Graves' disease (GD) and Thyroid Eye Disease (TED) are autoimmune disorders characterized by significant heterogeneity in treatment response. Up to 50% of GD patients relapse after antithyroid drug (ATD) withdrawal, and a substantial portion of TED patients (20-50%) are resistant to first-line glucocorticoid (GC) therapy. This review evaluates the current evidence on epigenetic modifications as predictive biomarkers to guide personalized treatment. We synthesized recent findings (up to 2025) from PubMed, focusing on DNA methylation and microRNAs (miRNAs). For GD, ATD relapse risk is linked to a persistent "epigenetic memory" in T cells, notably the hypomethylation of Th17-associated genes. Circulating miRNA signatures, including miR-346, miR-23b-5p, and miR-92a-3p, also show promise in predicting remission. For TED, GC sensitivity is strongly correlated with specific circulating miRNAs. High pre-treatment levels of miR-146a predict a positive response (100% positive predictive value), while low levels of miR-224-5p predict non-responsiveness. While DNA methylation is confirmed in TED pathogenesis, its predictive role is unstudied. Major research gaps persist, particularly the near-total absence of data on histone modifications as predictive markers and the lack of epigenetic predictors for new biologics treatments, which currently rely on genetic or pharmacokinetic markers. Epigenetic biomarkers represent a promising frontier for stratifying patients and optimizing therapeutic strategies in Graves' autoimmunity.

BackgroundEndocrine-related secondary osteoporosis (ERSOP) comprises disorders in which bone fragility results from hormonal abnormalities other than age-related or menopausal hypogonadism. Its prevalence is underestimated, and timely recognition is essential because many forms improve or reverse when the underlying endocrine disturbance is corrected.ObjectiveThis Review highlights the evolving concepts, unmet needs, and research opportunities in ERSOP, with focus on hypercortisolism, primary aldosteronism, male hypogonadism, hypercalciuria, and FGF23-dependent phosphate-wasting disorders.Recent findingsMild autonomous cortisol secretion (MACS) is increasingly recognized as a contributor to fracture risk even at near-normal cortisol levels.Primary aldosteronism promotes skeletal fragility via mineralocorticoid receptor activation, oxidative stress, hypercalciuria, and secondary hyperparathyroidism.Male hypogonadism is a major driver of bone loss, and optimal fracture prevention may require combined hormonal and anti-osteoporotic therapy.Differentiating PTH-dependent from PTH-independent hypercalciuria is crucial for management.FGF23-mediated phosphate-wasting disorders impair mineralization and may respond to targeted therapy, including burosumab.ConclusionERSOP should be considered in patients with atypical osteoporosis phenotypes, including men, younger adults, and individuals with normal BMD but fragility fractures. Optimal care requires structured endocrine assessment, correction of the primary disorder, and integration with bone-specific therapy where appropriate.

Introduction: Primary hyperparathyroidism (PHPT) is a common endocrine disorder, primarily caused by single adenomas or multiglandular disease. This study evaluates the economic impact of different PHPT treatment approaches from both the Italian National Health Service and societal perspectives. Methods: A micro-costing approach was used to estimate the costs of surgical and non-surgical treatments. Data were gathered through a survey among panel members responsible for the Italian PHPT treatment guidelines, ensuring alignment with national clinical practice. The survey examined various cost components, including diagnostic tests, pre-hospitalization assessments, surgery duration, drug use, healthcare professionals involved, disposable materials, and follow-up care requirements. Results: The total cost for PHPT diagnosis and comorbidity assessment is € 887.96. Parathyroidectomy (PTX) costs € 4,588.00. Non-surgical alternatives, including pharmacological treatment (€ 953.34 annually) and active surveillance (€ 197.42 annually), result in cumulative 30-year costs of € 28,590 and € 5,910, respectively. Since PTX is typically performed at age 55, pharmacological treatment over 30 years incurs an additional € 22,876 per patient compared to surgery. Conclusions: Despite its higher upfront cost, PTX demonstrated long-term cost efficiency due to the relatively low rates of follow-up complications and the absence of recurring annual costs associated with conservative strategies.

Parathyroid hormone controls calcium and phosphate metabolism. The latter is also regulated by both FGF23 and 1–25(OH)2VitaminD. The polymorphic variant c.716 C > T of the FGF23 gene was previously found to be associated with renal phosphate leak/nephrolithiasis. The aim of our research is to study the metabolism of phosphate in a cohort of patients with primary hyperparathyroidism (PHPT) and its impact on bone and kidney. We have retrospectively compared a large sample of sporadic PHPT patients (339) with historical comparison cohort (HCC 503: Olivetti Study Group and Siena Osteoporosis Study). Moreover, in 51 PHPT patients, phosphate metabolism indexes were also revaluated at least 2 years after surgical cure. The variant c.716 C > T of the FGF23 gene was genotyped in patients and in a small sample of the control group. In PHPT patients we found higher levels of serum calcium, PTH, alkaline phosphatase, beta-C-terminal telopeptide (CTx), urinary calcium, while serum phosphate, 25OH-VitaminD, maximal tubular renal phosphate reabsorption adjusted for glomerular filtration rate (TmPO4/GFR) were lower than what was found in HCC. In PHPT patients fibroblast growth factor 23 (FGF23) levels were higher than in controls. Patients with kidney stones carried the 716 T allele more frequently than patients without it (χ2 7.20, p = 0.027). In PHPT patients revaluated at least 2 years after surgery, we observed a significant reduction of 1–25(OH)2VitaminD and FGF23. According to the median of serum phosphate levels, PHPT patients were subdivided into two subgroups: ≤2.8 mg/dL and > 2.8 mg/dL. The lowest phosphate group had a significantly higher serum calcium, PTH, 1–25(OH)2VitaminD, urinary calcium and a higher prevalence of kidney stones than in the highest phosphate group. The rate of males in the lowest phosphate group was significantly higher than in the highest phosphate group. Our study shows that the regulators of phosphate metabolism in PHPT patients are higher than controls and they significantly reduce after surgical cure. PHPT patients with low serum phosphate have a worse biochemical and clinical phenotype.

PURPOSE:The study aimed to present the results of a Delphi consensus involving Italian experts focusing on the management of hypophosphatemia in adults. METHODS:A multidisciplinary advisory board of nine physicians, experts in hypophosphatemia management, was established. Next, a literature search was performed to identify international guidelines, consensus, and clinical pathways, which were later presented to the advisory board. Collaboratively, the advisory board and authoring team selected key statements for the consensus process and focused on areas of uncertainty related to the management of hypophosphatemia. The advisory board also indicated the experts to be invited to participate in the consensus process. The Delphi method was employed to reach a consensus. RESULTS:The literature search yielded one guideline, five consensus documents, and one clinical pathway. While our search strategy aimed to identify documents on the management of all types of hypophosphatemia, most of the guidelines and consensus documents retrieved focused on X-linked hypophosphatemia. The consensus process focused on 11 key issues, achieving strong convergence (over 70% consensus) in the first Delphi round for 8 out of the 11 statements. Three statements proceeded to the second round, with strong agreement reached for two. Notably, consensus was not reached for the statement concerning the measurement of fibroblast growth factor 23 for diagnostic purposes. CONCLUSION:The study revealed that the community of clinical experts is well-informed and in agreement regarding hypophosphatemia management. It emphasized the importance of developing clear national guidance documents to support clinicians and multidisciplinary teams in patient management. These documents are crucial not only for healthcare professionals but also for those responsible for defining pathways and services, facilitating a more accurate management of hypophosphatemic patients.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

INTRODUCTION:Paget's disease of bone is a focal skeletal disorder causing bone deformities and impairing bone quality. Despite the prevalence of asymptomatic cases is increasing, the progression of the disease can lead to invalidating complications that compromise the quality of life. Doubts on clinical and therapeutic management aspects exist, although beneficial effects of antiresorptive drugs, particularly bisphosphonates are known. However, limited information is available from randomized controlled trials on the prevention of disease complications so that somewhat contrasting positions about treatment indications between expert panels from the main scientific societies of metabolic bone diseases exist. This task force, composed by expert representatives appointed by the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases and members of the Italian Association of Paget's disease of bone, felt the necessity for more specific and up to date indications for an early diagnosis and clinical management.METHODS:Through selected key questions, we propose evidence-based recommendations for the diagnosis and treatment of the disease. In the lack of good evidence to support clear recommendations, available information from the literature together with expert opinion of the panel was used to provide suggestions for the clinical practice.RESULTS AND CONCLUSION:Description of the evidence quality and support of the strength of the statements was provided on each of the selected key questions. The diagnosis of PDB should be mainly based on symptoms and the typical biochemical and radiological features. While treatment is mandatory to all the symptomatic cases at diagnosis, less evidence is available on treatment indications in asymptomatic as well as in previously treated patients in the presence of biochemical recurrence. However, given the safety and long-term efficacy of potent intravenous bisphosphonates such as zoledronate, a suggestion to treat most if not all cases at the time of diagnosis was released.

Background and aims: Data on P homeostasis in insulin resistance (IR) are still conflicting. We investigated calcium-phosphate homeostasis parameters in men with/without IR. Methods and results: 177 volunteers (aged 61.62 +/- 12.11), whose body mass index (BMI) was 29.97 +/- 6.35, were studied. On fasting blood and spot urine samples, we measured serum creatinine, sodium (sNa), potassium (sK), chloride (sCl), calcium (sCa), phosphate (sP), alkaline phosphatase total activity (ALP), glucose, insulin, parathyroid hormone (PTH), 25-hydroxy-vitamin D [25(OH)D], and urinary electrolytes corrected for creatinine (uNa/Cr, uK/Cr, uCl/Cr, uCa/Cr, and uP/Cr). Through the QUICKI index, we separated subjects with (IR+, n = 68) or without (IR-, n = 109) IR, and their parameters were compared. Associations were assessed by age-adjusted partial correlation, whose coefficients were compared by Fisher's transform. IR + had higher sP (3.54 +/- 0.65 vs. 3.35 +/- 0.47, p = 0.044) and lower uCa/Cr levels (0.073 +/- 0.056 vs. 0.095 +/- 0.072, p = 0.047) than IR-. BMI correlated with sP (r = 0.21, p < 0.05) and PTH (r = 0.29, p < 0.01). QUICKI negatively correlated with sCa (r = -0.22, p < 0.05) and positively with uCa/Cr (r = 0.21, p < 0.05), in turn correlating with uNa/Cr (r = 0.45, p < 0.001). In both groups, uCa/Cr correlated with eGFR and uNa/Cr (p < 0.05 to p < 0.001). In IR + only, sP correlated with BMI, PTH with insulin, and uP/Cr (p < 0.05 for all). IR+ and IR-coefficients differed (p < 0.05 to p < 0.001) for the correlation of sP with BMI and of PTH with insulin and uP/Cr. Conclusion: The higher sP and lower uCa/Cr levels found in men with IR + suggest that IR could modulate calcium-phosphate homeostasis, likely by affecting their renal handling. (c) 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Primary hyperparathyroidism represents the third most prevalent endocrine disease in the general population, consisting of an excessive secretion of parathyroid hormone from one or, more frequently, more of the parathyroid glands, leading to a dysregulation of calcium homeostasis. Schematically, its development occurs primarily by pathophysiological events with genetic mutation, at the germline and/or somatic level, that favor the neoplastic transformation of parathyroid cells and promote their aberrant proliferation, and mutations determining the shift in the PTH “set-point”, thus interfering with the normal pathways of PTH secretion and leading to a “resetting” of Ca2+-dependent PTH secretion or to a secretion of PTH insensitive to changes in extracellular Ca2+ levels. Familial syndromic and non-syndromic forms of primary hyperparathyroidism are responsible for approximately 2–5% of primary hyperparathyroidism cases and most of them are inherited forms. The history of the genetic/molecular studies of parathyroid tumorigenesis associated with multiple endocrine neoplasia type 1 syndrome (MEN1) represents an interesting model to understand genetic–epigenetic–molecular aspects underlying the pathophysiology of primary hyperparathyroidism, both in relation to syndromic and non-syndromic forms. This minireview aims to take a quick and simplified look at the MEN1-associated parathyroid tumorigenesis, focusing on the molecular underlying mechanisms. Clinical, epidemiological, and observational studies, as well as specific guidelines, molecular genetics studies, and reviews, have been considered. Only studies submitted to PubMed in the English language were included, without time constraints.

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.

IntroductionPaget's disease of bone (PDB) is a focal bone disorder caused by a marked dysregulation of osteoblasts and osteoclasts in basic multicellular units, leading to abnormal and disorganized deposition of collagen fibers (the so-called 'woven bone'). Therefore, pagetic bones are increased in size, and at increased risk for bone pain, deformities, fractures, osteoarthritis, and, more rarely, neoplastic degeneration.Areas coveredIn this review, we revise the available information concerning the pharmacological treatment of PDB.Expert opinionPDB progresses slowly within the affected skeletal sites and, if untreated, often leads to bone overgrowth, with bone pain, deformity, and a likely increased risk of complications. Thus, the primary goal of treatment is the restoration of a normal bone turnover, in order to relieve bone pain or other symptoms and possibly prevent the complications. PDB long remained a poorly treatable disorder until the discovery of antiresorptive agents such as calcitonin first and bisphosphonates (BPs) later. With the recent development of potent intravenous BPs like zoledronate, allowing a better control of disease activity over the long term with a single infusion, has contributed to a marked improvement of the clinical management of this invalidating disorder.

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 T2Drelated 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

In these recent years many people are adopting a vegetarian type diet due to the numerous positive health effects of this regimen such as the reduction of the incidence of many chronic disorders like diabetes, hypertension, obesity and cancer. However this diet is quite restrictive and so it could be possible to have a deficiency in some specific nutrients, increasing the risk of osteoporosis and fractures. Although there are conflicting results on the effects of the vegetarian diet on bone health and fracture incidence, it is always recommendable in vegetarian people to have an adequate intake of calcium and vitamin D, through an increased intake of supplements, natural and fortified foods, an adequate intake of protein, fruit, vegetables, as well as vitamin B12. The aim of this literature review is to revise the actual knowledge of the effect of some nutrients and vegetarian diets on bone health.

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).