The Association of Vitamin D Receptor Polymorphisms with COVID-19 Severity.

BACKGROUND: Association studies of vitamin D receptor (VDR) polymorphisms with COVID-19 severity have produced inconsistent results in different populations. Herein we examined VDR gene polymorphisms in a Caucasian Greek cohort of COVID-19 patients. METHODS: This was a case-control study in a tertiary university hospital in Greece including 137 COVID-19 patients with varying disease severities and 72 healthy individuals. In total 209 individuals were genotyped for the FokI (rs10735810), ApaI (rs7975232), TaqI (rs731236) and BsmI (rs1544410) single-nucleotide polymorphisms (SNP) of the VDR gene by polymerase chain reaction and restriction fragment length polymorphism analysis (PCR-RFLPs). Statistical analyses were performed to determine the association between genotype and disease severity, adjusting for various confounding factors. RESULTS: Genotype distribution of the studied VDR SNPs in the control group was in Hardy-Weinberg equilibrium. The TaqI variant was differentially distributed between controls and COVID-19 patients according to the additive model (p = 0.009), and the CC genotype was significantly associated with an increased risk for severe COVID-19 according to the recessive model [OR: 2.52, 95%CI:1.2-5.29, p = 0.01]. Multivariate analysis demonstrated a robust association of COVID-19 severity and TaqI polymorphism in the recessive model even after adjusting for multiple confounders, including age, sex and CRP levels [Adj.OR:3.23, 95%CI:1.17-8.86, p = 0.023]. The distribution of FokI, ApaI and BsmI genotypes was similar between COVID-19 patients and controls. CONCLUSIONS: The CC genotype of TaqI polymorphism is significantly associated with an increased risk for severe COVID-19 independently of age, sex or degree of inflammation.

Diurnal production of cortisol and prediction of treatment response in rheumatoid arthritis: a 6-month, real-life prospective cohort study.

OBJECTIVES: A reduced adrenal reserve-associated cortisol production relative to the enhanced needs of chronic inflammation (disproportion principle) has been observed in rheumatoid arthritis (RA). We examined the possible clinical value of diurnal cortisol measurements in active RA on treatment response prediction. METHODS: Diurnal cortisol production (measured at: 08-12:00/18:00-22:00) was assessed by electrochemiluminescence immunoassay in 28 consecutive patients with moderately/highly active RA, as well as 3 and 6 months after treatment initiation or/escalation. Twenty-eight COVID-19 patients and 28 age-matched healthy individuals (HC) served as controls. RESULTS: Saliva diurnal cortisol production in patients with RA was similar to that of HC, despite 12-fold higher serum C reactive protein (CRP) levels, and lower than COVID-19 patients (area under the curve: RA: 87.0±37.6 vs COVID-19: 146.7±14.3, p<0.001), having similarly high CRP. Moreover, a disturbed circadian cortisol rhythm at baseline was evident in 15 of 28 of patients with RA vs 4 of 28 and 20 of 28 of HC and COVID-19 patients, respectively. Treatment-induced minimal disease activity (MDA) at 6 months was achieved by 16 of 28 patients. Despite comparable demographics and clinical characteristics at baseline, non-MDA patients had lower baseline morning cortisol and higher adrenocorticotropic hormone (ACTH) levels compared with patients on MDA (cortisol: 10.9±4.0 vs 18.4±8.2 nmol/L, respectively, p=0.005 and ACTH: 4.8±3.3 vs 2.4±0.4 pmol/L, respectively, p=0.047). Baseline morning cortisol <13.9 nmol/L predicted non-MDA at 6 months (75% sensitivity, 92% specificity, p=0.006). Prospective measurements revealed that individualised diurnal cortisol production remained largely unchanged from baseline to 3 and 6 months. CONCLUSIONS: An impaired adrenal reserve is present in patients with RA. Further studies to confirm that assessment of diurnal cortisol production may be useful in guiding treatment decisions and/or predicting treatment response in RA are warranted. TRIAL REGISTRATION NUMBER: NCT05671627.

The relationship between length of denosumab treatment for postmenopausal osteoporosis and serum TRAcP5b measured six months after the last injection.

To test the hypothesis that during treatment with denosumab osteomorphs and precursors recycle to higher number of osteoclasts with time, we measured TRAcP5b in serum taken 6 months after the last injection in postmenopausal women treated for 1-10 years. Serum TRAcP5b values were not related to time of exposure to denosumab. PURPOSE: In women with postmenopausal osteoporosis the aetiology of the observed inverse relationship between duration of denosumab (Dmab) therapy and bone loss after its discontinuation is currently unknown. In studies in mice inhibition of RANKL is associated with an increase in osteomorphs and osteoclast precursors that recycle into osteoclasts and may accumulate with time. We hypothesized that longer inhibition of RANKL by Dmab will be followed by the synchronous formation of a larger number of osteoclasts after stopping treatment. To test this hypothesis, we measured serum TRAcP5b, a marker of osteoclast numbers, in postmenopausal women treated with Dmab for different periods of time up to 10 years. METHODS: TRAcP5b, C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at 6.0 months ± 15 days after last Dmab injection in 59 women who had received Dmab for 4.0 ± 2.3 years (range 1-10 years). Of these, 38 were treatment naïve (group 1) and 21 had received other treatments prior Dmab (group 2). RESULTS: Duration of Dmab treatment was not related to serum TRAcP5b values or to TRAcP5b/CTX ratio either in the whole cohort or in each of the two groups separately. In contrast, serum TRAcP5b values were significantly correlated with serum CTX values (rs = 0.619; p < 0.001), but not with serum P1NP values or BMD at all skeletal sites. CONCLUSION: Our observations indicate that serum TRAcP5b, measured at 6 months after a Dmab injection, is not a useful early marker for time-dependent increased accumulation of osteoclasts in humans and for identification of patients at risk for a higher rebound increase in bone resorption.

Nocebo-associated treatment discontinuation with subcutaneous anti-osteoporotic drugs. A systematic review and meta-analysis of placebo-arm dropouts in randomized-controlled trials.

OBJECTIVE: Nocebo is a concept of therapeutics referring to unpleasant symptoms attributed by a patient to a drug, due to negative anticipation. Patients receiving oral anti-osteoporotic drugs in randomized controlled trials (RCT) can experience adverse events leading to dropout, implying that nocebo contributes to treatment discontinuation for these drugs. In this study we aim to investigate the nocebo effect of subcutaneous anti-osteoporotic drugs with a higher compliance rate than orally administered drugs. STUDY DESIGN: We searched MEDLINE, EMBASE, SCOPUS, and Cochrane databases for double-blind trials investigating subcutaneous anti-osteoporotic drugs for osteoporosis (namely, denosumab, teriparatide, abaloparatide and romosozumab) published up to May 2023. MAIN OUTCOME MEASURE: Dropouts due to reported adverse events in the placebo arms ("nocebo dropouts"). RESULTS: Data from 17 trials were extracted. Among 10,529 placebo-treated patients the pooled nocebo-dropout percentage was 3 % for denosumab (average: 0.03; 95 % CI: 0.01-0.05), 1 % for romosozumab (average: 0.01; 95 % CI: 0.00-0.03) and 6 % for teriparatide and abaloparatide (average: 0.06; 95 % CI: 0.05-0.07). Nocebo-dropouts were significantly higher in men than women (6 % vs. 3 %, respectively, p = 0.012), in older (mean age >68 years) than in younger patients (5 % vs. 1 %, respectively, p = 0.017) and in those with more severe osteoporosis (based on the percentage of participants with prior fragility-related fractures in the study cohort) compared with patients with no prior fracture history (4 % vs. 1 %, respectively, p = 0.046). CONCLUSION: Nocebo responses may contribute to treatment discontinuation with subcutaneous anti-osteoporotic drugs in clinical practice. Higher nocebo-related dropout rates in the higher-risk RCT population (older patients, males, those with prior fractures) show that nocebo mechanisms have the potential to hinder therapeutic efforts to specific populations who would benefit most. Prospero registration number CRD42020212843.

Association of hyponatremia with bone mineral density and fractures: a narrative review.

Recent studies suggest a possible association of hyponatremia with osteoporosis, falls and bone fractures. The objectives of this narrative review were to further explore this association and the related pathophysiological mechanisms and to suggest a practical approach to patients with osteoporosis or chronic hyponatremia in clinical practice. We conducted an extensive PubMed search until October 2022 with the combination of the following keywords: 'hyponatremia' or 'sodium' or 'SIADH' and 'fractures' or 'bone' or 'osteoporosis', as MeSH Terms. Review of numerous observational studies confirms a significant independent association of, even mild, hyponatremia with two- to three-fold increase in the occurrence of bone fractures. Hyponatremia is a risk factor for osteoporosis with a predilection to affect the hip, while the magnitude of association depends on the severity and chronicity of hyponatremia. Chronic hyponatremia also increases the risk for falls by inducing gait instability and neurocognitive deficits. Besides the detrimental impact of hyponatremia on bone mineral density and risk of falls, it also induces changes in bone quality. Emerging evidence suggests that acute hyponatremia shifts bone turnover dynamics towards less bone formation, while hyponatremia correction increases bone formation. The key unanswered question whether treatment of hyponatremia could improve osteoporosis and lower fracture risk highlights the need for prospective studies, evaluating the impact of sodium normalization on bone metabolism and occurrence of fractures. Recommendations for clinical approach should include measurement of serum sodium in all individuals with fracture or osteoporosis. Also, hyponatremia, as an independent risk factor for fracture, should be taken into consideration when estimating the likelihood for future fragility fracture and in clinical decision-making about pharmacological therapy of osteoporosis. Until it is proven that normalization of sodium can lower fracture occurrence, correcting hyponatremia cannot be universally recommended on this basis, but should be decided on a case-by-case basis.

Lipid Profile after Pharmacologic Discontinuation and Restoration of Menstruation in Women with Endometriosis: A 12-Month Observational Prospective Study.

The lipid profile is affected following menstrual cessation (MC). We aimed to evaluate the effects of goserelin-induced MC and subsequent menstrual restoration (MR) on lipid metabolism. Premenopausal women with histologically verified endometriosis (n = 15) received goserelin monthly for 6 months (6mο), resulting in MC, and were followed-up for another 6 months after MR (12mο). Serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), lipoprotein a ([Lp(a)] and lipidomics were measured at baseline, 6mo and 12mo. Shotgun quantitative deep lipidomics were determined at the level of lipid class category, subclass, species, and fatty acyl chain lengths and degree of saturation. TC (p = 0.006), LDL-C (p = 0.028), HDL-C (p = 0.002), and apoA1 (p = 0.013) increased during goserelin-induced MC and remained practically unchanged during MR. TG, apoB, and Lp(a) did not change. From the deep lipidomics analysis, multivariate statistical analysis demonstrated profound alterations in lipid species with MC, whereas no statistically valid models could be fitted for the restoration period. In conclusion, GnRH-analog-induced MC alters lipid profiles at various levels, from standard blood lipid and lipoprotein profiles to several lipid species as detected by lipidomics analysis. Changes largely persist for at least 6 m after MR.

Risk and management of osteoporosis due to inhaled, epidural, intra-articular or topical glucocorticoids.

Glucocorticoids (GCs) are widely used by several specialties for the treatment of a variety of diseases and conditions. The unfavorable effect of oral GCs on bone health is well-documented. The ensuing from their use glucocorticoid-induced osteoporosis (GIOP) is the most common cause of medication-induced osteoporosis and fractures. It is uncertain, however, if, and in what extent, GCs administered by other routes affect the skeleton. In the present review, we quote current evidence on the effect of inhaled GCs, epidural and intra-articular steroid injections, and topical GCs on bone outcomes. Although evidence is limited and weak, it seems that a small proportion of the administered GCs may be absorbed, enter the systemic circulation, and adversely affect the skeleton. Potent GCs, higher doses, and longer treatment duration seem to infer the greater risk for bone loss and fractures. There are scarce data, and only for inhaled GCs, regarding the efficacy of antiosteoporotic medications in patients receiving GCs through routes other than oral. Further studies are needed to clarify the relationship between GC administration through these routes and bone outcomes and to help establishing guidelines for the optimal management of such patients.

Structural Speciation of Ti(IV)-(α-Hydroxycarboxylic Acid) Complexes in Metabolism-Related (Patho)Physiology-In Vitro Approaches to (Pre)Adipocyte Differentiation and Mineralization.

The prospect of developing soluble and bioavailable Ti(IV) complex forms with physiological substrates, capable of influencing (patho)physiological aberrations, emerges as a challenge in the case of metabolism-related pathologies (e.g., diabetes mellitus 1 and 2). To that end, pH-specific synthetic efforts on binary Ti(IV)-(α-hydroxycarboxylic acid) systems, involving natural physiological chelator ligands (α-hydroxy isobutyric acid, D-quinic acid, 2-ethyl-2-hydroxybutyric acid) in aqueous media, led to the successful isolation of binary crystalline Ti(IV)-containing products. The new materials were physicochemically characterized by elemental analysis, FT-IR, TGA, and X-ray crystallography, revealing in all cases the presence of mononuclear Ti(IV) complexes bearing a TiO6 core, with three bound ligands of variable deprotonation state. Solution studies through electrospray ionization mass spectrometry (ESI-MS) revealed the nature of species arising upon dissolution of the title compounds in water, thereby formulating a solid-state-solution correlation profile necessary for further employment in biological experiments. The ensuing cytotoxicity profile (pre-adipocytes and osteoblasts) of the new materials supported their use in cell differentiation experiments, thereby unraveling their structure-specific favorable effect toward adipogenesis and mineralization through an arsenal of in vitro biological assays. Collectively, well-defined atoxic binary Ti(IV)-hydroxycaboxylato complexes, bearing bound physiological substrates, emerge as competent inducers of cell differentiation, intimately associated with cell maturation, thereby (a) associating the adipogenic (insulin mimetic properties) and osteogenic potential (mineralization) of titanium and (b) justifying further investigation into the development of a new class of multipotent titanodrugs.

Recent advancements in glucose dysregulation and pharmacological management of osteoporosis in transfusion-dependent thalassemia (TDT): an update of ICET-A (International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine).

PURPOSE OF REVIEW: The aim of this short review is to provide an update on glucose homeostasis, insulin secretion and pharmacological management of osteoporosis in transfusion-dependent thalassemia (TDT). RECENT FINDINGS: A retrospective study, documenting the changes in glucose-insulin homeostasis from early childhood to young adulthood, has advanced our understanding of the evolution of glucose regulation in patients with TDT. Magnetic Resonance Imaging (T2* MRI) is considered to be a reliable tool to measure pancreatic iron overload. Continuous glucose monitoring systems (CGMS) can be used in early diagnosis of glucose dysregulation and in disease management in patients with already diagnosed diabetes. Oral glucose-lowering agents (GLAs) are effective and safe for the treatment of diabetes mellitus (DM) in patients with TDT, achieving adequate glycemic control for a substantial period of time. Current modalities for the management of osteoporosis in adults with TDT include inhibitors of bone remodeling such as bisphosphonates and denosumab as well as stimulators of bone formation (e.g., teriparatide), Considering the unique characteristics of osteoporosis associated with TDT, early diagnosis, treatment initiation and treatment duration are critical issues in the management this special population. CONCLUSIONS: Advances in the care of TDT patients  have led to improved survival and quality of life. Nevertheless, many chronic endocrine complications still remain. Their routine screening and a high index of suspicion are imperative in order to provide timely diagnosis and  treatment.

Efficacy of denosumab monotherapy among adults with Langerhans cell histiocytosis: A prospective clinical trial.

This phase IIb clinical trial evaluated the efficacy of a bimonthly treatment schedule (Q8W) with 4 subcutaneous doses of denosumab 120 mg among adults with Langerhans cell histiocytosis needing first-line systemic therapy for either multifocal single-system disease or multisystem disease without risk organ involvement. Two months after the last treatment administration, seven patients showed disease regression, one stable disease, one non-active disease, and one disease progression. One year after treatment, progression was evident in two patients, while the remaining exhibited either a regression (three patients) or non-active disease (five patients). No permanent sequalae developed during the study and no adverse events were adjudicated in treatment. In conclusion, four doses of denosumab 120 mg Q8W subcutaneously are an effective treatment option in Langerhans cell histiocytosis patients without risk organ involvement exhibiting a response rate of 80%. Further studies are needed to confirm its role as a disease modifying agent.

Meta-analysis of placebo-arm dropouts in osteoporosis randomized-controlled trials and implications for nocebo-associated discontinuation of anti-osteoporotic drugs in clinical practice.

Dropout from placebo arms in randomized-controlled trials is a surrogate for nocebo responses, resulting from patients' negative expectations to treatment. Among 16,460 placebo-treated patients in oral anti-osteoporotic drug trials, nocebo dropouts were 8% on average, being higher in older patients. This implies that nocebo may contribute to the osteoporosis treatment gap in clinical practice. PURPOSE: Osteoporosis is a common disease requiring long-term treatment. Despite the availability of effective anti-osteoporotic drugs, adherence to treatment is low. Nocebo, a behavior mostly related to the negative expectations to a certain treatment, decreases adherence and negatively affects treatment outcomes and health-related care costs in chronic diseases. Since in double-blind placebo-controlled randomized trials any unfavorable outcome leading to discontinuation in placebo arms is considered as nocebo, we aimed to investigate the size of nocebo response in patients participating in osteoporosis trials. METHODS: We searched MEDLINE, EMBASE, SCOPUS, and Cochrane databases for dropouts due to reported adverse events in the placebo arms (nocebo dropouts) in all double-blind trials investigating anti-osteoporotic drugs published between January 1993 and March 2022. Only data on bisphosphonates and selective estrogen receptor modulators (SERMs) were analyzed (Prospero registration number CRD42020212843). RESULTS: Data from 44 trials were extracted. In 16,460 placebo-treated patients, the pooled nocebo-dropout was 8% both for bisphosphonates (average: 0.08; range 0.01-0.27; 95%CI 0.06-0.10) and SERMs (average: 0.08; range 0.03-0.15; 95%CI 0.05-0.13). Nocebo-dropouts were higher in bisphosphonate trials enrolling individuals ≥ 65 years (11%) (n = 18) compared to trials enrolling younger individuals (6%) (n = 18) (average: 0.11; 95%CI 0.08-0.13 vs. average: 0.06; 95%CI 0.05-0.08, respectively, p = 0.001). Participants' sex, dosing-intervals, publication year, or severity of osteoporosis had no impact on the nocebo-dropouts. CONCLUSION: Almost 1 in 10 osteoporosis patients receiving placebo in trials of bisphosphonates and SERMs experiences AEs leading to dropout, implying that nocebo contributes to treatment-discontinuation in clinical practice. Efforts to identify and minimize nocebo, especially in older patients, are warranted.

Approach to the management of ß thalassemia major associated osteoporosis - A long-standing relationship revisited.

Adults with ß- thalassemia major (ß-TM) develop low BMD and fragility fractures at a higher incidence and at a younger age compared to the general population. The disease itself, including direct effects of anemia and iron overload toxicity on bone turnover, genetic susceptibility, thalassemia-related endocrinopathies and acquittance of suboptimal peak bone mass contribute to low bone mass and increased bone fragility frequently encountered among these patients. Current management of osteoporosis requires long-term treatment that can be provided by agents that reduce the risk of all osteoporotic fractures by modulating bone metabolism with different mechanisms of action. These include inhibitors of bone remodeling (e.g., bisphosphonates, denosumab) and stimulators of bone formation (e.g., PTHR1 agonists and sclerostin antibodies). Considering the unique characteristics of osteoporosis associated with ß-TM and the clinical importance of balancing the risk/benefit of treatment in the long-term, appropriate use of these therapeutic approaches is essential for patient care. In this review we outline current literature on the use of anti-osteoporotic drugs in ß-TM patients with osteoporosis focusing on data on the efficacy, safety, and duration of treatment. In addition, we propose a long-term management plan for ß-TM -associated osteoporosis aiming at the optimal patient care for this special population.

Protracted stress-induced hypocortisolemia may account for the clinical and immune manifestations of Long COVID.

About one out of eight people to convalesce from COVID-19 suffer from the so called Long COVID, a syndrome of non-specific symptoms with unclear pathogenesis. In a recent study published in Cell Long COVID participants reporting respiratory symptoms had low cortisol levels. In an as yet unpublished analysis from Yale University low plasma cortisol levels discriminated Long COVID from asymptomatic convalescent or healthy non-infected controls. Although various immune perturbations were present in Long COVID, low levels of cortisol were prominent and strikingly, depression and anxiety were increased. It has become clear that Long COVID features may be similar to those described in myalgic encephalomyelitis/chronic fatigue syndrome, post-SARS sickness syndrome, and various chronic stress syndromes which have been linked to hypocortisolemia. Notably, lack of response of the hypothalamic-pituitary-adrenal axis to hypocortisolemia shows a suppressed axis in Long COVID. We suggest that the inability of hypothalamic-pituitary-adrenal axis to recover after the acute illness, perhaps due to protracted stress in predisposed individuals, may represent the pathogenetic basis of the Long COVID-associated clinical and immunological manifestations.

Novel Therapeutic Agents for Rare Diseases of Calcium and Phosphate Metabolism.

The last decade has been revolutionary regarding the management of rare bone diseases caused by impaired calcium and phosphate metabolism. Elucidation of the underlying genetic basis and pathophysiologic alterations has been the determinant factor for the development of new, disease-specific treatment agents. The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) possesses a critical role in the pathogenesis of various hypophosphatemic disorders. Among them, the genetic disorder of X-linked hypophosphatemia and the acquired syndrome of tumor-induced osteomalacia, although very rare, have attracted the scientific community's attention towards designing an FGF23-inhibitor as a potential specific therapy. The monoclonal antibody burosumab was approved for the treatment of children and adult patients with X-linked hypophosphatemia and recently for tumor-induced osteomalacia patients, demonstrating benefits regarding their symptoms, biochemical profile and bone mineralization status. Asfotase alfa is a hydroxyapatite-targeted recombinant alkaline phosphatase, an enzymatic replacement therapy, substituting the defective activity of tissue non-specific alkaline phosphatase, in patients suffering from hypophosphatasia. Promising data regarding its favorable effect on survival rate, bone quality, fracture healing, muscle strength, mobility, respiratory function, and general quality of life have led to the approval of the drug for the treatment of childhood-onset hypophosphatasia. Given the high costs of treatment for both agents and their limited clinical use until now, more data are needed to define patients' characteristics that make them ideal candidates for therapy. Long-term safety issues also need to be clarified.

Impaired adrenal cortex reserve in patients with rheumatic and musculoskeletal diseases who relapse upon tapering of low glucocorticoid dose.

OBJECTIVES: To examine adrenal cortex reserve in patients with rheumatic and musculoskeletal diseases (RMD) who relapse upon tapering of low glucocorticoid dose, despite concomitant treatment with disease-modifying anti-rheumatic drugs (DMARDs). METHODS: A morning standard dose of 250 mcg tetracosactide (Synacthen test) was given in 25 consecutive patients (13 rheumatoid arthritis, 2 psoriatic arthritis, 5 systemic lupus erythematosus, 2 dermatomyositis, 1 systemic sclerosis, 2 temporal arteritis) at the time of relapse upon small reductions (1-2 mg daily) of low prednisolone dose (<7.5 mg daily), while being on stable concomitant treatment with methotrexate, leflunomide, hydroxychloroquine, azathioprine, mycophenolate, tofacitinib, belimumab, anti-TNF, anti-IL-6 or anti-IL-1 regimens (n=14; 3; 9; 1; 2; 1; 1; 5; 2; 1, respectively). Sex-matched apparently healthy individuals (n=45) served as controls. RESULTS: Baseline cortisol levels and time-integrated cortisol response to tetracosactide were lower in patients than controls (12.01±4.47 vs. 15.63±4.16 mcg/dl, p=0.001, and 1050±286 vs. 1284±182, p<0.001, respectively). No significant associations were observed between the cortisol response to tetracosactide and age, duration of disease or glucocorticoid treatment. An abnormal Synacthen test, indicative of adrenal insufficiency, presumably secondary to chronic glucocorticoid administration, was noted in 5/25 patients. The remaining 20 patients (80%) had normal Synacthen test demonstrating, however, lower cortisol response than controls, independently of age (ß-coefficient=-0.373, p=0.033). CONCLUSIONS: Patients with RMD in remission under DMARDs who relapse upon concomitant low glucocorticoid dose tapering should be tested for iatrogenic adrenal insufficiency. Whether a marginally normal Synacthen test should discourage further attempts to withdraw glucocorticoid treatment in these patients warrants further investigation.

Prevalence and patterns of anti-osteoporotic drug use based on 2019 real-world nationwide data in Greece.

We used the Greek nationwide database to capture individuals on anti-osteoporotic treatment during 2019. From the estimated number of 683,679 osteoporotic individuals, only 42% were receiving treatment, with the total annual cost being almost one-tenth of the total cost of fractures. The treatment gap was significantly higher in males than in females. INTRODUCTION: Based on the 2019 European scorecard (SCOPE), osteoporosis is diagnosed in an estimated 683,679 individuals in Greece, with the direct cost of incident fractures being €694.7 million, although further relevant real-world data are scarce. METHODS: The e-Government Center for Social Security Services prescription database, which covers almost 100% of the Greek population, was used to capture all individuals on anti-osteoporotic treatment during 2019. RESULTS: A total of 288,983 among 8,641,341 people, corresponding to 3.3% of the total adult Greek population, had filled at least one anti-osteoporotic prescription (6.0% and 0.36% for females and males, respectively). Prevalence of anti-osteoporotic treatment increased with age, from 0.15% in those younger than 50 to 8.6% in those older than 70 years. Oral bisphosphonates were more frequently prescribed (58.8%), followed by denosumab (39.4%). Alendronate was more frequently prescribed in males and in people younger than 60 years. Denosumab was more frequently prescribed in females and in people older than 60 years. Selective estrogen-receptor modulators, teriparatide, and parenteral bisphosphonates accounted for 1.1%, 1.0%, and 0.02% of all prescriptions, respectively. Orthopedic surgeons (39.6%), endocrinologists (19.6%), general practitioners (19%), and rheumatologists (9.3%) prescribed the vast majority of anti-osteoporotic regimens, with significant differences in prescription patterns. The annual cost of treatment per patient increased significantly with age, being on average €323.33. CONCLUSIONS: Less than half of the estimated number of individuals with osteoporosis in 2019 in Greece received treatment, with the total annual cost being far less than the estimated cost of incident-fragility fractures. The impact of this undertreatment on related health care costs merits further investigation.

Management and Long-Term Follow-Up of Hyperparathyroidism in Multiple Endocrine Neoplasia Type 1: Single Center Experience.

BACKGROUND: Primary hyperparathyroidism (PHPT) in the most common and earliest manifestation of multiple endocrine neoplasia type-1 (MEN1). Epidemiological data have been reported in MEN1 patients but data on long-term follow-up focusing on PHPT are scarce. METHODS: In this retrospective cohort study, we included patients diagnosed with MEN1-related PHPT that were under regular follow-up in our institution. RESULTS: Data on 68 patients (39 males), with a mean age at MEN1-diagnosis of 39 ± 13.06 years, were analyzed. Pancreatic neuroendocrine tumors were encountered in 82% (71% nonsecreting) followed by pituitary adenomas in 66% (49% nonsecreting). Mean age at PHPT diagnosis was 35.2 ± 4.0 years. Parathyroidectomy was performed in 57 patients (82.3%), of whom 56% achieved long-term remission, while 12.2% and 31.5% had persistent and recurrent disease, respectively (median follow-up of 4 years; range 1-21 years). Cinacalcet restored serum calcium levels in 33.8%, both as first and as a second line treatment. Permanent hypoparathyroidism occurred in 19.2%. MEN1 pathogenic variants were identified in 77.2% of the tested individuals, but no genotype-phenotype associations were reported. CONCLUSIONS: MEN1-related PHPT involves a multiglandular disease and its management remains a therapeutic challenge, as recurrent disease can develop even after 20 years of follow-up. Prolonged follow-up of these patients at referral centers is critical for their optimal management.

Prevalence of the BRAF V600E mutation in Greek adults with Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia with a broad spectrum of clinical manifestations. The activation of the MAP kinase pathway plays an integral role in its pathogenesis with genetic alterations found in the majority of cases that most frequently involve a somatic mutation of the oncogenic BRAFV600E variant. In this study we investigated the prevalence of the BRAFV600E mutation and its clinical relevance in adult Greek patients with LCH. Among 37 patients studied, the BRAFV600E mutation was identified in 12 out of 31 (38.7%), whereas in six patients (19.3%) the results were in conclusive. The presence of the mutation did not correlate with age at diagnosis, organ involvement, disease extent, response to initial treatment, development of diabetes insipidus and relapse risk. In our series the prevalence of the BRAFV600E mutation is at the lower range of the relative percentage found in children, but in line to that obtained in previous studies of adult patients with LCH that have found an up to 50% prevalence of the BRAFV600E mutation in these patients. Further studies with a larger number of adults are needed to identify the exact prevalence of mutations in the RAS-RAF-MEK-ERK pathway and their role on clinical parameters and disease outcomes.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2022.2029988 .