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Objetivos: Las fracturas atípicas de fémur (FAF) son un tipo de fracturas poco frecuentes, a menudo relacionadas con un tratamiento prolongado con bisfosfonatos (BPs). Actualmente no se conocen con exactitud sus mecanismos patogénicos y no hay pruebas para identificar aquellos pacientes con un alto riesgo de sufrir una FAF. El objetivo de este trabajo es investigar las bases genéticas de las FAFs. Material y métodos: Se secuenció el exoma completo de 3 hermanas y de 3 pacientes adicionales no relacionadas, todas tratadas con BPs durante más de 5 años. Se seleccionaron variantes compartidas por las hermanas, de baja frecuencia y potencialmente patogénicas, y se construyó una red de interacciones de genes y proteínas con los datos hallados. Resultados: Identificamos 37 variantes raras (en 34 genes) compartidas por las 3 hermanas, algunas de ellas no descritas anteriormente. La variante más llamativa fue la mutación p.Asp188Tyr en el enzima geranilgeranil pirofosfato sintasa (codificada por el gen GGPS1), de la vía del mevalonato y esencial para la función del osteoclasto. Otro hallazgo interesante fueron dos mutaciones (una en las 3 hermanas y una en una paciente no relacionada) en el gen CYP1A1, implicado en el metabolismo de los esteroides. Identificamos otras variantes que también podrían estar involucradas en la susceptibilidad a las FAFs o en el fenotipo osteoporótico subyacente, tales como las presentes en los genes SYDE2, NGEF, COG4 y la FN1. Conclusiones: Nuestros datos son compatibles con un modelo donde la acumulación de variantes de susceptibilidad podría participar en la base genética de las FAFs.

Calcifediol and glucocorticoids have been repositioned for the treatment of COVID-19 and may reduce severity, the need for intensive care unit admission and death., Objective: to identify class or profiles of patients hospitalized and treated with COVID-19 pneumonia using latent class clustering methods to assess the clinical and prognostic relevance of the resulting patients' profiles. Poor prognosis was defined as death or need for ICU admission, good prognosis, the opposite. With special interest in differential responses to calcifediol., Setting: Reina Sofia University Hospital, Córdoba Spain., Patients: Retrospective observational cohort study of patients admitted for COVID-19., Clinicaltrials: gov public database (NCT05819918)., Inclusion Criteria: (i) Age ≥ 18 and ≤ 90 years, (ii) Pneumonia characterized by the presence of infiltrates on chest X-ray or CT scan, (iii) SARS-CoV-2 infection, confirmed, and (iv) CURB Scale 65 >1., Design: Latent class analysis, for obtaining homogeneous clusters, without specifying a priori the belonging group, and selecting the optimal number of clusters by minimizing information criteria. Evaluating the differences between groups for each variable by means of chi-square, Fisher's exact test and Kruskal-Wallis test., Results: 707 patients hospitalized from 10 March 2020 until 4 March 2022 were included. For the treatment variable, differences were found between class 3 (60 % treated with calcifediol only) and classes 1 (less than 1 % calcifediol only vs. 82 % treated with both), 2 (less than 1 % calcifediol only vs. 82 % treated with both) and 4 (1 % calcifediol only vs. 84 % treated with both). Class 3, (60 % with calcifediol), had a significantly better prognosis compared to patients treated with glucocorticoids alone (OR: 15.2, 95 % CI: [3.73-142], p<0.001) or no treatment (OR: 7.38, 95 % CI: [2.63-30.2], p<0.001)., Conclusions: our real-life study shows that calcifediol treatment significantly reduces the need for ICU admission and improved prognosis in patients hospitalized for COVID-19 pneumonia, especially in the profile of patients receiving it without glucocorticoids., Competing Interests: Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

An archetypal anti-inflammatory compound against cytokine storm would inhibit it without suppressing the innate immune response. AG5, an anti-inflammatory compound, has been developed as synthetic derivative of andrographolide, which is highly absorbable and presents low toxicity. We found that the mechanism of action of AG5 is through the inhibition of caspase-1. Interestingly, we show with in vitro generated human monocyte derived dendritic cells that AG5 preserves innate immune response. AG5 minimizes inflammatory response in a mouse model of lipopolysaccharide (LPS)-induced lung injury and exhibits in vivo anti-inflammatory efficacy in the SARS-CoV-2-infected mouse model. AG5 opens up a new class of anti-inflammatories, since contrary to NSAIDs, AG5 is able to inhibit the cytokine storm, like dexamethasone, but, unlike corticosteroids, preserves adequately the innate immunity. This is critical at the early stages of any naïve infection, but particularly in SARS-CoV-2 infections. Furthermore, AG5 showed interesting antiviral activity against SARS-CoV-2 in humanized mice., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: “AG5 andrographolide derivative for use in the treatment of inflammatory diseases associated with a cytokine storm” is a formal Spanish Patent (ES2908500) since March 15th, 2023. PBA, ERB, CVA, BN, AF, CS, GGA, FP, JA, APL and JMB are co-inventors of this patent., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Vitamin D deficiency remains prevalent, with about 7% of the world's population living with severe vitamin D deficiency and about one third with mild deficiency. We compare the relative merits of calcifediol or 25-hydroxyvitamin D (25OHD) compared to vitamin D itself for supplementation as to prevent or cure vitamin D deficiency. The intestinal absorption of calcifediol is nearly 100% and thus higher than that of vitamin D itself. Moreover, calcifediol is absorbed by the intestinal cells and transported through the portal vein and thus immediately accessible to the circulation, while vitamin D is transported with chylomicrons through the lymph system. Therefore, in case of fat malabsorption or after bariatric surgery, calcifediol is much better absorbed in comparison with vitamin D itself. Serum 25OHD increases linearly with increasing doses of calcifediol, whereas serum 25OHD reaches a plateau when higher oral doses of vitamin D are used. Calcifediol, on a weight basis, is about 3 times more potent than vitamin D in subjects with mild vitamin D deficiency. This potency is even 6-8 times higher than vitamin D when baseline serum 25OHD is higher or when large doses are compared. In conclusion, calcifediol is an alternative option to correct vitamin D deficiency and may even be the preferred strategy in case of intestinal fat malabsorption, after bariatric surgery or in case of other conditions with suspected impaired 25-hydroxylase activity in the liver., Competing Interests: Conflict of interest RB received small lecture fees from Abiogen (Italy) and FAES Farma (Spain). JMQG received small lecture fees from Lilly (Spain) and FAES Farma (Spain)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The COVID-19 pandemic is the greatest challenge facing modern medicine and public health systems. The viral evolution of SARS-CoV-2, with the emergence of new variants with in-creased infectious potential, is a cause for concern. In addition, vaccination coverage remains in-sufficient worldwide. Therefore, there is a need to develop new therapeutic options, and/or to optimize the repositioning of drugs approved for other indications for COVID-19. This may include the use of calcifediol, the prohormone of the vitamin D endocrine system (VDES) as it may have potential useful effects for the treatment of COVID-19. We review the aspects associating COVID-19 with VDES and the potential use of calcifediol in COVID-19. VDES/VDR stimulation may enhance innate antiviral effector mechanisms, facilitating the induction of antimicrobial peptides/autophagy, with a critical modulatory role in the subsequent host reactive hyperinflammatory phase during COVID-19: By decreasing the cytokine/chemokine storm, regulating the renin-angiotensin-bradykinin system (RAAS), modulating neutrophil activity and maintaining the integrity of the pulmonary epithelial barrier, stimulating epithelial repair, and directly and indirectly decreasing the increased coagulability and prothrombotic tendency associated with severe COVID-19 and its complications. Available evidence suggests that VDES/VDR stimulation, while maintaining optimal serum 25OHD status, in patients with SARS-CoV-2 infection may significantly reduce the risk of acute respiratory distress syndrome (ARDS) and severe COVID-19, with possible beneficial effects on the need for mechanical ventilation and/or intensive care unit (ICU) admission, as well as deaths in the course of the disease. The pharmacokinetic and functional characteristics of calcifediol give it superiority in rapidly optimizing 25OHD levels in COVID-19. A pilot study and several observational intervention studies using high doses of calcifediol (0.532 mg on day 1 and 0.266 mg on days 3, 7, 14, 21, and 28) dramatically decreased the need for ICU admission and the mortality rate. We, therefore, propose to use calcifediol at the doses described for the rapid correction of 25OHD deficiency in all patients in the early stages of COVID-19, in association, if necessary, with the new oral antiviral agents.

COVID-19 is a major worldwide health problem because of acute respiratory distress syndrome, and mortality. Several lines of evidence have suggested a relationship between the vitamin D endocrine system and severity of COVID-19. We present a survival study on a retrospective cohort of 15,968 patients, comprising all COVID-19 patients hospitalized in Andalusia between January and November 2020. Based on a central registry of electronic health records (the Andalusian Population Health Database, BPS), prescription of vitamin D or its metabolites within 15-30 days before hospitalization were recorded. The effect of prescription of vitamin D (metabolites) for other indication previous to the hospitalization was studied with respect to patient survival. Kaplan-Meier survival curves and hazard ratios support an association between prescription of these metabolites and patient survival. Such association was stronger for calcifediol (Hazard Ratio, HR = 0.67, with 95% confidence interval, CI, of [0.50-0.91]) than for cholecalciferol (HR = 0.75, with 95% CI of [0.61-0.91]), when prescribed 15 days prior hospitalization. Although the relation is maintained, there is a general decrease of this effect when a longer period of 30 days prior hospitalization is considered (calcifediol HR = 0.73, with 95% CI [0.57-0.95] and cholecalciferol HR = 0.88, with 95% CI [0.75, 1.03]), suggesting that association was stronger when the prescription was closer to the hospitalization., (© 2021. The Author(s).)

Preclinical data strongly suggest that the vitamin D endocrine system (VDES) may have extraskeletal effects. Cells of the immune and cardiovascular systems and lungs can express the vitamin D receptor, and overall these cells respond in a coherent fashion when exposed to 1,25-dihydroxyvitamin D, the main metabolite of the VDES. Supplementation of vitamin D-deficient subjects may decrease the risk of upper respiratory infections. The VDES also has broad anti-inflammatory and anti-thrombotic effects, and other mechanisms argue for a potential beneficial effect of a good vitamin D status on acute respiratory distress syndrome, a major complication of this SARS-2/COVID-19 infection. Activation of the VDES may thus have beneficial effects on the severity of COVID-19. Meta-analysis of observational data show that a better vitamin D status decreased the requirement of intensive care treatment or decreased mortality. A pilot study in Cordoba indicated that admission to intensive care was drastically reduced by administration of a high dose of calcifediol early after hospital admission for COVID-19. A large observational study in Barcelona confirmed that such therapy significantly decreased the odds ratio (OR) of mortality (OR = 0.52). This was also the conclusion of a retrospective study in five hospitals of Southern Spain. A retrospective study on all Andalusian patients hospitalized because of COVID-19, based on real-world data from the health care system, concluded that prescription of calcifediol (hazard ratio [HR] = 0.67) or vitamin D (HR = 0.75), 15 days before hospital admission decreased mortality within the first month. In conclusion, a good vitamin D status may have beneficial effects on the course of COVID-19. This needs to be confirmed by large, randomized trials, but in the meantime, we recommend (rapid) correction of 25 hydroxyvitamin D (25OHD) deficiency in subjects exposed to this coronavirus. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., Competing Interests: RB received small lecture fees from Abiogen (Italy), FAES‐Farma (Spain), and Fresenius (Germany). JMQG received small lecture fees from Amgen (Spain) and FAES‐Farma (Spain)., (© 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Context: COVID-19 is a major health problem because of saturation of intensive care units (ICU) and mortality. Vitamin D has emerged as a potential treatment able to reduce the disease severity., Objective: This work aims to elucidate the effect of 25(OH)D3 (calcifediol) treatment on COVID-19-related outcomes., Methods: This observational cohort study was conducted from March to May 2020, among patients admitted to COVID-19 wards of Hospital del Mar, Barcelona, Spain. A total of 930 patients with COVID-19 were included; 92 were excluded because of previous calcifediol intake. Of the remaining 838, a total of 447 received calcifediol (532 μg on day 1 plus 266 μg on days 3, 7, 15, and 30), whereas 391 were not treated at the time of hospital admission (intention-to-treat). Of the latter, 53 patients were treated later during ICU admission and were allocated in the treated group in a second analysis. In healthy individuals, calcifediol is about 3.2-fold more potent on a weight basis than cholecalciferol. Main outcome measures were ICU admission and mortality., Results: ICU assistance was required by 102 (12.2%) participants. Out of 447 patients treated with calcifediol at admission, 20 (4.5%) required the ICU, compared to 82 (21%) out of 391 nontreated (P < .001). Logistic regression of calcifediol treatment on ICU admission, adjusted by age, sex, linearized 25-hydroxyvitamin D levels at baseline, and comorbidities showed that treated patients had a reduced risk of requiring the ICU (odds ratio [OR] 0.13; 95% CI 0.07-0.23). Overall mortality was 10%. In the intention-to-treat analysis, 21 (4.7%) out of 447 patients treated with calcifediol at admission died compared to 62 patients (15.9%) out of 391 nontreated (P = .001). Adjusted results showed a reduced mortality risk with an OR of 0.21 (95% CI, 0.10-0.43). In the second analysis, the obtained OR was 0.52 (95% CI, 0.27-0.99)., Conclusion: In patients hospitalized with COVID-19, calcifediol treatment significantly reduced ICU admission and mortality., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Calcifediol has been proposed as a potential treatment for COVID-19 patients., Objective: To compare the administration or not of oral calcifediol on mortality risk of patients hospitalized because of COVID-19., Design: Retrospective, multicenter, open, non-randomized cohort study., Settings: Hospitalized care., Patients: Patients with laboratory-confirmed COVID-19 between 5 February and 5 May 2020 in five hospitals in the South of Spain., Intervention: Patients received calcifediol (25-hydroxyvitamin D 3 ) treatment (0.266 mg/capsule, 2 capsules on entry and then one capsule on day 3, 7, 14, 21, and 28) or not., Main Outcome Measure: In-hospital mortality during the first 30 days after admission., Results: A total of 537 patients were hospitalized with COVID-19 (317 males (59%), median age, 70 years), and 79 (14.7%) received calcifediol treatment. Overall, in-hospital mortality during the first 30 days was 17.5%. The OR of death for patients receiving calcifediol (mortality rate of 5%) was 0.22 (95% CI, 0.08 to 0.61) compared to patients not receiving such treatment (mortality rate of 20%; p < 0.01). Patients who received calcifediol after admission were more likely than those not receiving treatment to have comorbidity and a lower rate of CURB-65 score for pneumonia severity ≥ 3 (one point for each of confusion, urea > 7 mmol/L, respiratory rate ≥ 30/min, systolic blood pressure < 90 mm Hg or diastolic blood pressure ≤ 60 mm Hg, and age ≥ 65 years), acute respiratory distress syndrome (moderate or severe), c-reactive protein, chronic kidney disease, and blood urea nitrogen. In a multivariable logistic regression model, adjusting for confounders, there were significant differences in mortality for patients receiving calcifediol compared with patients not receiving it (OR = 0.16 (95% CI 0.03 to 0.80)., Conclusion: Among patients hospitalized with COVID-19, treatment with calcifediol, compared with those not receiving calcifediol, was significantly associated with lower in-hospital mortality during the first 30 days. The observational design and sample size may limit the interpretation of these findings.

Objective: The vitamin D endocrine system may have a variety of actions on cells and tissues involved in COVID-19 progression especially by decreasing the Acute Respiratory Distress Syndrome. Calcifediol can rapidly increase serum 25OHD concentration. We therefore evaluated the effect of calcifediol treatment, on Intensive Care Unit Admission and Mortality rate among Spanish patients hospitalized for COVID-19., Design: Parallel pilot randomized open label, double-masked clinical trial., Setting: University hospital setting (Reina Sofia University Hospital, Córdoba Spain.) PARTICIPANTS: 76 consecutive patients hospitalized with COVID-19 infection, clinical picture of acute respiratory infection, confirmed by a radiographic pattern of viral pneumonia and by a positive SARS-CoV-2 PCR with CURB65 severity scale (recommending hospital admission in case of total score > 1)., Procedures: All hospitalized patients received as best available therapy the same standard care, (per hospital protocol), of a combination of hydroxychloroquine (400 mg every 12 h on the first day, and 200 mg every 12 h for the following 5 days), azithromycin (500 mg orally for 5 days. Eligible patients were allocated at a 2 calcifediol:1 no calcifediol ratio through electronic randomization on the day of admission to take oral calcifediol (0.532 mg), or not. Patients in the calcifediol treatment group continued with oral calcifediol (0.266 mg) on day 3 and 7, and then weekly until discharge or ICU admission. Outcomes of effectiveness included rate of ICU admission and deaths., Results: Of 50 patients treated with calcifediol, one required admission to the ICU (2%), while of 26 untreated patients, 13 required admission (50 %) p value X 2 Fischer test p < 0.001. Univariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment versus without Calcifediol treatment: 0.02 (95 %CI 0.002-0.17). Multivariate Risk Estimate Odds Ratio for ICU in patients with Calcifediol treatment vs Without Calcifediol treatment ICU (adjusting by Hypertension and T2DM): 0.03 (95 %CI: 0.003-0.25). Of the patients treated with calcifediol, none died, and all were discharged, without complications. The 13 patients not treated with calcifediol, who were not admitted to the ICU, were discharged. Of the 13 patients admitted to the ICU, two died and the remaining 11 were discharged., Conclusion: Our pilot study demonstrated that administration of a high dose of Calcifediol or 25-hydroxyvitamin D, a main metabolite of vitamin D endocrine system, significantly reduced the need for ICU treatment of patients requiring hospitalization due to proven COVID-19. Calcifediol seems to be able to reduce severity of the disease, but larger trials with groups properly matched will be required to show a definitive answer., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Coronavirus infection is a serious health problem awaiting an effective vaccine and/or antiviral treatment. The major complication of coronavirus disease 2019 (COVID-19), the Acute Respiratory Distress syndrome (ARDS), is due to a variety of mechanisms including cytokine storm, dysregulation of the renin-angiotensin system, neutrophil activation and increased (micro)coagulation. Based on many preclinical studies and observational data in humans, ARDS may be aggravated by vitamin D deficiency and tapered down by activation of the vitamin D receptor. Several randomized clinical trials using either oral vitamin D or oral Calcifediol (25OHD) are ongoing. Based on a pilot study, oral calcifediol may be the most promising approach. These studies are expected to provide guidelines within a few months., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Modest and even severe vitamin D deficiency is widely prevalent around the world. There is consensus that a good vitamin D status is necessary for bone and general health. Similarly, a better vitamin D status is essential for optimal efficacy of antiresorptive treatments. Supplementation of food with vitamin D or using vitamin D supplements is the most widely used strategy to improve the vitamin status. Cholecalciferol (vitamin D 3 ) and ergocalciferol (vitamin D 2 ) are the most widely used compounds and the relative use of both products depends on historical or practical reasons. Oral intake of calcifediol (25OHD 3 ) rather than vitamin D itself should also be considered for oral supplementation. We reviewed all publications dealing with a comparison of oral cholecalciferol with oral calcifediol as to define the relative efficacy of both compounds for improving the vitamin D status. First, oral calcifediol results in a more rapid increase in serum 25OHD compared to oral cholecalciferol. Second, oral calcifediol is more potent than cholecalciferol, so that lower dosages are needed. Based on the results of nine RCTs comparing physiologic doses of oral cholecalciferol with oral calcifediol, calcifediol was 3.2-fold more potent than oral cholecalciferol. Indeed, when using dosages ≤ 25 μg/day, serum 25OHD increased by 1.5 ± 0.9 nmol/l for each 1 μg cholecalciferol, whereas this was 4.8 ± 1.2 nmol/l for oral calcifediol . Third, oral calcifediol has a higher rate of intestinal absorption and this may have important advantages in case of decreased intestinal absorption capacity due to a variety of diseases. A potential additional advantage of oral calcifediol is a linear dose-response curve, irrespective of baseline serum 25OHD, whereas the rise in serum 25OHD is lower after oral cholecalciferol, when baseline serum 25OHD is higher. Finally, intermittent intake of calcifediol results in fairly stable serum 25OHD compared with greater fluctuations after intermittent oral cholecalciferol.

Objective: Simultaneous assessment of the status of lipid-soluble vitamins; retinol, alpha-tocopherol, 25 hydroxyvitamin D(3) and 24,25 dihydroxyvitamin D(3) in serum of blood donors, paradigm of a healthy population., Patients and Methods: Serum samples were supplied by the Regional Blood Donors Center in Cordoba from 215 healthy Spanish individuals (166 males and 99 females). Target analytes were determined using liquid-liquid extraction and separation-detection by HPLC., Results: The method was validated using standard reference material (SRM 968c, NIST). Standard errors were 1.4%, 2.1% and 1.8% for 25OHD(3), vitamin A and vitamin E, respectively. The ranges thus assessed were as follows: 17.1+/-8.0 nmol/L, for 24,25(OH)(2)D(3), 40.3+/-34.6 nmol/L for 25OHD(3), 2.57+/-0.7 micromol/L for retinol and 22.13+/-8.30 micromol/L for alpha-tocopherol. Females showed lower serum levels of retinol (p<0.01), alpha-tocopherol (p<0.01) and 25OHD(3) (p=0.028). A total of 10.4% subjects showed vitamin E deficiency, 85.4% had normal levels and 4.2% had high levels of vitamin E. 65.6% of the target subjects showed normal levels of retinol, and 1.6% had moderate or severe vitamin A deficiency. High levels of vitamin A were found in 32.8% of the subjects. Fourteen percent of the healthy subjects showed severe vitamin D deficiency (serum levels of 25OHD(3) <25 nmol/L), 50.8% had vitamin D(3) insufficiency (25OHD(3) from 25 to 50 nmol/L), 17.6% of the subjects had suboptimal 25OHD(3) serum levels (25OHD(3) from 50 to 75 nmol/L), only 16.8% had an adequate status of 25OHD(3) and 0.8% had high levels of vitamin D (25OHD(3)>200 nmol/L). Among subjects with vitamin D below 50 nmol/L, 49.38% had high levels of retinol (over 2.4 mumol/L). This association is considered a risk factor for osteoporosis and fracture., Conclusions: The reported data of high prevalence of lipid-soluble vitamin values outside the physiological range have important repercussions on public health. These data also uphold the need for simultaneous measurement of fat-soluble vitamins as a valuable tool in clinical practice as well as in epidemiological studies for awareness and correction.