Background/Objectives: Adequate vitamin D levels are critical for overall health, yet vitamin D deficiency remains prevalent. This study aims to evaluate the efficacy and safety of a standardized weekly supplementation regimen of 100 μg calcifediol for patients with varying degrees of vitamin D deficiency. Methods: A post hoc pool analysis was conducted from a randomized, double-blind, placebo-controlled, multicenter, two-cohort trial. Cohort 1 included vitamin D mild deficiency patients (25(OH)D levels > 10 < 20 ng/mL) and Cohort 2 severe deficiency patients (25(OH)D levels ≤ 10 ng/mL). As both had placebo and weekly calcifediol 100 μg arms (ratio 1:2), a pooled analysis of safety and efficacy was conducted. The primary outcome was the percentage of subjects achieving 25(OH)D levels ≥ 20 ng/mL and/or ≥30 ng/mL at various time points. Results: A total of 401 participants across both cohorts were included in the analysis, 130 who received a placebo and 271 calcifediol 100 µg weekly. By week 52, 94.5% of individuals in the calcifediol group achieved 25(OH)D levels ≥ 20 ng/mL, compared to 25.3% in the placebo group (p < 0.0001). At this same week, 80.5% of subjects in the calcifediol group, but none in the placebo group (p < 0.0001), had 25(OH)D levels ≥ 30 ng/mL. The mean 25(OH)D level plateaued around 40.7 ng/mL from weeks 16 to 52. The frequency of treatment-emergent adverse events was similar in both groups, placebo and calcifediol. Conclusions: Weekly supplementation of 100 μg calcifediol effectively restores vitamin D levels in individuals with both mild and severe deficiencies, demonstrating a favourable safety profile.

Chronic kidney disease (CKD) is a common complication of patients affected by chronic hypoparathyroidism managed with conventional therapies. However, no data are currently available regarding the endocrine and metabolic determinants of renal function in these patients.

This was a multicenter observational study performed in three health-care centres. Patients with hypoparathyroidism were consecutively enrolled during follow-up visits in 2022-2023. These exclusion criteria were adopted: patients managed with dialysis, proteinuria (>200 mg/24 h), use of antihypertensive drugs including thiazides, ACE-inhibitors, angiotensin-II-receptor antagonists, alpha-beta blocking-agents, aldosterone-antagonists, and insulin-treated diabetes.

A total of 46 patients were enrolled. Median age was 53 years, 34 (74%) were female and the median disease duration was 11 years. In all patients, the calcium-phosphate product was within the normal range. The 23.7% of patients was obese (BMI ≥ 30) and CKD (defined with an eGFR < 60 mL/min1.73m2) was found in the 21.7% of patients. Patients with CKD were older, affected by a longer-disease, more frequently obese and with higher BMI. In multivariate analyses, obesity resulted as the only significant independent risk factor associated with CKD. In addition, a significant negative correlation was found between BMI and eGFR, and ROC analyses showed a significant global-performances of BMI to predict CKD. Patients with CKD were characterized also by higher FGF23 levels. A significant negative correlation was found between FGF23 and eGFR, however, evaluating separately those with and without CKD, this correlation remained significant only in the second group.

For the first-time, obesity was demonstrated to be independently associated with CKD in patients with hypoparathyroidism, and a blunted eGFR-related response of FGF23 was shown in patients with CKD potentially worsening the renal function in the context of hypoparathyroidism.

Vitamin D plays a crucial role in the regulation of the immune system, with immunomodulatory effects that are key in the prevention of colorectal cancer (CRC). Over the past decades, research has shown that this steroid hormone impacts much more than bone health, significantly influencing immune responses. Vitamin D enhances immune organ functions such as the spleen and lymph nodes, and boosts T-cell activity, which is essential in defending the body against tumors. Additionally, vitamin D mitigates inflammatory responses closely linked to cancer development, reducing the inflammation that contributes to CRC. It acts via vitamin D receptors (VDRs) expressed on immune cells, modulating immune responses. Adequate vitamin D levels influence gene expression related to inflammation and cell proliferation, inhibiting tumor development. Vitamin D also activates mechanisms that suppress cancer cell survival, proliferation, migration, and metastasis. Low levels of vitamin D have been associated with an increased risk of CRC, with deficiency correlating with higher disease incidence. Lifestyle factors, such as a diet high in red meat and calories but low in fiber, fruits, and vegetables, as well as physical inactivity, contribute significantly to CRC risk. Insufficient calcium and vitamin D intake are also linked to disease occurrence and poorer clinical outcomes. Maintaining optimal vitamin D levels and adequate dietary intake is crucial in preventing CRC and improving patient prognosis. This review explores the role of vitamin D in immune regulation and summarizes findings from randomized clinical trials assessing the effects of vitamin D supplementation on CRC outcomes.

Skeletal comorbidities are frequent and clinically relevant findings in Cushing's syndrome (CS) since an uncoupled suppressed bone formation and enhanced bone resorption leads to a marked skeletal damage with a rapid increase of fracture risk. Reduced Bone Mineral Density (BMD) has been consistently reported and osteopenia or osteoporosis are typical findings in patients with CS. Vertebral Fractures (VFs) are frequently reported and may occur even in patients with an only mild reduction of BMD. Since CS is diagnosed late due to often difficult biochemical and radiological confirmation as well as to signs and symptoms common in other much more frequent diseases an approach suggested for overcoming underdiagnosis is to screen patients with manifestations which may overlap with those of CS such as arterial hypertension, diabetes mellitus and osteoporosis. Our review will focus on the rationale and best practice for screening osteoporotic patients for CS.

There is still uncertainty regarding the optimal serum levels 25-Hydroxy-vitamin D [25(OH)D] and the most effective supplementation strategies, including the choice of molecule and its dosing frequency. The aim of the study is to compare the effects of calcifediol versus two different frequencies of cholecalciferol administration on vitamin D supplementation, and to identity the key parameters that predict response to treatment.

This retrospective, real-world cohort study included 105 patients, who were divided into three groups. Group 1 (n = 21) received cholecalciferol 50,000 international units (UI) once a month, Group 2 (n = 27) received cholecalciferol 25,000 UI every two weeks, and Group 3 (n = 57) received calcifediol 0.266 mg (mg) once a month. The primary outcome measured was the delta increase in 25(OH)D levels after 6 months of treatment, compared to pre-treatment levels.

The study revealed a significant greater delta increase in 25(OH)D levels in Group 1, which received cholecalciferol 50,000 IU once a month, compared to the other two groups. However, multiple regression analysis indicated that neither the type of molecule nor the frequency of administration independently influenced the treatment outcome. Only pre-treatment serum 25(OH)D levels were found to significantly affect the outcome. Based on the receiver operating characteristic curve, serum 25(OH)D levels below 19.5 ng/dL were predictive of a doubling of pre-treatment values, with high sensitivity and specificity.

Pre-treatment serum 25(OH)D levels are valuable for selecting patients who should undergo supplementation. This finding suggests the importance of tailoring therapy according to the degree of vitamin D deficiency.

Vitamin D deficiency is associated with poorer functional outcomes and increased complication rates after total knee arthroplasty (TKA). Yet, there is no longer term study evaluating vitamin D levels and supplementation after TKA. Our study aimed to compare quantitative vitamin D levels and supplementation regimens after TKA stratified by patient sex and race.

A retrospective cohort study of primary TKA patients at a single hospital from 2015 to 2022 was conducted. We analyzed vitamin D preoperatively and postoperatively up to 2 years. Vitamin D deficiency was defined as <30 ng/mL. A subgroup analysis was conducted in patients with vitamin D <21 ng/mL. Supplementation categories included none, low (<1,001 IU), medium (1,001 to 5,000 IU), and high (>5,000 IU).

A total of 400 (66.0% female) patients who underwent 430 primary TKA procedures were included, and 65.3% received supplementation. Patients who were vitamin D sufficient preoperatively demonstrated higher vitamin D levels and ability to maintain sufficiency postoperatively using low-dose supplementation compared with no supplementation ( P = 0.004). Those who were vitamin D deficient preoperatively demonstrated higher vitamin D levels postoperatively using medium to high doses ( P = 0.02). For patients who became deficient postoperatively, supplementation was associated with achieving repletion at an average of 10.2 months ( P < 0.001). Black patients demonstrated 2.8 times higher odds of having a vitamin D level less than 30 ng/mL ( P = 0.03).

Our study demonstrated that low-dose vitamin D supplementation (<1,001 IU) was beneficial for vitamin D-sufficient TKA patients to achieve higher levels and maintain vitamin D sufficiency. Vitamin D-deficient TKA patients benefitted from medium-to-high dose supplementation (1,001 to 5,000+), but only 33.7% achieved vitamin D repletion. This work highlights the need to continue vitamin D surveillance postoperatively and the need to continue vitamin D repletion.

A global deficiency in vitamin D is now widely prevalent. Extensive scientific research has provided compelling evidence of the detrimental effects of vitamin D deficiency on the skeletal system. Furthermore, vitamin D supplementation not only helps prevent bone fractures but may also slow the progression of various conditions, such as diabetes, autoimmune disorders, and cardiovascular disease. Achieving optimal circulating vitamin D levels can be challenging, particularly in certain clinical scenarios. Moreover, the effect of vitamin D supplementation varies depending on factors such as body weight, pregnancy status, absorption capacity, metabolic rate, and renal function. This review aims to explore which vitamin D formulations are most effective in specific clinical contexts where reaching adequate vitamin D levels may not be straightforward.

In addition to its classical role in calcium and phosphate metabolism regulation, vitamin D also has an important impact on immunity modulation. Vitamin D regulates the immune response, shifting from a proinflammatory state to a more tolerogenic one by increasing the release of anti-inflammatory cytokines while downregulating proinflammatory cytokines. Thus, low levels of vitamin D have been associated with an increased risk of developing autoimmune diseases like multiple sclerosis and type 1 diabetes. Furthermore, this prohormone also enhances the release of well-known antimicrobial peptides, like cathelicidin LL-37 and β-defensins; therefore, it has been proposed that vitamin D serum levels might be related to the risk of well-known pathogen infections, including herpesviruses. These are a group of widely spread viral pathogens that can cause severe encephalitis or tumors like Kaposi's sarcoma and Burkitt lymphoma. However, there is no consensus on the minimum levels of vitamin D or the recommended daily dose, making it difficult to establish a possible association between these two factors. This narrative non-systematic review will analyze the mechanisms by which vitamin D regulates the immune system and recent studies about whether there is an association between vitamin D serum levels and herpesvirus infections.

There is a growing need to predict the severity of vitamin D deficiency (VDD) through non-invasive methods due to its significant global health concerns. For vitamin D-level assessments, the 25-hydroxy vitamin D (25-OH-D) blood test is the standard, but it is often not a practical test. This study is focused on developing a machine learning (ML) model that is clinically acceptable for accurately detecting vitamin D status and eliminates the need for 25-OH-D determination while addressing overfitting. To enhance the capacity of the classification system to predict multiple classes, preprocessing procedures such as data reduction, cleaning, and transformation were used on the raw vitamin D dataset. The improved whale optimization (IWOA) algorithm was used for feature selection, which optimized weight functions to improve prediction accuracy. To gauge the effectiveness of the proposed IWOA algorithm, evaluation metrics like precision, accuracy, recall, and F1-score were used. The results showed a 99.4% accuracy, demonstrating that the proposed method outperformed the others. A comparative analysis demonstrated that the stacking classifier was the superior choice over the other classifiers, highlighting its effectiveness and robustness in detecting deficiencies. Incorporating advanced optimization techniques, the proposed method's promise for generating accurate predictions is highlighted in the study.

Hypoparathyroidism is characterized by inadequate parathyroid hormone (PTH) secretion or action and results in hypocalcaemia, and can lead to hyperphosphataemia and hypercalciuria. Most cases of hypoparathyroidism occur as a complication of surgery, with the remainder due to causes including autoimmune disease, genetic causes, infiltrative diseases, mineral deposition or due to abnormalities in serum levels of magnesium. Hypoparathyroidism can cause multisystem disease, with long-term complications resulting from ectopic calcification as well as renal complications with nephrocalcinosis, nephrolithiasis and renal impairment in addition to respiratory, cardiac or neurological manifestations. Conventional therapy consists of oral calcium salts and active vitamin D but it has limitations, including fluctuations in serum levels of calcium and a high pill burden, and can increase the risk of long-term complications. By contrast, PTH replacement therapy can effectively achieve normal serum levels of calcium, and lower serum levels of phosphate. The long-acting PTH analogue, palopegteriparatide, has been shown to normalize urine levels of calcium. In addition, PTH replacement therapy reduces the pill burden. Palopegteriparatide is also associated with improved quality of life in comparison to conventional therapy. This Review summarizes current recommendations regarding the pathophysiology, evaluation and management of hypoparathyroidism and also references the 2022 international hypoparathyroidism guidelines. Palopegteriparatide has now been approved as PTH replacement therapy for hypoparathyroidism. Emerging therapies will also be presented in this Review.

Osteosarcopenia is an emerging clinical condition highly prevalent in the older people. Affected subjects due to their intrinsic skeletal fragility and propensity to falls are at elevated risk of hip fractures which can increase morbidity and mortality. Strategies for attenuating the impact of predisposing factors on hip fractures are not yet well defined and should derive from multidisciplinary care and collaborations. Our aim was to narratively review available data on the preventive role of vitamin D and hip protectors on hip fractures in older patients with sarcopenia. Older subjects are at high risk of vitamin D deficiency and of falls due to several concomitant factors besides osteosarcopenia. Vitamin D protective actions against hip fractures may be mediated by both skeletal (increased mineralization) and extra-skeletal (reduced risk of falls) actions. Hip protectors may act downstream attenuating the effects of falls although their use is still not yet enough widespread due to the suboptimal compliance obtained by traditional hard devices. Concomitant use of vitamin D and hip protectors may represent an effective strategy in the prevention of hip fractures which need to be tested in ad hoc designed clinical trials.

The body has evolved homeostatic mechanisms to maintain free levels of Ca+2 and 1,25-dihydroxyvitamin D (1,25(OH)2D) within narrow physiological ranges. Clinical guidelines emphasize important contributions of parathyroid hormone (PTH) in maintaining this homeostasis.

This work aimed to investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status.

This crossover clinical trial studied community participants before and after VitD3 supplementation. Participants included 11 otherwise healthy individuals with VitD deficiency (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL). VitD3 supplements (50 000 IU once or twice a week depending on body mass index, for 4-6 weeks) were administered to achieve 25(OH)D of 30 ng/mL or greater.

VitD3 supplementation significantly increased mean 25(OH)D by 2.7-fold and 24,25-dihydroxyvitamin D (24,25(OH)2D) by 4.3-fold. In contrast, mean levels of PTH, fibroblast growth factor-23, and 1,25(OH)2D did not change. Mathematical modeling suggested that 24-hydroxylase activity was maximal for 25(OH)D 50 ng/mL or greater and achieved a minimum (∼90% suppression) with 25(OH)D less than 10 to 20 ng/mL. The 1,25(OH)2D/24,25(OH)2D ratio better predicted modeled 24-hydroxylase activity (h) (ρ = -0.85; P = .001) compared to total plasma 25(OH)D (ρ = 0.51; P = .01) and the 24,25(OH)2D/25(OH)D ratio (ρ = 0.37; P = .3).

Suppression of 24-hydroxylase provides a first line of defense against symptomatic VitD deficiency by decreasing metabolic clearance of 1,25(OH)2D. The 1,25(OH)2D/24,25(OH)2D ratio provides a useful index of VitD status since it incorporates 24,25(OH)2D levels, and therefore provides insight into 24-hydroxylase activity. When VitD availability is limited, this suppresses 24-hydroxylase activity-thereby decreasing the level of 24,25(OH)2D and increasing the 1,25(OH)2D/24,25(OH)2D ratio. Thus, an increased 1,25(OH)2D/24,25(OH)2D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD deficiency.

Vitamin D deficiency is highly prevalent in India, yet no standardized guidelines exist for classifying vitamin D status or its prevention and treatment. Even more, there is no consensus specific to vitamin D supplementation for the Indian population, and there are inconsistencies in the cut-off values for deficiency, severe deficiency, and insufficiency across various guidelines, which this evidence-based consensus seeks to resolve, thus guiding healthcare professionals in identifying, preventing, and managing vitamin D deficiency. An expert group of 41 endocrinologists from across India developed the consensus using the DELPHI method, achieving over 90% agreement on all recommendations. The consensus defines vitamin D deficiency, severe deficiency, and insufficiency, recommending supplementation strategies to maintain physiological 25(OH) D levels of 40-60 ng/mL (100-150 nmol/L). Tailored treatment regimens for neonates, infants, children, adolescents, adults, the elderly, pregnant and lactating women, and individuals with co-morbid conditions are provided to ensure optimal health for all age groups in India.

Autism spectrum disorder (ASD) presents unique challenges related to feeding and nutritional management. Children with ASD often experience feeding difficulties, including food selectivity, refusal, and gastrointestinal issues. Various interventions have been explored to address these challenges, including dietary modifications, vitamin supplementation, feeding therapy, and behavioral interventions.

To provide a comprehensive overview of the current evidence on nutritional management in ASD. We examine the effectiveness of dietary interventions, vitamin supplements, feeding therapy, behavioral interventions, and mealtime practices in addressing the feeding challenges and nutritional needs of children with ASD.

We systematically searched relevant literature up to June 2024, using databases such as PubMed, PsycINFO, and Scopus. Studies were included if they investigated dietary interventions, nutritional supplements, or behavioral strategies to improve feeding behaviors in children with ASD. We assessed the quality of the studies and synthesized findings on the impact of various interventions on feeding difficulties and nutritional outcomes. Data extraction focused on intervention types, study designs, participant characteristics, outcomes measured, and intervention effectiveness.

The review identified 316 studies that met the inclusion criteria. The evidence indicates that while dietary interventions and nutritional supplements may offer benefits in managing specific symptoms or deficiencies, the effectiveness of these approaches varies. Feeding therapy and behavioral interventions, including gradual exposure and positive reinforcement, promise to improve food acceptance and mealtime behaviors. The findings also highlight the importance of creating supportive mealtime environments tailored to the sensory and behavioral needs of children with ASD.

Nutritional management for children with ASD requires a multifaceted approach that includes dietary modifications, supplementation, feeding therapy, and behavioral strategies. The review underscores the need for personalized interventions and further research to refine treatment protocols and improve outcomes. Collaborative efforts among healthcare providers, educators, and families are essential to optimize this population's nutritional health and feeding practices. Enhancing our understanding of intervention sustainability and long-term outcomes is essential for optimizing care and improving the quality of life for children with ASD and their families.

Bone impairment associated with Cushing's disease (CD) is a complex disorder, mainly involving deterioration of bone quality and resulting in an increased fracture rate, often despite normal bone mineral density. Bone complications are common in patients with CD at the time of diagnosis but may persist even after successful treatment. There is currently no agreement on the optimal diagnostic methods, thresholds for anti-osteoporotic therapy and its timing in CD. In this review, we summarize the current data on the pathophysiology, diagnostic approach and management of bone complications in CD.

Active acromegaly may lead to irreversible complications. Among them, acromegaly osteopathy and fragility (vertebral and hip) fractures have emerged as frequent and precocious events in the natural history of the disease, being correlated with longer disease duration and higher growth hormone (GH) levels, accounting for patients' reported poor quality of life, physical performance and other life-impacting complications. Differently from primary osteoporosis, bone mineral density is not a reliable tool to predict fracture risk in this clinical setting, as patients with active disease frequently have normal or slightly reduced bone mass; whereas bone quality is particularly compromised, as determined by low trabecular bone score (TBS) in patients with active disease as compared to healthy controls or patients with cured/controlled disease. The evidence of impaired bone microstructure has been profoundly investigated with different computed tomography (CT) techniques, reporting low trabecular number and thickness as well as wide but more porous cortical bone, providing an explanation for such a high prevalence of vertebral fractures (up to 40-50% in selected cohorts). Since data on bone-active drugs are scanty, disease control remains a cornerstone to prevent fractures. Nonetheless, some potential protective effects may derive from vitamin D supplementation and pasireotide therapies, independently from disease status. Aim of this manuscript is to review the current and emerging evidence on skeletal fragility in patients with active and resistant acromegaly.

Prolactinomas account for more than half of pituitary adenomas, and besides their clinical impact on fertility and gonadal function, they lead to detrimental effects on bone. Patients with prolactinoma are prone to deterioration of bone structure caused not only by prolactin (PRL) induced hypogonadism but also by its direct actions on bone cells and calcium metabolism. However, clinical studies have shown inconsistent evidence regarding whether PRL could have a deleterious effect independently from gonadal insufficiency on skeletal integrity. Seminal studies from our group reported an increased prevalence of vertebral fractures (VFs) in both female and male patients with prolactinoma. Treatment of prolactinoma with dopamine agonists can restore gonadal function and improve bone mineral density. Since the presence of VFs may be related to more aggressive disease, bone comorbidities in prolactinoma should be managed by a multidisciplinary team in line with the recent concept of 'pituitary tumors centers of excellence'. The review aims to evaluate the mechanism of PRL actions on bone, as well as to provide practical indications for a modern approach to the management of skeletal complications of patients with prolactin-secreting adenoma considering different clinical characteristics and outcomes.

Metabolic and bariatric surgery (MBS) is often considered to be associated with macro- and micronutrient deficiency. A possible treatment option can be the implementation of pancreatic enzyme replacement (PERT) and may lead to better outcomes. We designed a prospective trial investigating the possible impact of PERT in patients undergoing MBS at a high-volume center.

A prospective two-arm randomized controlled trial was conducted on patients who underwent either sleeve gastrectomy or gastric bypass procedures at a high-volume center. Patients underwent bariatric surgery and follow-up examinations at 3, 6, and 12 months after surgery. Patients were stratified either to the treatment group with PERT or to the control group. The primary endpoint of the study was a change in BMI. Lab testing was carried out to measure secondary endpoints, including albumin and vitamin D levels.

Overall, 204 patients were enrolled. Due to missing follow-ups, surgical complications, and side effects due to Kreon medication, 65 were excluded. Analysis of primary endpoints indicates that PERT does not lead to slower weight loss or BMI reduction. Analysis of secondary endpoints showed significantly better vitamin D levels in patients undergoing MBS and PERT. No statistical difference was seen regarding albumin. In both arms, fatty liver disease improved. Quality of life is positively judged as comparable by patients in both groups.

Herein, we show an association between PERT and higher vitamin D levels in patients undergoing MBS. An optimized enzymatic environment due to PERT may therefore result in higher vitamin D levels and may improve clinical outcomes in patients undergoing MBS.

Epidemiological studies have shown that subnormal levels of vitamin D (25[OH]D) are associated with a more aggravated clinical course of ulcerative colitis [UC]. Despite an increased focus on the therapeutic importance of vitamin D and vitamin D receptor [VDR] signalling, the mechanisms underlying the effects of the vitamin D-VDR axis on UC remain elusive. Therefore, we aimed to investigate whether exposure to active vitamin D (1,25[OH]2D3/VDR) signalling in human organoids could influence the maintenance of the colonic epithelium.

Intestinal VDR expression was studied by immunohistochemistry, RNA expression arrays, and single-cell RNA sequencing of colonic biopsy specimens obtained from patients with UC and healthy individuals. To characterise the functional and transcriptional effects of 1,25[OH]2D3, we used patient-derived colonic organoids. The dependency of VDR was assessed by knocking out the receptor with CRISPR/Cas9.

Our results suggest that 1,25[OH]2D3/VDR stimulation supports differentiation of the colonic epithelium and that impaired 1,25[OH]2D3/VDR signalling thereby may compromise the structure of the intestinal epithelial barrier, leading to flares of UC. Furthermore, a transcriptional response to VDR activity was observed primarily in fully differentiated cells at the top of the colonic crypt, and this response was reduced during flares of UC.

We identified an important role of vitamin D signalling in supporting differentiated cell states in the human colonic epithelium, and thereby maintenance of the intestinal barrier integrity. This makes the vitamin D-VDR signalling axis an interesting target for therapeutic efforts to achieve and maintain remission in patients with UC.

Low vitamin D levels were reported to negatively influence the outcomes of acute COVID-19, as well as other biochemical markers were linked to COVID-19, including microRNAs (miRNAs). This study aimed to prospectively evaluate miRNAs and vitamin D relationship in predicting COVID-19 outcomes.

COVID-19 patients were part of a previously reported cohort and enrolled in a matched-ratio based on the presence/or not of severe disease at hospital admission. 25(OH) vitamin D levels and miRNAs expression were evaluated.

Patients affected by non-severe COVID-19 were characterized by a higher expression of miRNAs hsa-miR-3115 and hsa-miR-7151-3p, as compared to those affected by severe disease. In non-severe patients, these miRNAs were more frequently expressed in those who subsequently did not develop worsening outcomes. In addition, patients with miRNA-7151 expression and without worsening disease were characterized by higher 25(OH) vitamin D levels and lower prevalence of vitamin D deficiency.

The expression of two novel miRNAs was reported for the first-time to be associated with a less severe COVID-19 form and to prospectively predict the occurrence of disease outcome. Furthermore, the association observed between vitamin D deficiency and lack of miRNA-7151 expression in COVID-19 patients with worse outcomes may support the hypothesis that the co-existence of these two conditions may have a strong negative prognostic role.

Vitamin D encapsulation can significantly improve its bioavailability, stability, and solubility. Various biopolymers viz. whey protein isolate, carboxymethyl cellulose, alginate and gum arabic were studied for their potential to be used as wall material and gum arabic was selected for encapsulating vitamin D3 as it possesses lesser particle size, apparent viscosity and better stability in terms of zeta potential. Box Behnken design was employed for optimizing the process conditions for developing vitamin D3 nanoemulsion. Box Behnken design was constructed using ultrasonic amplitude, sonication time and vitamin D3/wall material percent as independent factors. The optimum conditions obtained were ultrasonic amplitude (80 %), sonication time (12 min) and vitamin D3/wall material percent (5). The designed nanoemulsion showed a particle size of 20.04 nm, zeta potential of -28.2 mV, and encapsulation efficiency of 71.9 %. Chemical interactions were observed in the developed nanoemulsion as demonstrated by Differential scanning calorimeter thermograms and Fourier transform infrared spectra of the nanoemulsion. The Korsmeyer-Peppas model was the most suitable for describing the release of vitamin D3 from the nanoemulsion. Fabricated nanoemulsion has the potential to be used in food and pharmaceutical industries.

The association between vitamin D and kidney stones is characterized by a remarkable multi-dimensional complexity involving numerous physiological and metabolic pathways. Vitamin D is pivotal in maintaining calcium-phosphorus metabolic homeostasis and bone health. However, fluctuations in its intake, whether excessive or insufficient, May potentially increase the risk of kidney stones. Vitamin D exerts its influence on kidney stone formation indirectly by increasing the efficiency of intestinal calcium absorption and regulating renal calcium excretion. Moreover, there is a robust correlation between various states of vitamin D, particularly its active form, 1,25-dihydroxyvitamin D, and the development of numerous kidney stones. This finding underscores the necessity of individualized medical treatment in vitamin D supplementation and kidney stone prevention. When developing treatment strategies, it is essential to consider the patient's genetic background, lifestyle, environmental factors, and overall health. To prevent the formation of kidney stones, it is recommended that patients adopt a comprehensive approach, which May include measures such as moderate sun exposure, dietary modification, moderate exercise, and weight management. These preventive measures are designed to maintain healthy calcium and phosphorus metabolism and reduce kidney stone formation risk. Future studies should aim to elucidate the detailed mechanisms of vitamin D metabolism, individual differences, and the role of genes in this process. Furthermore, the role of lifestyle interventions in preventing kidney stones requires greater attention. Moreover, the implementation of large-scale, long-term prospective studies and randomized controlled trials will facilitate the assessment of the actual effects of diverse vitamin D supplementation strategies, thereby providing a robust scientific foundation for advancing more precise prevention strategies and clinical guidelines.

The 6th International Conference, "Controversies in Vitamin D," was convened to discuss controversial topics, such as vitamin D metabolism, assessment, actions, and supplementation. Novel insights into vitamin D mechanisms of action suggest links with conditions that do not depend only on reduced solar exposure or diet intake and that can be detected with distinctive noncanonical vitamin D metabolites. Optimal 25-hydroxyvitamin D (25(OH)D) levels remain debated. Varying recommendations from different societies arise from evaluating different clinical or public health approaches. The lack of assay standardization also poses challenges in interpreting data from available studies, hindering rational data pooling and meta-analyses. Beyond the well-known skeletal features, interest in vitamin D's extraskeletal effects has led to clinical trials on cancer, cardiovascular risk, respiratory effects, autoimmune diseases, diabetes, and mortality. The initial negative results are likely due to enrollment of vitamin D-replete individuals. Subsequent post hoc analyses have suggested, nevertheless, potential benefits in reducing cancer incidence, autoimmune diseases, cardiovascular events, and diabetes. Oral administration of vitamin D is the preferred route. Parenteral administration is reserved for specific clinical situations. Cholecalciferol is favored due to safety and minimal monitoring requirements. Calcifediol may be used in certain conditions, while calcitriol should be limited to specific disorders in which the active metabolite is not readily produced in vivo. Further studies are needed to investigate vitamin D effects in relation to the different recommended 25(OH)D levels and the efficacy of the different supplementary formulations in achieving biochemical and clinical outcomes within the multifaced skeletal and extraskeletal potential effects of vitamin D.

Endocrine regulation of bone metabolisms is the focus of the "Skeletal Endocrinology" series of meetings.

To report on the outcome of the discussion on the role of vitamin D/PTH axis in endocrine osteopathies held during the 10th Skeletal Endocrinology Meeting which took place in Stresa (Italy) in March 2023.

Vitamin D/PTH axis has relevant influence on several outcomes in the general population and in patients affected by endocrinopathies such as hypoparathyroidism and secreting pituitary adenomas.

Assessing the status of the vitamin D/PTH axis and using vitamin D and PTH as therapeutic agents is mandatory in several endocrine-related bone metabolic conditions.

The research aimed to determine the importance of vitamin D and markers of bone metabolism in the overall assessment of bone mineralization during a child's first year of life.

The 198 children were selected by screening all infants seen at our pediatric clinic over a 2-year period from 2020-2022 and including those who met the eligibility criteria of being aged 0 to 1 year, healthy with no chronic conditions, and not on vitamin D supplementation. Children were divided into 3 groups depending on the content of vitamin D in the blood serum: sufficient, insufficient, and deficient. The markers of bone tissue status included: markers of mineral metabolism (calcium, phosphorus, parathyroid hormone, calcitonin), a marker of bone formation (osteocalcin), resorption marker (deoxypyridinoline). Laboratory values were obtained at the time of study enrollment during the initial study visit. Labs were not repeated during the course of the study.

A quarter of the infants exhibited vitamin D deficiency at enrollment with serum 25OHD concentrations below 20 ng/mL, which showed a positive correlation with serum calcium and phosphorus -concentrations and a negative correlation with PTH, while osteocalcin and deoxypyridinoline concentrations remained consistent regardless of vitamin D status.

The study's practical significance allows for the recommendation of using vitamin D -concentrations as a marker to detect bone formation and mineral metabolism disorders in children during their first year of life. By identifying and addressing these issues early on, the health care system aims to ensure better musculoskeletal health for children.

Vertebral fractures (VFs), the hallmark of skeletal fragility, have been reported as an emerging complication in patients with pituitary diseases associated with hormonal excess and/or deficiency, independently from bone mineral density. Non-functioning pituitary adenoma (NFPA) is amongst the most frequent pituitary adenomas; however, skeletal health in this context has never been investigated. We aimed at assessing the prevalence and the determinants of morphometric VFs in patients with NFPA.

We enrolled 156 patients (79 M/77F, mean age 55.75 ± 12.94 years) at admission in Neurosurgery Unit before trans-sphenoidal surgery and compared them with an age and sex-matched control group of subjects with neither history/risk factors for secondary osteoporosis nor pituitary disorders. We performed a vertebral morphometric evaluation of the thoracic spine on pre-operative X-ray images (MTRx) and collected biochemical, demographic, and clinical data from the entire cohort.

The prevalence of thoracic VFs in patients with NFPA was significantly higher than the control group (26.3% vs. 10.3%; p < 0.001). In the NFPA group, 20 patients (48.8% of the fractured patients) showed multiple VFs, 14 (34.1% of them) showed moderate/severe VFs. Patients with VFs were significantly older and had lower serum free triiodothyronine (fT3) levels than non-fractured ones (p = 0.002 and p = 0.004; respectively). The prevalence of secondary male hypogonadism was higher among men with VFs as compared to those with no VFs (72% vs. 48.1%; p = 0.047). Consistently, total testosterone levels in males were significantly lower in fractured patients than in non-fractured ones (p = 0.02). The prevalence of gonadotroph adenomas was significantly higher among patients with VFs (p = 0.02). In multiple logistic regression analysis, older age and lower serum fT3 levels were independent factors predicting the risk for VFs.

For the first time, we reported a high prevalence of thoracic radiological VFs in patients with NFPAs. Our data should prompt clinicians to proceed with a clinical bone fragility evaluation already during the diagnostic work-up, particularly in those with concomitant hypogonadism, or in those with older age and/or with lower fT3.

Vitamin D3, a fat-soluble vitamin known for its critical function in calcium homeostasis and bone health, is gaining interest for its anticancer properties. Observational studies have suggested a negative relationship between vitamin D levels and the incidence of some malignancies throughout the years, prompting substantial investigation to find its anticancer effects. The purpose of this comprehensive review is to investigate the diverse function of vitamin D3 in cancer prevention and therapy. We explored the molecular mechanism underlying its effects on cancer cells, which range from cell cycle control and death to angiogenesis and immune response modulation. Insights from in vitro and in vivo studies provide valuable evidence supporting its anticancer potential. Furthermore, we look at epidemiological and clinical studies that investigate the relationship between vitamin D3 levels and cancer risk or treatment results. Vitamin D3 supplementation's safety profile and cost-effectiveness increase its attractiveness as an adjuvant therapy in conjunction with traditional treatment regimens. Our critical review of the current literature provides an in-depth understanding of vitamin D3's anticancer effect, covering the obstacles and possibilities in realizing its promise for cancer prevention and therapy. The findings of this study might pave the way for the development of innovative treatment techniques that take use of the advantages of vitamin D3 to fight cancer and improve patient care. As research progresses, a better understanding of vitamin D3's anticancer processes will surely simplify its incorporation into personalized cancer care techniques, hence enhancing patient outcomes in the battle against cancer.

In recent years, lipophilic bioactive compounds have gained much attention due to their wide range of health-benefiting effects. However, their low solubility and susceptibility to harsh conditions such as high temperatures and oxidation stress have limited their potential application for the development of functional foods and nutraceutical products in the food industry. Nanoencapsulation can help to improve the stability of hydrophobic bioactive compounds and protect these sensitive compounds during food processing conditions, thus overcoming the limitation of their pure use in food products. The objective of this work was to co-entrap vitamin D3 (VD3) and omega 3 (ω3) as hydrophobic bioactive compounds providing significant health benefits in beeswax solid lipid nanoparticles (BW. SLNs) for the first time and to investigate the effect of different concentrations of VD3 (5 and 10 mg/mL) and ω3 (8 and 10 mg) on encapsulation efficiency (EE). Our findings revealed that the highest EE was obtained for VD3 and ω3 at concentrations of 5 mg/mL and 10 mg, respectively. VD3/ω3 loaded BW. SLNs (VD3/ω3-BW. SLNs) were prepared with zeta potential and size of-32 mV and 63.5 nm, respectively. Results obtained by in-vitro release study indicated that VD3 release was lower compared to ω3 in the buffer solution. VD3 and ω3 incorporated in BW. SLNs demonstrated excellent stability under alkaline and acidic conditions. At highly oxidizing conditions, 96.2 and 90.4% of entrapped VD3 and ω3 remained stable in nanoparticles. Moreover, nanoparticles were stable during 1 month of storage, and no aggregation was observed. In conclusion, co-loaded VD3 and ω3 in BW. SLNs have the great potential to be used as bioactive compounds in food fortification and production of functional foods.

Vitamin D status and its association with age-related decline in physical performance and strength have already been highlighted in various ways, but data on the situation in developing countries are scarce. This study aimed to investigate vitamin D status, its association with muscle mass and function, and other potential determinants such as age, sex, lifestyle factors (physical activity, dietary behavior), self-perceived health status, medication intake, education and financial situation in adults from Kosovo.

This cross-sectional study included 297 participants (54.5% women), aged ≥ 40 years. Serum 25-hydroxyvitamin D (25(OH)D) concentration, hand grip strength and physical performance tests, body composition, vitamin D dietary intake and knowledge were assessed. The interaction between serum 25(OH)D status, lifestyle factors and muscle traits was investigated.

Vitamin D deficiency (< 50 nmol/L) was observed in 47.5% of the total population, of whom 14.7% of them were severely deficient (< 30 nmol/L). No associations were found between 25(OH)D concentration and age. Daily dietary intake of vitamin D was low (1.89 ± 0.67 µg) and 87.6% of individuals did not take vitamin D supplements. However, vitamin D supplementation was the only variable that added statistical significance (p < 0.05) to the prediction of vitamin D status (3.8%). On the other hand, age, medication intake and vitamin D level contributed significantly to the overall regression model, explaining 24.9% of the 30-s chair stand performance as an indicator of lower-body strength endurance.

Vitamin D deficiency is highly prevalent among community-dwelling adults in Kosovo and low serum 25(OH)D has been associated with low muscle strength. This implies an urgent need for the development of comprehensive prevention strategies, focusing on pharmacological (supplementation) but also on non-pharmacological strategies such as education, food fortification or lifestyle advices.

Vitamin D, as a steroid hormone, has multiple effects on human body and its deficiency has been associated with an increased risk of heart failure (HF) and unfavorable outcomes. The present study investigated the prevalence of vitamin D deficiency (VDD) and its relationship with cardiometabolic parameters in patients hospitalized for HF living in the city of Recife (latitude 8° South).

Analytical cross-sectional study, with men and women aged 40-64 years. The HF group was recruited during hospitalization due to decompensation. A matched control group was recruited from the general endocrine clinics. Vitamin D status was assessed by measuring serum 25-hydroxyvitamin D (25OHD), considering deficiency when 25OHD <20 ng/mL (<50 nmol/L).

A total of 243 patients were evaluated (HF group: 161, control group: 82). Lower serum 25OHD levels were observed in the HF group (25.2±9.4 vs. 30.0±7.7ng/mL; p<0.001), as well as a higher prevalence of VDD (27.3% vs. 9.8%; prevalence ratio, 2.80; 95% confidence interval, 1.38-5.67; p=0.002). In patients with HF, VDD was associated with diabetes mellitus (65.9% vs. 41.0%; p=0.005) and female sex (65.9% vs. 44.4%; p=0.015). In the subgroup with VDD, higher values of hemoglobin A1c (7.9% [6.0-8.9] vs. 6.2% [5.7-7.9]; p=0.006) and dyslipidemia were also observed.

We found higher rates of VDD in patients hospitalized for HF and this was associated with deleterious laboratory metabolic parameters.

Celiac disease (CD) is an immune-mediated condition affecting the small intestine. Its reported global prevalence falls within the range of 0.7% to 1.4%. Notably, historically, higher rates, reaching 1% in Western Ireland, have been documented. Recent research has even revealed prevalence rates as elevated as 2% in northern Europe. These findings underscore the urgency for swift and cost-effective diagnosis, especially in individuals identified through screening efforts. At present, the diagnosis of CD relies on a multifaceted approach involving positive serological markers such as IgA anti-tissue transglutaminase (anti-TTG) and anti-endomysial antibodies (anti-EMA). These serological findings are assessed in conjunction with classical histological alterations, as outlined in the Marsh classification. CD is an inflammatory condition triggered by the consumption of gluten, resulting from intricate interactions between genetic, immunological, and environmental factors. CD is linked to malabsorption, leading to nutritional deficiencies. Individuals with CD are required to adhere to a gluten-free diet, which itself can lead to nutrient deficiencies. One such deficiency includes vitamin D, and there is substantial experimental evidence supporting the notion of a bidirectional relationship between CD and vitamin D status. A low level of vitamin D has a detrimental impact on the clinical course of the disease. Here we summarize the key characteristics of CD and explore the prominent roles of vitamin D in individuals with CD.

Previous studies have reported the association between maternal vitamin D deficiency and preeclampsia. However, the efficacy of vitamin D supplementation in reducing the occurrence of preeclampsia remains unclear. The objective of this study was to evaluate the effect of cholecalciferol supplementation on the incidence of preeclampsia in primigravid women and its related maternal and foetal outcomes.

A single-blinded clinical trial was conducted in fourteen antenatal care health facilities in the North (Goma, Mwesso, Nyiragongo) and South Kivu (Bukavu-Panzi) provinces of the Democratic Republic of Congo from March 1, 2020, to June 30, 2021. A total of 1300 primigravid women not exceeding 16 weeks of gestation were randomised with a 1:1 ratio to either the supplemented (A) or control (B) group. Each pregnant woman (A) presenting for antenatal care received a single monthly dose of cholecalciferol (60,000 IU) orally for 6 months. The control group received no vitamin D supplementation or placebo. Serum 25(OH)D was measured at recruitment and at 34 weeks of gestation. Outcomes were assessed monthly until delivery.

The median maternal age was 21 years (14-40), while the median gestational age was 15 weeks (5.4-29.0). A significant reduction in the risk of preeclampsia [RR = 0.36 (0.19-0.69); p = 0.001] and preterm delivery [RR = 0.5 (0.32-0.78); p = 0.002] was observed in the intervention group. An RR of 0.43 [(0.27-0.67); p < 0.001] was found for low birth weight. The RR for caesarean section was 0.63 [(0.52-0.75); p < 0.001]. The APGAR score at the 5th minute (p = 0.021) and the size of the newborn were significantly higher in the supplemented group (p = 0.005).

A single monthly dose (60,000 IU) of vitamin D supplementation, started in earlypregnancy, significantly reduced the incidence of preeclampsia and its maternal and foetal complications.

ISRCTN Register with ISRCTN46539495 on 17 November 2020.

There is a strong rationale for using vitamin D in combination with anti-osteoporotic drugs. Still, available trials do not give clear indications in this setting, presenting a suboptimal and heavily inhomogeneous experimental design. Health authorities should revise requirements for using vitamin D in anti-osteoporotic drug trials to maximise their effect and produce reliable indications for clinical practice in this setting.

The SARS-CoV-2 virus may cause severe infection, which is associated with diverse clinical manifestations. Vitamin D has immunomodulating properties and may enhance the body's defense system against invading pathogenic organisms. The aim was to assess 25(OH)D3 levels in patients hospitalized for severe infection from the SARS-CoV-2 virus and explore the relationship between 25(OH)D3 and outcomes. In a group of 88 patients hospitalized for severe infection from the SARS-CoV-2 virus and a control group matched for age and sex, the levels of 25(OH)D3 were analyzed. Levels of 25(OH)D3 were 17.36 ± 8.80 ng/mL (mean ± SD) compared with 24.34 ± 10.34 ng/mL in patients with severe SARS-CoV-2 infection and the control group, respectively, p < 0.001 (Student's t-test). 25(OH)D3 levels were significantly related to outcomes, i.e., survival as opposed to non-survival, as more patients with 25(OH)D3 deficiency (0-10 ng/mL) and insufficiency (10-20 ng/mL) had a fatal outcome as compared with those with vitamin D sufficiency (p < 0.001, chi-square test, p < 0.001, Fisher's exact test). Levels of 25(OH)D3 were inversely related to C-reactive protein (CRP), ferritin, d-dimer, and fibrinogen levels (p < 0.001, linear regression analysis, beta coefficient of variation, -0.176, -0.160, -0.178, and -0.158, respectively). Vitamin D deficiency observed in severe SARS-CoV-2 infection was related to disease outcomes.

Vitamin D deficiency is considered a public health problem due to its worldwide high prevalence and adverse clinical consequences regarding musculoskeletal health. In addition, vitamin D may also be crucial for the prevention of certain extraskeletal diseases. Despite decades of intensive scientific research, several knowledge gaps remain regarding the precise definition of vitamin D deficiency and sufficiency, the health benefits of improving vitamin D status, and the required vitamin D intakes. Consequently, various societies and expert groups have released heterogeneous recommendations on the dosages for vitamin D supplementation. In this brief narrative review, we outline and discuss recent advances regarding the scientific evidence arguing for a daily vitamin D supplementation with 2000 international units (IU) (50 µg) of vitamin D3 to prevent and treat vitamin D deficiency. According to data from randomized controlled trials (RCTs), such a dose may improve some health outcomes and is sufficient to raise and maintain serum 25(OH)D concentrations above 50 nmol/L (20 ng/mL) and above 75 nmol/L (30 ng/mL) in >99% and >90% of the general adult population, respectively. According to large vitamin D RCTs, there are no significant safety concerns in supplementing such a dose for several years, even in individuals with an already sufficient vitamin D status at baseline. A daily vitamin D supplementation with 2000 IU (50 µg) may be considered a simple, effective, and safe dosage to prevent and treat vitamin D deficiency in the adult general population.

Canagliflozin has been reported to increase the risk of bone fracture-possibly mediated by decreasing 1,25-dihydroxyvitamin D (1,25(OH)2D) and increasing parathyroid hormone (PTH).

This work investigated whether baseline vitamin D (VitD) deficiency renders individuals vulnerable to this adverse effect and whether VitD3 supplementation is protective.

This community-based, outpatient study had a paired design comparing individual participants before and after VitD3 supplementation. Eleven VitD-deficient (25-hydroxyvitamin D [25(OH)D] ≤ 20 ng/mL) individuals were recruited from the Amish population in Lancaster, Pennsylvania. Participants underwent 2 canagliflozin challenge protocols (300 mg daily for 5 days): the first before and the second after VitD3 supplementation. In the VitD3 supplementation protocol, participants received VitD3 supplementation (50 000 IU once or twice a week depending on body mass index for 4-6 weeks) to achieve 25(OH)D of 30 ng/mL or greater. Two coprimary end points were identified: effects of VitD3 supplementation on canagliflozin-induced changes in 1,25(OH)2D and PTH. Secondary end points included effects of VitD3 supplementation on baseline levels of VitD metabolites and PTH.

VitD3 supplementation increased mean 25(OH)D from 16.5 ± 1.6 to 44.3 ± 5.5 ng/mL (P = .0006) and 24,25-dihydroxyvitamin D (24,25(OH)2D) from 1.0 ± 0.1 to 4.3 ± 0.6 ng/mL (P = .0002). Mean 1,25(OH)2D and PTH were unchanged. VitD3 supplementation decreased the magnitude of canagliflozin-induced changes in 1,25(OH)2D (from -31.3%±4.7% to -9.3%±8.3%; P = .04) and PTH (from +36.2%±6.2% to +9.7%±3.7%; P = .005).

VitD deficiency rendered individuals more vulnerable to adverse effects of canagliflozin on biomarkers associated with bone health. VitD3 supplementation was protective against canagliflozin's short-term adverse effects on 1,25(OH)2D and PTH.

Skeletal fragility is observed in 30% to 60% of acromegaly patients, representing an emerging complication of the disease that increases disability. Despite several studies having investigated the clinical and hormonal prognostic factors for the occurrence of vertebral fractures (VFs) in acromegaly, very few data are available on their prevention/treatment including the effect of vitamin D (VD) supplementation, which has been reported to have a fracture-protective effect in several studies in patients with osteoporosis.

We aimed to investigate the role of cholecalciferol (D3) supplementation in the prevention of incident VFs (i-VFs) in acromegaly.

A longitudinal, retrospective and multicenter study was performed on 61 acromegaly patients treated and untreated with D3 supplementation.

Twenty-six patients were treated with D3 supplementation according to clinical guidelines. The median D3 weekly dosage was 8500 IU (interquartile range [IQR]: 3900). The median duration of D3 supplementation was 94 months (IQR: 38). At last follow-up, i-VFs were diagnosed in 14 patients (23%). I-VFs were less prevalent in patients on D3 supplementation (14.3% of cases) compared to patients not treated with D3 (85.7%; P = .02). The final level of serum V25OH-D was significantly lower in patients who developed i-VFs (28.6 ng/mL, IQR: 4.1) compared to patients who did not develop i-VFs (34.2 ng/mL, IQR: 9.6; P = .05). The logistic regression confirmed the protective role of D3 supplementation on the occurrence of i-VFs (odds ratio: 0.16; 95% CI, 0.03-0.79; P = .01).

It is likely that D3 supplementation could lead to a reduction in i-VFs in acromegaly.

Vitamin D (VD) exerts a wide variety of biological functions including calcemic activity. VD nutritional status is closely associated with the onset and development of chronic diseases. To develop a VD analog with the desired VD activity but without calcemic activity, we screened synthetic VDR antagonists. We identified 1α,25-dihydroxyvitamin D3-26-23-lactams (DLAM)-2a-d (DLAM-2s) as nuclear vitamin D receptor (VDR) ligands in a competitive VDR binding assay for 1α,25(OH)2 vitamin D3 (1α,25(OH)2D3), and DLAM-2s showed an antagonistic effect on 1α,25(OH)2 D3-induced cell differentiation in HL60 cells. In a luciferase reporter assay in which human VDR was exogenously expressed in cultured COS-1 cells, DLAM-2s acted as transcriptional antagonists. Consistently, DLAM-2s had an antagonistic effect on the 1α,25(OH)2D3-induced expression of a known VD target gene [Cytochrome P450 24A1 (CYP24A1)], and VDR bound DLAM-2s was recruited to an endogenous VD response element in chromatin in human keratinocytes (HaCaT cells) endogenously expressing VDR. In an ATAC-seq assay, the effects of 1α,25(OH)2 D3 and DLAM-2b on chromatin reorganization were undetectable in HaCaT cells, while the effect of an androgen receptor (AR) antagonist (bicalutamide) was confirmed in prostate cancer cells (LNCaP) expressing endogenous AR. However, whole genome analysis using RNA-seq and ATAC (Assay for Transposase Accessible Chromatin)-seq revealed differential gene expression profiles regulated by DLAM-2b versus 1α,25(OH)2D3. The upregulated and downregulated genes only partially overlapped between cells treated with 1α,25(OH)2D3 and those treated with DLAM-2b. Thus, the present findings illustrate a novel VDR ligand with gene regulatory activity differing from that of 1α,25(OH)2D3.

Since our discovery in 2006 that acromegaly is associated with an increased risk of vertebral fractures, many authors have confirmed this finding in both cross-sectional and prospective studies. Due to the high epidemiological and clinical impact of this newly discovered comorbidity of acromegaly, this topic has progressively become more important and prominent over the years, and the pertinent literature has been enriched by new findings on the pathophysiology and treatment. The aim of this narrative review was to discuss these novel findings, integrating them with the seminal observations, in order to give the reader an updated view of how the field of acromegaly and bone is developing, from strong clinical observations to a mechanistic understanding and possible prevention and treatment.