed a prevalent vertebral fracture (sensitivity 90%, negative predictive value 98%). The two patients who experienced an incident fracture would have been pharmacologically treated at baseline. CONCLUSIONS: The clinical consensus recommendations showed a very good sensitivity in identifying T2D postmenopausal women at high fracture risk. Among those with treatment indication as many as 13% of patients experienced an incident fracture, and, conversely, among those without treatment indication no incident fractures were observed.

Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside.

Mild hypercortisolism is defined as biochemical evidence of abnormal cortisol secretion without the classical detectable manifestations of overt Cushing's syndrome and, above all, lacking catabolic characteristics such as central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Mild hypercortisolism is frequently discovered in patients with adrenal incidentalomas, with a prevalence ranging between 5 and 50%. This high variability is mainly due to the different criteria used for defining this condition. This subtle cortisol excess has also been described in patients with incidentally discovered pituitary tumors with an estimated prevalence of 5%. To date, the mechanisms responsible for the pathogenesis of mild hypercortisolism of pituitary origin are still not well clarified. At variance, recent advances have been made in understanding the genetic background of bilateral and unilateral adrenal adenomas causing mild hypercortisolism. Some recent data suggest that the clinical effects of glucocorticoid (GC) exposure on peripheral tissues are determined not only by the amount of the adrenal GC production but also by the peripheral GC metabolism and by the GC sensitivity. Indeed, in subjects with normal cortisol secretion, the combined estimate of cortisol secretion, cortisone-to-cortisol peripheral activation by the 11 beta-hydroxysteroid dehydrogenase enzyme and GC receptor sensitizing variants have been suggested to be associated with the presence of hypertension, diabetes and bone fragility, which are three well-known consequences of hypercortisolism. This review focuses on the pathophysiologic mechanism underlying both the different sources of mild hypercortisolism and their clinical consequences (bone fragility, arterial hypertension, subclinical atherosclerosis, cardiovascular remodeling, dyslipidemia, glucose metabolism impairment, visceral adiposity, infections, muscle damage, mood disorders and coagulation).

Management of bone fragility in type 2 diabetes: Perspective from an interdisciplinary expert panel.

AIM: Bone fragility is increasingly recognized as a relevant complication of type 2 diabetes (T2D) and diabetic patients with fragility fractures have higher mortality rates than non diabetic individuals or diabetic patients without fractures. However, current diagnostic approaches for fracture risk stratification, such as bone mineral density measurement or the use of risk assessment algorithms, largely underestimate fracture risk in T2D patients. A multidisciplinary expert panel was established in order to in order to formulate clinical consensus recommendations on bone health assessment and management of fracture risk in patients with T2D. DATA SYNTHESIS: The following key questions were addressed: a) which are the risk factors for bone fragility in T2D?, b) which diagnostic procedures can be currently used to stratify fracture risk in T2D patients?, c) which are the effects of antidiabetic treatments on bone?, and d) how to prevent and treat bone fragility in T2D patients? Based on the available data members of this panel suggest that the stratification of fracture risk in patients with diabetes should firstly rely on the presence of a previous fragility fracture and on the individual risk profile, with the inclusion of T2D-specific risk factors (namely T2D duration above 10 yrs, presence of chronic T2D complications, use of insulin or thiazolidinediones and persistent HbA1c levels above 8% for at least 1 year). Two independent diagnostic approaches were then suggested in the presence or the absence of a prevalent fragility fracture, respectively. CONCLUSIONS: Clinical trials in T2D patients at risk for fragility fractures are needed to determine the efficacy and safety of available antiresorptive and anabolic agents in this specific setting.

Phosphate Metabolism and Pathophysiology in Parathyroid Disorders and Endocrine Tumors.

The advent of new insights into phosphate metabolism must urge the endocrinologist to rethink the pathophysiology of widespread disorders, such as primary hyperparathyroidism, and also of rarer endocrine metabolic bone diseases, such as hypoparathyroidism and tumor-induced hypophosphatemia. These rare diseases of mineral metabolism have been and will be a precious source of new information about phosphate and other minerals in the coming years. The parathyroid glands, the kidneys, and the intestine are the main organs affecting phosphate levels in the blood and urine. Parathyroid disorders, renal tubule defects, or phosphatonin-producing tumors might be unveiled from alterations of such a simple and inexpensive mineral as serum phosphate. This review will present all these disorders from a 'phosphate perspective'.

Energy Metabolism and Ketogenic Diets: What about the Skeletal Health? A Narrative Review and a Prospective Vision for Planning Clinical Trials on this Issue.

The existence of a common mesenchymal cell progenitor shared by bone, skeletal muscle, and adipocytes cell progenitors, makes the role of the skeleton in energy metabolism no longer surprising. Thus, bone fragility could also be seen as a consequence of a "poor" quality in nutrition. Ketogenic diet was originally proven to be effective in epilepsy, and long-term follow-up studies on epileptic children undergoing a ketogenic diet reported an increased incidence of bone fractures and decreased bone mineral density. However, the causes of such negative impacts on bone health have to be better defined. In these subjects, the concomitant use of antiepileptic drugs and the reduced mobilization may partly explain the negative effects on bone health, but little is known about the effects of diet itself, and/or generic alterations in vitamin D and/or impaired growth factor production. Despite these remarks, clinical studies were adequately designed to investigate bone health are scarce and bone health related aspects are not included among the various metabolic pathologies positively influenced by ketogenic diets. Here, we provide not only a narrative review on this issue, but also practical advice to design and implement clinical studies on ketogenic nutritional regimens and bone health outcomes. Perspectives on ketogenic regimens, microbiota, microRNAs, and bone health are also included.

Management and Medical Therapy of Mild Hypercortisolism.

Mild hypercortisolism (mHC) is defined as an excessive cortisol secretion, without the classical manifestations of clinically overt Cushing's syndrome. This condition increases the risk of bone fragility, neuropsychological alterations, hypertension, diabetes, cardiovascular events and mortality. At variance with Cushing's syndrome, mHC is not rare, with it estimated to be present in up to 2% of individuals older than 60 years, with higher prevalence (up to 10%) in individuals with uncontrolled hypertension and/or diabetes or with unexplainable bone fragility. Measuring cortisol after a 1 mg overnight dexamethasone suppression test is the first-line test for searching for mHC, and the degree of cortisol suppression is associated with the presence of cortisol-related consequences and mortality. Among the additional tests used for diagnosing mHC in doubtful cases, the basal morning plasma adrenocorticotroph hormone, 24-h urinary free cortisol and/or late-night salivary cortisol could be measured, particularly in patients with possible cortisol-related complications, such as hypertension and diabetes. Surgery is considered as a possible therapeutic option in patients with munilateral adrenal incidentalomas and mHC since it improves diabetes and hypertension and reduces the fracture risk. In patients with mHC and bilateral adrenal adenomas, in whom surgery would lead to persistent hypocortisolism, and in patients refusing surgery or in whom surgery is not feasible, medical therapy is needed. Currently, promising though scarce data have been provided on the possible use of pituitary-directed agents, such as the multi-ligand somatostatin analog pasireotide or the dopamine agonist cabergoline for the-nowadays-rare patients with pituitary mHC. In the more frequently adrenal mHC, encouraging data are available for metyrapone, a steroidogenesis inhibitor acting mainly against the adrenal 11-ßhydroxylase, while data on osilodrostat and levoketoconazole, other new steroidogenesis inhibitors, are still needed in patients with mHC. Finally, on the basis of promising data with mifepristone, a non-selective glucocorticoid receptor antagonist, in patients with mild cortisol hypersecretion, a randomized placebo-controlled study is ongoing for assessing the efficacy and safety of relacorilant, a selective glucocorticoid receptor antagonist, for patients with mild adrenal hypercortisolism and diabetes mellitus/impaired glucose tolerance and/or uncontrolled systolic hypertension.

Management of Osteoporosis in Men: A Narrative Review.

Male osteoporosis is a still largely underdiagnosed pathological condition. As a consequence, bone fragility in men remains undertreated mainly due to the low screening frequency and to controversies in the bone mineral density (BMD) testing standards. Up to the 40% of overall osteoporotic fractures affect men, in spite of the fact that women have a significant higher prevalence of osteoporosis. In addition, in males, hip fractures are associated with increased morbidity and mortality as compared to women. Importantly, male fractures occur about 10 years later in life than women, and, therefore, due to the advanced age, men may have more comorbidities and, consequently, their mortality is about twice the rate in women. Gender differences, which begin during puberty, lead to wider bones in males as compared with females. In men, follicle-stimulating hormones, testosterone, estrogens, and sex hormone-binding levels, together with genetic factors, interact in determining the peak of bone mass, BMD maintenance, and lifetime decrease. As compared with women, men are more frequently affected by secondary osteoporosis. Therefore, in all osteoporotic men, a complete clinical history should be collected and a careful physical examination should be done, in order to find clues of a possible underlying diseases and, ultimately, to guide laboratory testing. Currently, the pharmacological therapy of male osteoporosis includes aminobisphosphonates, denosumab, and teriparatide. Hypogonadal patients may be treated with testosterone replacement therapy. Given that the fractures related to mortality are higher in men than in women, treating male subjects with osteoporosis is of the utmost importance in clinical practice, as it may impact on mortality even more than in women.

Calcium citrate: from biochemistry and physiology to clinical applications.

Adequate daily calcium intake should normally be achieved by dietary sources. Since low calcium diets are quite common in subjects that do not reach the recommended intake and particularly those at risk of fractures, calcium supplements may become necessary. Different forms of calcium salts are available, but products containing calcium citrate and calcium carbonate complexes are the most frequently used. Although only limited evidence on the efficacy and long-term safety of calcium citrate is available, these supplements may represent a valuable product for the management of different chronic pathological conditions. The aim of this review was to evaluate the current and potential clinical applications of calcium citrate. In particular, we focused on the use of calcium citrate supplementation in subjects with osteoporosis or in bariatric patients. Other pathological conditions that could benefit calcium citrate supplementation may include achloridria, chronic hypoparathyroidism and hypocitraturic subjects with moderate/high risk of nephrolithiasis. Indeed, citrate salts are widely used in the treatment of nephrolithiasis, since they have shown an inhibitory effect on kidney stone formation and recurrence.

Recommendations for evaluation and management of bone disease in HIV.

Thirty-four human immunodeficiency virus (HIV) specialists from 16 countries contributed to this project, whose primary aim was to provide guidance on the screening, diagnosis, and monitoring of bone disease in HIV-infected patients. Four clinically important questions in bone disease management were identified, and recommendations, based on literature review and expert opinion, were agreed upon. Risk of fragility fracture should be assessed primarily using the Fracture Risk Assessment Tool (FRAX), without dual-energy X-ray absorptiometry (DXA), in all HIV-infected men aged 40-49 years and HIV-infected premenopausal women aged ≥40 years. DXA should be performed in men aged ≥50 years, postmenopausal women, patients with a history of fragility fracture, patients receiving chronic glucocorticoid treatment, and patients at high risk of falls. In resource-limited settings, FRAX without bone mineral density can be substituted for DXA. Guidelines for antiretroviral therapy should be followed; adjustment should avoid tenofovir disoproxil fumarate or boosted protease inhibitors in at-risk patients. Dietary and lifestyle management strategies for high-risk patients should be employed and antiosteoporosis treatment initiated.

Calcaneal quantitative ultrasound (QUS) and dual X-ray absorptiometry (DXA) bone analysis in adult HIV-positive patients.

Human immunodeficiency virus (HIV)-infected patients have an increased risk of developing osteopenia or osteoporosis compared with healthy individuals. Our aim was to compare dual X-ray absorptiometry (DXA), the gold standard for measuring bone mineral density (BMD), with bone quantitative ultrasound (QUS), an alternative technique for predicting fractures and screening low BMD, at least in postmenopausal populations. We analyzed DXA and QUS parameters to investigate their accuracy in the diagnosis and prediction of bone alterations in a cohort of 224 HIV-1-positive patients. The speed of sound (SOS), broadband ultrasound attenuation (BUA) and stiffness index (SI) parameters showed a moderate correlation with DXA, especially with total-body BMD (r coefficient of 0.38, 0.4 and 0.42 respectively), particularly in the female subgroup. In addition, multivariate analysis of HIV-positive patients assessed for vertebral fractures indicated that QUS was more effective than DXA at predicting the risk of fracture. QUS can be used as an additional tool for analyzing bone density in HIV-positive patients and its case of use and low cost make it especially suitable for resource-limited settings where DXA is not employed.

Difficult Diagnosis and Management of Concealed Cushing.

BACKGROUND: Adrenocorticotropic Hormone (ACTH)-secreting tumors account for 5- 10% of Cushing syndrome cases and are often difficult to diagnose and treat. CASE REPORT: A 44-year-old man presented with arterial hypertension and weight gain. On the physical examination, he exhibited central obesity, abdominal striae rubrae, and facial plethora. Due to the clinical suspicion of Cushing syndrome, the Nugent test and Liddle-1 test were performed, which showed a lack of cortisol suppression. ACTH levels were also high (138 pg/mL), so pituitary MRI and dynamic tests were performed, including the Corticotropin-releasing Hormone (CRH) stimulation test and Liddle-2. MRI showed a 3 mm pituitary microadenoma, but hormonal testing suggested ectopic ACTH production. Chest CT detected a 10-mm nodule in the upper lobe of the right lung, suspicious for a carcinoid tumor. However, the nodule did not exhibit any enhancement on 68-Gallium-DOTATOC PET-CT, and further, 18-FDG PET-CT was inconclusive. In addition, the nodule was deemed non-biopsiable due to its location. Meanwhile, the patient developed osteoporosis, resulting in two vertebral fractures and one rib fracture, which was treated with zoledronate. Furthermore, the patient developed acute aortic insufficiency. During bioprosthetic valve replacement, the thoracic surgeon performed wedge resection of the right upper lung lobe. The histological examination of the lesion revealed a typical lung carcinoid (1.2x0.9 cm, pT1bNXR0, Ki671%, ACTH positive in 95% of neoplastic elements). ACTH levels dropped to 4 pg/mL on the fourth postoperative day. CONCLUSION: ACTH-secreting tumors are particularly challenging diseases. A comprehensive hormonal and instrumental valuation is often required, necessitating a multidisciplinary approach.

Italian Guidelines for the Management of Sporadic Primary Hyperparathyroidism.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of sporadic primary hyperparathyroidism (PHPT) in adults. PHPT management in pregnancy was not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) and Società Italiana dell'Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro (SIOMMMS) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for the clinical practice recommendations. RESULTS: The present GL provides recommendations about the roles of pharmacological and surgical treatment for the clinical management of sporadic PHPT. Parathyroidectomy is recommended in comparison to surveillance or pharmacologic treatment in any adult (outside of pregnancy) or elderly subject diagnosed with sporadic PHPT who is symptomatic or meets any of the following criteria: • Serum calcium levels >1 mg/dL above the upper limit of normal range. • Urinary calcium levels >4 mg/kg/day. • Osteoporosis disclosed by DXA examination and/or any fragility fracture. • Renal function impairment (eGFR <60 mL/min). • Clinic or silent nephrolithiasis. • Age ≤50 years. Monitoring and treatment of any comorbidity or complication of PHPT at bone, kidney, or cardiovascular level are suggested for patients who do not meet the criteria for surgery or are not operated on for any reason. Sixteen indications for good clinical practice are provided in addition to the recommendations. CONCLUSION: The present GL is directed to endocrinologists and surgeons - working in hospitals, territorial services or private practice - and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Cinacalcet in the management of primary hyperparathyroidism: post marketing experience of an Italian multicentre group.

OBJECTIVE: To report the Italian experience on cinacalcet use following its approval by the European Medical Agency (EMA) to control hypercalcaemia in patients with primary hyperparathyroidism (PHPT). DESIGN: Retrospective data collection from 100 patients with sporadic (sPHPT) and 35 with familial PHPT (fPHPT) followed in eight Italian centres between October 2008 and March 2011. MEASUREMENTS: Albumin-adjusted serum calcium, PTH, 25OHD, daily cinacalcet dose and adverse events were recorded during the follow-up (1-46 months). RESULTS: Baseline serum calcium was 2·90 ± 0·27 nmol/l in sPHPT and 2·75 ± 0·17 nmol/l in fPHPT patients (P = 0·007). The cinacalcet EMA labelling was met in 53% sPHPT and 26% fPHPT patients. High surgical risk (34%), negative preoperative imaging (19%), control of hypercalcaemia before parathyroidectomy (PTx) (24%), and refusal of PTx (19%) accounted for cinacalcet prescription in 96% of sPHPT patients. Conversely, initial treatment (34%), persistent/relapsing PHPT after surgery (31%), and refusal of PTx (14%) were the indications in 79% fPHPT patients. Cinacalcet was started at 30 mg/daily in 64% of sPHPT and 91% of fPHPT and increased until normocalcaemia was reached or side effects occurred. The final daily dose ranged between 15 and 120 mg. The majority of patients (65% of sPHPT and 80% of fPHPT) become normocalcaemic. Treatment was withdrawn in six patients because of side effects. CONCLUSIONS: There is a wide heterogeneity in the prescription of cinacalcet in PHPT patients in Italy and the EMA labelling is not always followed, particularly in fPHPT patients. Cinacalcet effectively reduces serum calcium in patients with either sPHPT or fPHPT.

Phalangeal quantitative ultrasound: cheaper methods for screening and follow-up of bone pathologies in HIV-infected women?

This study estimated the prevalence of bone pathologies in a cohort of HIV-infected women in comparison with a cohort of HIV-negative women. Bone mineral density was measured by phalangeal quantitative ultrasound (AD-SoS: amplitude- dependent speed of sound; UBPI: ultrasound bone profile index). Risk of fracture, expressed by UBPI, was considered for value <0.39. Comparisons between groups and multivariate analyses were carried out using an ANOVA model. Correlations were evaluated using the Pearson correlation coefficient. Osteopenia and osteoporosis were present in 34.4% and 2% of patients, respectively. UBPI was pathologic in 5.7%. In a multivariate linear regression model significant correlations were found between AD-SoS z-score, duration of HIV-infection and BMI value. We also compared our cohort with 499 HIV-negative women as a historical control group of healthy subjects. AdSoS (2100 versus 2070 m/s) and UBPI (0.89 versus 0.74) were lower in HIV-infected women (p<0.001). Significant differences were also found in T-score values (p = 0.0013). These data show a high prevalence of bone diseases in women with HIV infection, correlated with duration of HIV-infection and BMI values. This non-invasive technique opens up new interesting perspectives, suggesting a possible use for bone mass screening in HIV-infected women.

Calcium Citrate Versus Calcium Carbonate in the Management of Chronic Hypoparathyroidism: A Randomized, Double-Blind, Crossover Clinical Trial.

In hypoparathyroidism (HypoPT), calcium supplementation is virtually always required, although the disease is likely to be associated with an increased risk of nephrolithiasis. The use of calcium citrate (Ca-Cit) theoretically could have a positive impact on the nephrolithiasis risk because citrate salts are used to reduce this risk. Our objective was to evaluate the potential therapeutic advantage of Ca-Cit in comparison with calcium carbonate (CaCO3 ) in HypoPT, on nephrolithiasis risk factors, as well as to their ability to maintain desirable serum calcium levels. We also evaluated these preparations on quality of life (QOL). This randomized, double-blind, crossover trial recruited 24 adults with postsurgical chronic hypoparathyroidism at Campus Bio-Medico University of Rome. Participants were randomized 1:1 to Ca-Cit or CaCO3 for 1 month and then crossed over to the other treatment for another month. The primary outcomes were changes in albumin-adjusted serum calcium and in ion activity product of calcium oxalate levels (AP[CaOx] index). Secondary efficacy outcomes included changes in SF-36 survey score, fatigue score, constipation, and adverse events. No difference in terms of AP(CaOx) index was observed between the two groups. However, Ca-Cit was associated with a significant reduction in the oxalate/creatinine ratio compared with CaCO3 (-2.46 mmol/mol [SD 11.93] versus 7.42 mmol/mol [SD 17.63], p = 0.029). Serum calcium and phosphorus concentration was not different between the two calcium preparations. Ca-Cit was associated with less constipation (p = 0.047). No difference was found in QOL scores. Although Ca-Cit did not modify the AP(CaOx) index when compared with CaCO3, it was associated with a reduction in urinary oxalate excretion that could have a potential beneficial effect on nephrolithiasis risk. These results are likely to have clinical implications in HypoPT, particularly those who do not tolerate CaCO3 and those affected by nephrolithiasis. A longer-term experience is needed to confirm these findings. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Predicting five-year recurrence rates of kidney stones: an artificial neural network model.

OBJECTIVE: Due to high recurrence rates of urolithiasis, many attempts have been performed to identify tools for predicting the risk of stone formation. The application of Artificial Neural Networks (ANNs) seems to be a valid candidate for reaching this endpoint. The aim of this study was to find a set of parameters able to predict recurrence episodes immediately after clinical and metabolic evaluation performed at the first visit in a 5-year window. MATERIAL AND METHODS: Data were collected from 80 outpatients who presented idiopathic calcium stone disease both at baseline and after 5 years; patients underwent treatment including both general measures and medical therapy. After 5 years, patients were classified into two subsets, namely SSFs (without recurrence episodes), consisting of 45 subjects (56.25%) and RSFs, with at least one episode of recurrence after the baseline, consisting of 35 subjects (43.75%). Helped by conventional statistics (One-way ANOVA and three Discriminant Analyses: standard, backward stepwise and forward stepwise), an Artificial Neural Network (ANN) approach was used to predict recurrence episodes. RESULTS: An optimal set of 6 parameters was identified from amongst the different combinations in order to efficiently predict the outcome of stone recurrence in approximately 90% of cases. This set consist of serum Na and K as well as Na, P, Oxalate and AP (CaP) index from urine. The results obtained with ANN seem to suggest that some kind of relationship is present between the identified parameters and future stone recurrence. This relationship is probably very complex (in the mathematical sense) and non-linear In fact, a Logistic Regression was built as a comparative method and performed less good results at least in terms of accuracy and sensitivity. CONCLUSIONS: The application of ANN to the database led to a promising predicting algorithm and suggests that a strongly non-linear relationship seems to exist between the parameters and the recurrence episodes. In particular, the ANN approach identifies as optimal parameters serum concentration of Na and K as well as urinary excretion of Na, P, Oxalate and AP (CaP) index. This study suggest that ANNs could potentially be a useful approach because of their ability to work with complex dynamics such as recurrent stone formation seems to have.

A Retrospective Cohort Study of Histology-Proven Neuroendocrine Neoplasms in the Italian Area of Udine.

AIMS: The aim of this study was to investigate the epidemiology of histology-proven Neuroendocrine neoplasms (NENs) in an Italian area. BACKGROUND: NENs are a rare and poorly known disease and the global incidence and prevalence appear to be increasing over the past decades. OBJECTIVE: The objectives of this study were to estimate the incidence and trends of NENs in a 250,000-inhabitant area in the North-East of Italy in the 1998-2018 period and to compare them with international data. METHODS: This retrospective cohort study was based on the analysis of anonymous health administrative databases, linked with each other at individual patient level through an anonymous stochastic key. NENs were identified from the anatomical pathology database. The standardized incidence rate (2010ESP and US2000) ± 95% CI per 100,000 were calculated, both annually and globally, for the whole period. Incidence was also calculated for specific anatomical sites and by gender. Trends for the considered periods and sites were summarized through the annual percent change (APC) and average increase (cases per 100,000 per year). RESULTS: In the 1998-2018 period, the standardized incidence rate of NENs in the area of Udine was 2.49 (APC 3.33). A total of 162 cases were observed (51.2% males). Differences in incidence and trend were observed between sexes. The obtained results were consistent with those reported in other countries, confirming a significant and steady increase in NENs incidence in the last twenty years. CONCLUSION: This study provides new epidemiological data on NENs in Italy. The observed sex differences deserve further investigations.

The Impact of Antiosteoporotic Drugs on Glucose Metabolism and Fracture Risk in Diabetes: Good or Bad News?

Osteoporosis and diabetes mellitus represent global health problems due to their high, and increasing with aging, prevalence in the general population. Osteoporosis can be successfully treated with both antiresorptive and anabolic drugs. While these drugs are clearly effective in reducing the risk of fracture in patients with postmenopausal and male osteoporosis, it is still unclear whether they may have the same efficacy in patients with diabetic osteopathy. Furthermore, as bone-derived cytokines (osteokines) are able to influence glucose metabolism, it is conceivable that antiosteoporotic drugs may have an effect on glycemic control through their modulation of bone turnover that affects the osteokines' release. These aspects are addressed in this narrative review by means of an unrestricted computerized literature search in the PubMed database. Our findings indicate a balance between good and bad news. Active bone therapies and their modulation of bone turnover do not appear to play a clinically significant role in glucose metabolism in humans. Moreover, there are insufficient data to clarify whether there are any differences in the efficacy of antiosteoporotic drugs on fracture incidence between diabetic and nondiabetic patients with osteoporosis. Although more studies are required for stronger recommendations to be issued, bisphosphonates appear to be the first-line drug for treatment of osteoporosis in diabetic patients, while denosumab seems preferable for older patients, particularly for those with impaired renal function, and osteoanabolic agents should be reserved for patients with more severe forms of osteoporosis.

Selenium: A Trace Element for a Healthy Skeleton - A Narrative Review.

Inadequate serum selenium levels may delay the growth and physiological changes in bone metabolism. In humans, reduced serum selenium concentrations are associated with both increased bone turnover and reduced bone mineral density. Moreover, a reduced nutritional intake of selenium may lead to an increased risk of bone disease. Therefore, selenium is an essential nutrient playing a role in bone health, probably due to specific selenium-proteins. Some selenium-proteins have an antioxidation enzymatic activity and participate in maintaining the redox cellular balance, regulating inflammation and proliferation/differentiation of bone cells too. At least nine selenium-proteins are known to be expressed by fetal osteoblasts and appear to protect bone cells from oxidative stress at bone microenvironment. Mutations of selenium-proteins and reduced circulating levels of selenium are known to be associated with skeletal diseases such as the Kashin-Beck osteoarthropathy and postmenopausal osteoporosis. In addition, the intake of selenium appears to be inversely related to the risk of hip fragility fractures. Recent data suggest that an altered selenium state may affect bone mass even in males and selenium-proteins and selenium concentrations were positively associated with the bone mass at femoral, total and trochanteric sites. However, selenium, but not selenium-proteins, seems to be associated with femoral neck bone mass after adjustment for many bone fracture risk factors. The present review summarizes the findings of observational and interventional studies, which have been designed for investigating the relationship between selenium and bone metabolism.

Cardiovascular complications of mild autonomous cortisol secretion.

Adrenal incidentalomas (AI) may be associated with a mild autonomous cortisol secretion (MACS) in up to one third of cases. There is growing evidence that MACS patients actually present increased risk of cardiovascular disease and higher mortality rate, driven by increased prevalence of known cardiovascular risk factors, as well as accelerated cardiovascular remodelling. Adrenalectomy seems to have cardiometabolic beneficial effects in MACS patients but their management is still a debated topic due to the lack of high-quality studies. Several studies suggested that so called "non-functioning" AI may be actually "functioning" with an associated increased cardiovascular risk. Although the individual cortisol sensitivity and peripheral activation have been recently suggested to play a role in influencing the cardiovascular risk even in apparently eucortisolemic patients, to date the degree of cortisol secretion, as mirrored by the cortisol levels after dexamethasone suppression test remains the best predictor of an increased cardiovascular risk in AI patients. However, whether or not the currently used cut-off set at 50 nmol/L for cortisol levels after dexamethasone suppression could be considered completely reliable in ruling out hypercortisolism remains unclear.