European Expert Consensus on Practical Management of Specific Aspects of Parathyroid Disorders in Adults and in Pregnancy: Recommendations of the ESE Educational Program of Parathyroid Disorders.

This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders (PARAT) in 2019, were discussed during two virtual workshops in 2021, and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosing to familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represent areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT, need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborns children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed for a broader clinical audience, and were developed with focus on endocrinologists in training.

Impact of preoperative glycometabolic status on outcomes in cardiac surgery: Systematic review and meta-analysis.

BACKGROUND: Historically, impaired glucose metabolism has been associated with early and late complicated clinical outcomes after cardiac surgery; however, such a condition is not specific to subjects with diabetes mellitus and involves a larger patient population. METHODS: Databases were screened (January 2000 to December 2020) to identify eligible articles; studies that evaluated the association between preoperative metabolic status, as assessed by glycosylated hemoglobin levels and clinical outcomes, were considered. The studies were stratified in thresholds by baseline glycosylated hemoglobin level (lower vs higher). RESULTS: Thirty studies, involving 34,650 patients, were included in the review. In a meta-analysis stratified by glycosylated hemoglobin levels, early mortality was numerically reduced in each threshold comparison and yielded the highest reductions when less than 5.5% versus greater than 5.5% glycosylated hemoglobin levels were compared (risk ratio, 0.39; 95% confidence interval, 0.18-0.84; P = .02). Comparing higher glycosylated hemoglobin threshold values yielded comparable results. Late mortality was reduced with lower levels of glycosylated hemoglobin. Low preoperative glycosylated hemoglobin was associated with the lowest risk of sternal wound infections (risk ratio, 0.50; 95% confidence interval, 0.32-0.80; P = .003 and risk ratio, 0.53; 95% confidence interval, 0.39-0.70; P < .0001) for comparisons of less than 7.5% versus greater than 7.5% and less than 7.0% versus greater than 7.0% glycosylated hemoglobin thresholds, respectively. Additionally, levels of glycosylated hemoglobin lower than 7% were associated with reduced hospital stay, lower risk of stroke/transient ischemic attack (risk ratio 0.53; 95% confidence interval, 0.39-0.70; P < .0001), and acute kidney injury (risk ratio, 0.65; 95% confidence interval, 0.54-0.79; P < .0001). CONCLUSIONS: Lower levels of glycosylated hemoglobin in patients undergoing cardiac surgery are associated with a lower risk of early and late mortality, as well as in the incidence of postoperative acute kidney injury, neurologic complications, and wound infection, compared with higher levels.

Vitamin D: Dosing, levels, form, and route of administration: Does one approach fit all?

The 4th International Conference on Controversies in Vitamin D was held as a virtual meeting in September, 2020, gathering together leading international scientific and medical experts in vitamin D. Since vitamin D has a crucial role in skeletal and extra-skeletal systems, the aim of the Conference was to discuss improved management of vitamin D dosing, therapeutic levels and form or route of administration in the general population and in different clinical conditions. A tailored approach, based on the specific mechanisms underlying vitamin D deficiency in different diseases that were discussed, was recommended. Specifically, in comparison to healthy populations, higher levels of vitamin D and greater amounts of vitamin D were deemed necessary in osteoporosis, diabetes mellitus, obesity (particularly after bariatric surgery), and in those treated with glucocorticoids. Emerging and still open issues were related to target vitamin D levels and the role of vitamin D supplementation in COVID-19 since low vitamin D may predispose to SARS-CoV-2 infection and to worse COVID-19 outcomes. Finally, whereas oral daily cholecalciferol appears to be the preferred choice for vitamin D supplementation in the general population, and in most clinical conditions, active vitamin D analogs may be indicated in patients with hypoparathyroidism and severe kidney and liver insufficiency. Parenteral vitamin D administration could be helpful in malabsorption syndromes or in states of vitamin D resistance.Specific guidelines for desired levels of vitamin D should be tailored to the different conditions affecting vitamin D metabolism with the goal to define disease-specific normative values.

The Interaction of Lean Body Mass With Fat Body Mass Is Associated With Vertebral Fracture Prevalence in Women With Early Breast Cancer Undergoing Aromatase Inhibitor Therapy.

Aromatase inhibitors (AIs) induce depletion of estrogen levels, causing bone loss and increased fracture risk in women with breast cancer. High-fat body mass (FBM) emerged as an independent factor associated with the prevalence of morphometric vertebral fractures (VFs) in patients undergoing AIs. We explored the role of lean body mass (LBM) and the interaction of LBM with FBM in predicting the occurrence of VFs in postmenopausal women who were either AI-naïve or AI-treated. A total of 684 consecutive breast cancer patients were enrolled in this cross-sectional study. Each woman underwent a dual-energy X-ray absorptiometry (DXA) scan, measuring bone mineral density (BMD), LBM, and FBM; VFs were assessed using a quantitative morphometric analysis of DXA images. After propensity score matching, the study population was restricted to 480 women, 240 AI-naïve and 240 AI-treated. We used multivariable logistic regression models to explore the associations between baseline characteristics, VF prevalence and the interaction between LBM, FBM and AI therapy. No interaction between LBM and AI therapy on VF prevalence was shown. Conversely, we reported a significant interaction between LBM, FBM and AI therapy (p = .0311). Among AI-treated women having LBM below and FBM above or equal the median value, VF prevalence was numerically higher (15/31; 48.4%) than in other subgroups (VF prevalence: 35.7% in high-LBM and low-FBM group, 23.2% in high-LBM and high-FBM group, and 19.8% in low-LBM and low-FBM group). Among AI-naïve women, the greatest VF proportion was observed in the subgroup with LBM and FBM below median value (25/92; 27.2%). This study suggests a synergism between LBM and FBM in predicting the morphometric VF in women with early breast cancer undergoing AIs. This observation is new and deserves further investigation. The assessment of body composition by DXA might be useful when estimating fracture risk in this population. © 2020 American Society for Bone and Mineral Research © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Effects of Medical Treatment of Prostate Cancer on Bone Health.

Medical treatment of prostate cancer (PC) is multidisciplinary, resulting in prolonged survival. Androgen-deprivation therapy (ADT) can have negative effects on skeletal metabolism, particularly if combined with glucocorticoids. We discuss the pathophysiology and effects of ADT and glucocorticoids on skeletal endpoints, as well as the awareness and management of bone fragility. Coadministration of glucocorticoids is necessary with abiraterone because this causes a novel acquired form of 17-hydroxylase deficiency and synergistically increases the risk of fracture by affecting bone quality. Bone antiresorptive agents [selective estrogen receptor modulators (SERMS), bisphosphonates, and denosumab] increase bone mineral density (BMD) and in some instances reduce fracture risk in PC patients on ADT. Awareness and management of bone health in PC can be improved by integrating endocrinologists into the multidisciplinary PC team.

Autofluorescence and Indocyanine Green in Thyroid Surgery: A Systematic Review and Meta-Analysis.

OBJECTIVES/HYPOTHESIS: To estimate the impact of optical techniques on prevention of post-operative hypocalcemia and hypoparathyroidism after total thyroidectomy. STUDY DESIGN: Systematic review and meta-analysis. METHODS: A literature search was conducted in Pubmed, EMBASE, SCOPUS, and Cochrane databases. The main inclusion criteria for eligible articles for meta-analysis were patients with benign or malignant thyroid pathologies who underwent total thyroidectomy, utilization of optical techniques to support PGs preservation, the availability of calcium and/or PTH levels. The primary outcome was to evaluate the variation of calcium and PTH levels when adopting optical technologies compared to standard naked-eye surgery. RESULTS: In total, 13 papers with 1484 procedures were included. Pooled proportion for short- and medium-term hypocalcemia rates were 8% (95% CI, 5%:11%) and 1% (95% CI, 0%:4%) for optical techniques, while for naked-eye surgery were 15% (95% CI, 9%:23%) and 5% (95% CI, 2%:9%), respectively. CONCLUSIONS: Optical technologies reduced short and medium term hypocalcemia compared to conventional surgery. LEVEL OF EVIDENCE: NA Laryngoscope, 131:1683-1692, 2021.

Controversies in Vitamin D: A Statement From the Third International Conference.

The Third International Conference on Controversies in Vitamin D was held in Gubbio, Italy, September 10-13, 2019. The conference was held as a follow-up to previous meetings held in 2017 and 2018 to address topics of controversy in vitamin D research. The specific topics were selected by the steering committee of the conference and based upon areas that remain controversial from the preceding conferences. Other topics were selected anew that reflect specific topics that have surfaced since the last international conference. Consensus was achieved after formal presentations and open discussions among experts. As will be detailed in this article, consensus was achieved with regard to the following: the importance and prevalence of nutritional rickets, amounts of vitamin D that are typically generated by sun exposure, worldwide prevalence of vitamin D deficiency, the importance of circulating concentrations of 25OHD as the best index of vitamin D stores, definitions and thresholds of vitamin D deficiency, and efficacy of vitamin D analogues in the treatment of psoriasis. Areas of uncertainly and controversy include the following: daily doses of vitamin D needed to maintain a normal level of 25OHD in the general population, recommendations for supplementation in patients with metabolic bone diseases, cutaneous production of vitamin D by UVB exposure, hepatic regulation of 25OHD metabolites, definition of vitamin D excess, vitamin D deficiency in acute illness, vitamin D requirements during reproduction, potential for a broad spectrum of cellular and organ activities under the influence of the vitamin D receptor, and potential links between vitamin D and major human diseases. With specific regard to the latter area, the proceedings of the conference led to recommendations for areas in need of further investigation through appropriately designed intervention trials. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Multidisciplinary management of acromegaly: A consensus.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.

The optimal numerosity of the referral population of pituitary tumors centers of excellence (PTCOE): A surgical perspective.

Surgical experience is of paramount importance to reach therapeutic success and minimize operative complications. In the field of pituitary surgery, this led to the concept of Pituitary Center of Excellence (PTCOE) defined as a center where an interdisciplinary team works in collaboration and where surgeons can be trained appropriately to reach and keep excellence in daily practice. To review the literature to define the optimal referral population size to establish a PTCOE to optimize both training and specific field research. A review of the literature was performed about epidemiology. The time needed to observe 200 cases of PAs in a single PTCOE and to reach the minimal surgical experience threshold (MSET) was calculated for different referral population groups. The time needed to reach MSET decreased as population size increased. We defined a population as the optimal one to be served by a single PTCOE with a single dedicated neurosurgeon. PTCOEs should be established after an analysis of the referral population, number of cases suitable for surgical treatment and number of dedicated neurosurgeons.

Association of Fat Body Mass With Vertebral Fractures in Postmenopausal Women With Early Breast Cancer Undergoing Adjuvant Aromatase Inhibitor Therapy.

Importance: Aromatase inhibitors induce a profound depletion in serum estrogen levels. Postmenopausal obese women receiving aromatase inhibitor therapy may be at increased risk of bone fractures owing to the detrimental association of adiposity with bone quality and the loss of the protective effect of estrogens on bone mineral density. Objective: To determine whether fat body mass (FBM), as measured by dual-energy x-ray absorptiometry, is associated with vertebral fracture prevalence in postmenopausal women undergoing adjuvant aromatase inhibitor therapy for breast cancer. Design, Setting, and Participants: In this single-center, cross-sectional study, 556 postmenopausal women with early-stage breast cancer were consecutively enrolled from October 15, 2013, to June 30, 2018, and stratified according to whether they were aromatase inhibitor-naive or aromatase inhibitor-treated for at least 2 years. The database was locked on December 31, 2018, and data analysis was completed on February 28, 2019. Eligible patients in both groups had normal renal function, no metabolic diseases, and no previous or current treatment with antiosteoporotic drugs or glucocorticoids. Previous chemotherapy, but not tamoxifen, was permitted. Data were gathered once, at baseline. Main Outcomes and Measures: Vertebral fracture prevalence associated with FBM in aromatase inhibitor-naive and aromatase inhibitor-treated patients. Results: Of the 556 women enrolled, the mean age was 63.0 years (95% CI, 62.2-63.8 years). The 195 aromatase inhibitor-treated patients were older than the 361 aromatase inhibitor-naive patients (mean age, 66.1 vs 61.3 years; P < .001), had a higher body mass index (mean, 26.4 vs 25.3; P = .009), were less likely to engage in physical activity (65.3% vs 73.7%; P = .03), and were less likely to consume alcoholic beverages (68.4% vs 80.9%; P = .001). Among the aromatase inhibitor-naive patients, the vertebral fracture prevalence was higher in the subgroup with FBM below the median value than in those with high FBM, but the difference was not statistically significant (19.2% vs 13.3%; P = .13). Conversely, the proportion of vertebral fractures in the aromatase inhibitor-treated group was 20.0% in patients with low FBM vs 33.3% in patients with high FBM (P = .04). An opposite trend in the association of FBM with vertebral fracture prevalence according to aromatase inhibitor group was shown by multivariable analysis in the propensity score-matched sample: odds ratio, 0.38 (95% CI, 0.12-1.19) and 1.94 (95% CI, 0.67-5.64) in the aromatase inhibitor-naive and aromatase inhibitor-treated groups, respectively (odds ratio for the interaction, 5.77 [95% CI, 1.08-30.81]; P for interaction term = .03). Conclusions and Relevance: Fat body mass may be associated with fragility-related fractures in patients with breast cancer who undergo aromatase inhibitor therapy. If these data are confirmed, obesity could be included in the algorithm for assessing fracture risk and selecting patients to receive bone resorption inhibitors.

Higher Risk of Fragility Fractures in Prostate Cancer Patients Treated with Combined Radium-223 and Abiraterone: Prednisone May Be the Culprit.

Results from the ERA 223 trial of abiraterone combined with radium-223 among men with chemotherapy-naïve castration-resistant prostate cancer and bone metastases show no improvement in survival free from symptomatic skeletal events. We hypothesize that this finding might be attributable to bone loss induced by the concomitantly administered prednisone.

High Prevalence of Radiological Vertebral Fractures in Patients With TSH-Secreting Pituitary Adenoma.

BACKGROUND: Bone loss and high risk of fractures have been reported in patients with primary hyperthyroidism, whereas data on skeletal health in TSH-secreting adenoma (TSH-oma) are scant, and the risk of fractures in this specific clinical context has not been investigated so far. In this cross-sectional study, we aimed at evaluating for the first time, to our knowledge, the prevalence and determinants of radiological vertebral fractures (VFs) in patients with TSH-oma. METHODS: Twenty-two patients (10 males, 12 females; median age 47 years) with TSH-oma and 44 patients (20 males, 24 females; median age 49 years) with nonfunctioning pituitary adenoma (NFPA) were retrospectively evaluated for thoracic VFs using a morphometric approach on lateral chest X-ray routinely performed in the presurgical diagnostic workup. RESULTS: The prevalence of VFs was significantly higher in TSH-oma vs NFPA (59.1% vs 22.7%; P = 0.003), the difference being still significant (odds ratio, 10.5; P = 0.005) after correction for the size of pituitary adenomas and biochemical parameters. In TSH-oma, the prevalence of VFs was significantly associated with older age (P = 0.007) and higher serum free T4 values (P = 0.02). In 20 patients, data on presurgical medical therapies of TSH-oma were available. All patients not treated with somatostatin receptor ligands were fractured compared with 25% of those who were treated with these drugs (P = 0.001). No significant (P = 0.25) association between VFs and treatment with methimazole was found. CONCLUSIONS: This study provides the first evidence, to our knowledge, that patients with TSH-oma may develop VFs in close relationship with severity of hyperthyroidism.

Possible delayed diagnosis and treatment of metastatic differentiated thyroid cancer by adopting the 2015 ATA guidelines.

OBJECTIVE: According to the 2015 American Thyroid Association (ATA) guidelines, thyroid ablation by iodine-131 (I-131) therapy is absolutely recommended only in patients with high-risk differentiated thyroid cancer (DTC). Often distant metastases are not recognized early and they can stay silent for long time. The aim of our study was to retrospectively analyze the prevalence of metastatic disease before and after I-131 and to evaluate the influence of the new ATA guidelines in the management of DTC. METHODS: We retrospectively analyzed 140 patients showing distant metastases. All metastases were detected by whole-body scan after I-131 and confirmed by histology and/or other imaging modalities. RESULTS: In 26/140 patients metastases were detected before I-131, while in 114/140 were discovered after I-131. Comparing patients with metastases detected before and after I-131, no differences were demonstrated considering age, sex, histotype, tumor size, multifocality of cancer and metastatic localization. Metastatic DTC discovered before radioiodine had higher thyroglobulin and received a higher radioiodine total activity and number of treatments. Considering patients with distant metastases, according to the 2015 ATA guidelines, 38 patients would have been categorized as high risk, 22 as low risk and 80 as intermediate risk. Among intermediate-risk patients, only in 25 cases (31%) I-131 treatment would have been appropriate according to 2015 ATA recommendations; in the remaining 56 cases (69%), I-131 would not have been recommended. CONCLUSIONS: According to the 2015 ATA guidelines, most of metastatic patients would not have been treated after surgery, with the risk of late diagnosis and delayed treatment.

High Prevalence of Radiological Vertebral Fractures in Women on Thyroid-Stimulating Hormone-Suppressive Therapy for Thyroid Carcinoma.

Context: Bone loss and nonvertebral fractures have been reported in patients with differentiated thyroid carcinoma (DTC) undergoing thyroid-stimulating hormone (TSH) suppressive therapy. Radiological vertebral fractures (VFs) are an early and clinically crucial marker of bone fragility. Objective and Design: A cross-sectional study to evaluate the prevalence and determinants of radiological VFs in women receiving l-thyroxine (L-T4) therapy for DTC. Patients and Interventions: A total of 179 consecutive women (median age, 59 years; n = 178 postmenopausal) who had undergone thyroidectomy for DTC and were currently receiving L-T4 were evaluated for radiological VFs and bone mineral density (BMD). There were three TSH target levels [<0.5 mU/L, group 1 (n = 83); 0.5 to 1.0 mU/L, group 2 (n = 50); >1.0 mU/L, group 3 (n = 46)]. Results: VFs were found in 51 patients (28.5%), with significantly (P < 0.001) higher prevalence in group 1 (44.6%) as compared with group 2 (24.0%) and group 3 (4.3%). VF prevalence was not significantly different among patients in group 1 with normal BMD, osteopenia, or osteoporosis, whereas in groups 2 and 3, VFs were more frequent in patients with osteoporosis than in those with either osteopenia or normal BMD. In the whole population, VFs were significantly and independently associated with TSH level <1.0 mU/L; densitometric diagnosis of osteoporosis at lumbar spine, femoral neck, or total hip; age of patients; and duration of L-T4 therapy. Conclusion: The prevalence of VFs was high in women with DTC who were undergoing long-term, suppressive L-T4 therapy.

Growth hormone deficiency in treated acromegaly and active Cushing's syndrome.

Growth hormone deficiency (GHD) in adults is characterized by reduced quality of life and physical fitness, skeletal fragility, increased weight and cardiovascular risk. It may be found in (over-) treated acromegaly as well as in active Cushing's syndrome. Hypopituitarism may develop in patients after definitive treatment of acromegaly, although the exact prevalence of GHD in this population is still uncertain because of limited awareness, and scarce and conflicting data so far available. Because GHD associated with acromegaly and Cushing's syndrome may yield adverse consequences on similar target systems, the final outcomes of some complications of both acromegaly and Cushing's syndrome may be further affected by the occurrence of GHD. It is still largely unknown, however, whether GHD in patients with post-acromegaly or active Cushing's syndrome (e.g. pharmacologic glucocorticoid treatment) may benefit from GH replacement. We review the diagnostic, clinical and therapeutic aspects of GHD in adults treated for acromegaly and in those with active Cushing's syndrome.

Morphometric vertebral fractures in breast cancer patients treated with adjuvant aromatase inhibitor therapy: A cross-sectional study.

BACKGROUND: The impact of long-term adjuvant therapy with aromatase inhibitors (AIs) on vertebral fracture (VF) risk is still unclear. OBJECTIVE: In this cross-sectional study, we explored the prevalence and determinants of VFs in breast cancer (BC) patients before and during AI therapy. Each woman underwent a dual-energy X-ray absorptiometry (DXA) to evaluate bone mineral density (BMD) and identify VFs by a quantitative morphometric approach. Blood samples were collected to measure serum hormone and calcium levels. RESULTS: We consecutively included 263 postmenopausal women with hormone receptor-positive early BC. One-hundred-sixty-nine women were AI-naïve, and 94 were AI-treated. AI-treated patients had lower BMD at total hip (p=0.01) and lumbar spine (p=0.03), higher serum vitamin D (p<0.001) and parathyroid hormone (p=0.006) values as compared to AI-naïve patients. The prevalence of VFs was 18.9% in AI-naïve patients, and 31.2% in those assessed during AI therapy (odds ratio 1.90, 95% CI 1.1-3.5, p=0.03). In AI-naïve patients, VFs were associated with older age (p=0.002) and lower BMD values at femoral neck (p=0.04) and total hip (p=0.007), whereas VFs occurred without association with any parameter analyzed in AI-treated patients. In AI-treated group, the prevalence of VFs was not significantly different between patients with osteoporosis and those with normal BMD (36.7% vs. 20.0%; p=0.31). CONCLUSIONS: In women with early BC, AI therapy is associated with high prevalence of radiological VFs, which were shown to be independent of BMD values during the adjuvant treatment. These findings may be clinically relevant since they may lead to a change in management of AI-induced skeletal fragility. Specifically, the results of this study provide a rationale for performing a morphometric evaluation of VFs in all women undergoing treatment with AIs.

Current and future medical treatments for patients with acromegaly.

INTRODUCTION: Acromegaly is a relatively rare condition of growth hormone (GH) excess associated with significant morbidity and, when left untreated, high mortality. Therapy for acromegaly is targeted at decreasing GH and insulin-like growth hormone 1 levels, ameliorating patients' symptoms and decreasing any local compressive effects of the pituitary adenoma. The therapeutic options for acromegaly include surgery, medical therapies (such as dopamine agonists, somatostatin receptor ligands and the GH receptor antagonist pegvisomant) and radiotherapy. However, despite all these treatments option, approximately 50% of patients are not adequately controlled. AREAS COVERED: In this paper, the authors discuss: 1) efficacy and safety of current medical therapy 2) the efficacy and safety of the new multireceptor-targeted somatostatin ligand pasireotide 3) medical treatments currently under clinical investigation (oral octreotide, ITF2984, ATL1103), and 4) preliminary data on the use of new injectable and transdermal/transmucosal formulations of octreotide. EXPERT OPINION: This expert opinion supports the need for new therapeutic agents and modalities for patients with acromegaly.