A PAI-1 antagonist ameliorates hypophosphatemia in the Hyp vitamin D-resistant rickets model mouse.

Congenital fibroblast growth factor 23 (FGF23)-related hypophosphatemic rickets/osteomalacia is a rare bone metabolism disorder characterized by hypophosphatemia and caused by genetic abnormalities that result in excessive secretion of FGF23. Hyp mice are a model of X-linked hypophosphatemia (XLH) caused by deletion of the PHEX gene and excessive production of FGF23. The purpose of this study was to investigate the potential of TM5614 as a therapeutic agent for the treatment of congenital FGF23-related hypophosphatemic rickets and osteomalacia in humans by administering TM5614 to Hyp mice and examining its curative effect on hypophosphatemia. After a single oral administration of TM5614 10 mg·kg-1 to female Hyp mice starting at 17 weeks of age, the serum phosphate concentration increased with a peak at 6 h after administration. ELISA confirmed that TM5614 administration decreased the intact FGF23 concentration in the blood. Expression of 25-hydroxyvitamin D-1α-hydroxylase protein encoded by Cyp27b1 mRNA in the kidney was suppressed in Hyp mice, and treatment with 10 mg·kg-1 of TM5614 normalized the expression of 25-hydroxyvitamin D-1α-hydroxylase protein and Cyp27b1 mRNA in the kidneys of these mice. Our data indicate that oral administration of TM5614 ameliorates hypophosphatemia in Hyp mice, suggesting that TM5614 may be an effective treatment for congenital FGF23-related hypophosphatemic rickets and osteomalacia.

Dendritic cells, engineered to overexpress 25-hydroxyvitamin D 1α-hydroxylase and pulsed with a myelin antigen, provide myelin-specific suppression of ongoing experimental allergic encephalomyelitis.

Multiple sclerosis (MS) is caused by immune-mediated damage of myelin sheath. Current therapies aim to block such immune responses. However, this blocking is not sufficiently specific and hence compromises immunity, leading to severe side effects. In addition, blocking medications usually provide transient effects and require frequent administration, which further increases the chance to compromise immunity. In this regard, myelin-specific therapy may provide the desired specificity and a long-lasting therapeutic effect by inducing myelin-specific regulatory T (Treg) cells. Tolerogenic dendritic cells (TolDCs) are one such therapy. However, ex vivo generated TolDCs may be converted into immunogenic DCs in a proinflammatory environment. In this study, we identified a potential novel myelin-specific therapy that works with immunogenic DCs, hence without the in vivo conversion concern. We showed that immunization with DCs, engineered to overexpress 25-hydroxyvitamin D 1α-hydroxylase for de novo synthesis of a focally high 1,25-dihydroxyvitamin D concentration in the peripheral lymphoid tissues, induced Treg cells. In addition, such engineered DCs, when pulsed with a myelin antigen, led to myelin-specific suppression of ongoing experimental allergic encephalomyelitis (an MS animal model), and the disease suppression depended on forkhead-box-protein-P3(foxp3)+ Treg cells. Our data support a novel concept that immunogenic DCs can be engineered for myelin-specific therapy for MS.-Li, C.-H., Zhang, J., Baylink, D. J., Wang, X., Goparaju, N. B., Xu, Y., Wasnik, S., Cheng, Y., Berumen, E. C., Qin, X., Lau, K.-H. W., Tang, X. Dendritic cells, engineered to overexpress 25-hydroxyvitamin D 1α-hydroxylase and pulsed with a myelin antigen, provide myelin-specific suppression of ongoing experimental allergic encephalomyelitis.

Recomendaciones de vitamina D para la población general / Recommended vitamin D levels in the general population

Objetivo: Proporcionar recomendaciones basadas en la evidencia sobre el manejo del déficit de vitaminaD en población general. Participantes: Miembros del Grupo de Trabajo de Osteoporosis y Metabolismo Mineral de la SEEN. Métodos: Se empleó el sistema Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) para establecer tanto la fuerza de las recomendaciones como el grado de evidencia. Se realizó una búsqueda sistemática en Medline de la evidencia disponible para vitaminaD y el título de cada capítulo. Se revisaron artículos escritos en inglés con fecha de inclusión hasta 17 de marzo del 2016. Tras la formulación de las recomendaciones, estas se discutieron de manera conjunta en el grupo de trabajo. Conclusiones: Este documento resume los datos acerca del déficit de vitaminaD en lo que respecta a su prevalencia, etiología, indicaciones de cribado, niveles adecuados y efectos de la suplementación a nivel óseo y extraóseo (AU)

Objective: To provide recommendations based on evidence on the management of vitaminD deficiency in the general population. Participants: Members of the Bone Metabolism Working Group of the Spanish Society of Endocrinology. Methods: Recommendations were formulated using the GRADE system (Grading of Recommendations, Assessment, Development, and Evaluation) to describe both the strength of recommendations and the quality of evidence. A systematic search was made in MEDLINE (Pubmed) using the term VitaminD and the name of each issue. Papers in English and Spanish with publication date before 17 March 2016 were included. Recommendations were jointly discussed by the Working Group. Conclusions: This document summarizes the data about vitaminD deficiency in terms of prevalence, etiology, screening indications, adequate levels and effects of supplementation on bone and non-skeletal health outcomes (AU)

Equivalent anticancer activities of dietary vitamin D and calcitriol in an animal model of breast cancer: importance of mammary CYP27B1 for treatment and prevention.

Calcitriol [1,25(OH)2D3], the hormonally active form of vitamin D exerts anti-proliferative, pro-apoptotic, anti-inflammatory effects and other anticancer actions in breast cancer (BCa) cell cultures and animal models of BCa. Our research is focused on investigating the potential beneficial effects of dietary vitamin D3 compared to calcitriol and the underlying mechanisms in BCa treatment and chemoprevention. We recently found that dietary vitamin D3 exhibits significant tumor inhibitory effects in xenograft models of BCa that are equivalent to those elicited by the administration of the active hormone calcitriol. At the easily achievable dose tested in our studies, dietary vitamin D3 exhibited substantial tumor inhibitory activity and, unlike calcitriol, did not cause hypercalcemia demonstrating its relative safety. We found elevations in circulating calcitriol as well as increased CYP27B1 expression in the tumor and the intestine in tumor-bearing mice ingesting a vitamin D3-supplemented diet. We hypothesize that the elevation in circulating 25(OH)D induced by dietary vitamin D3 supplements stimulates local synthesis of calcitriol in the mammary tumor microenvironment and the ensuing paracrine/autocrine actions play a major role in the anticancer activity of dietary vitamin D3. Our findings suggest that the endocrine activity of calcitriol derived from tumor and other extra-renal sources such as the intestine, probably also plays a role in mediating the anticancer effects of dietary vitamin D3. Thus it appears that multiple sites of 1α-hydroxylation contribute to the anticancer effects of dietary vitamin D3. Our data strongly suggest that dietary vitamin D will be useful in the chemoprevention and treatment of BCa since it is a safe, economical and easily available nutritional agent that is equivalent to calcitriol in exerting anticancer effects, at least in mouse models. Furthermore, adequate vitamin D nutrition and avoidance of vitamin D deficiency appear to be important in reducing BCa risk. These findings warrant clinical trials in BCa patients and in women at high risk for BCa to evaluate the benefits of dietary vitamin D3 supplementation. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Reumatología y osteoporosis (RETOSS): osteoporosis posmenopáusica en la consulta de reumatología / Rheumatology and osteoporosis (RETOSS): a vision of postmenopausal osteoporosis in rheumatology departments throughout Spain

Objetivo. Conocer las características de las mujeres posmenopáusicas con osteoporosis que acuden a las consultas hospitalarias de reumatología en España. Métodos. Desde junio a septiembre de 2008 se realizó un estudio epidemiológico, observacional, transversal y multicéntrico en 63 consultas de reumatología en toda España. Se evaluaron 629 mujeres posmenopáusicas con osteoporosis utilizando un cuestionario diseñado para recoger datos demográficos, clínicos, radiológicos, de densidad ósea y de función física. Cada médico participante escogió una paciente por día; la primera que cumplía los criterios de inclusión y exclusión. Resultados. La media de la edad fue de 66,6 (9,2) años, del peso fue de 64,6 (10,1)kg y del índice de masa corporal (IMC): 26,1 (4,1)kg/m2. La pérdida de talla media fue de 3,1 (2,8)cm en relación a la media de la talla histórica. El 35,7% tenía antecedentes familiares de fractura, el 40,7% había tenido alguna fractura, de las cuales el 54,8% eran fracturas vertebrales. En las pacientes que presentaban calcidiol <20ng/ml se observó una mayor frecuencia de caídas (p=0,033) y de fracturas (p=0,006), respecto al grupo con valores de calcidiol >20ng/ml. Se encontró un aumento significativo de la probabilidad de caídas asociadas a la edad, y el 51,5% de las mujeres que se había caído, había sufrido algún tipo de fractura por fragilidad. El 75% de las mujeres tenía una ingesta baja de calcio (400mg/d). El test Get up & go mostró un incremento significativo de la probabilidad de test > 20 segundos en relación con la edad, de forma lineal, y con un aumento de la incidencia de fracturas. El 71,8% de las pacientes tenía dolor de espalda y entre estas, el 85,3% presentaba dolor de moderado a severo. Conclusiones. La mayoría de las mujeres españolas posmenopáusicas con osteoporosis que acuden a las consultas de reumatología tiene una ingesta baja de calcio y un tercio de ellas tiene antecedentes familiares de fractura. La incidencia de fracturas muestra una clara relación con la edad, la capacidad funcional y el dolor de espalda. La determinación de la concentración de calcidiol sérico se realiza en un bajo porcentaje de pacientes (AU)

Objective. To know the characteristics of the postmenopausal women with osteoporosis consulting Rheumatology Hospital Divisions in Spain. Methods. An epidemiologic, observational, transverse and multicentric study was performed from June to September 2008 in 63 rheumatology divisions in Spain. Six hundred and twenty nine osteoporotic postmenopausal women were studied using a questionnaire designed to get demographic, clinical, radiological, bone density, and functional information. Every physician had to choose only one patient per day, usually the first woman to come in and fulfill the inclusion and exclusion criteria. Results. Mean age of included women was 66,6 [9,2) years, weight:64,6[10,1] kg and body mass index: 26,1[4,1] kg/m2. They were 3,1[2,8] cm shorter than the maximal historical height. 35,7% of them had a family history of fracture and 40,7% had a past history of fracture, of which 54,8% were vertebral fractures. Patients who received calcidiol <20ng/ml sustained more falls (p=0,033) and fractures (p=0,006) than women receiving calcidiol >20ng/ml. Risk of falls and fractures increased with advancing age and 51,5% of women who fell, had a fracture. 75% of women had poor calcium intake (<=400mg/day). The Get up & go test showed a linear trend to an increased probability of >20s in relationship with the age as well as with an increased incidence of fractures. 71,8% of patients had back pain and in 85,3% it went from moderate to severe. In conclusion. Most osteoporotic postmenopausal Spanish women have a low calcium intake, one out of three has a family history of fractures that increases fracture incidence and this shows a relationship with age and functional capacity; four out of ten have had any type of fractures, one out of three have fallen during the past year and half of these present back pain. Calcidiol levels have been evaluated in a small group of patients (AU)

Uncommon case of ankylosing spondylitis associated with spontaneous occurring hypoparathyroidism.

Hypoparathyroidism and ankylosing spondylitis are two conditions with distinctive features which allow their differentiation. Hypoparathyroidism can be responsible for clinical and radiological changes resembling those seen in patients with ankylosing spondylitis. We report an exceptional case of a patient with an association between ankylosing spondylitis and a severe idiopathic hypoparathyroidism with difficulties in diagnosis. To our knowledge, this is the first case of such an occurrence.

Colecalciferol o calcidiol. ¿Qué metabolito utilizar en el déficit de Vitamina D? / Calciol or cholecalciferol. What metabolite should be used in vitamin D deficit?

Introducción. La hipovitaminosis D es frecuente entre la población de nuestro país. El tratamiento sustitutivo del déficit de vitamina D se puede realizar con colecalciferol o con calcidiol, pero se desconoce si estos dos metabolitos tienen una eficacia equivalente. En este estudio nos propusimos como objetivos, en primer lugar valorar la eficacia de una pauta de calcidiol para corregir en un corto plazo el déficit de vitamina D y compensar el hiperparatiroidismo secundario en pacientes con hipovitaminosis D, y en segundo lugar comparar la eficacia de dos pautas, una con calcidiol y otra con colecalciferol para mantener normales los niveles séricos de vitamina D y mantener compensado el hiperparatiroidismo secundario en pacientes con niveles ya previamente normalizados de 25-OHD3. Pacientes y métodos. Estudio prospectivo con inclusión consecutiva de todos los individuos que presentaban déficit de vitamina D, procedentes de una consulta ambulatoria de reumatología. Al inicio, y durante un mes, se realizó un tratamiento con calcidiol (16.000 UI vía oral en dosis única semanal y durante 4 semanas) para normalizar niveles de 25-OHD3. Se realizaron determinaciones en sangre (calcio, fósforo, fosfatasa alcalina, 25-OHD3 y hormona paratiroidea intacta [PTHi]) y en orina (calciuria de 24 horas) al inicio y fin del tratamiento. Los pacientes que normalizaron niveles de 25-OHD3 se incluyeron en un protocolo prospectivo aleatorizado, para mantener niveles de 25-OHD3 (con 800 UI de colecalciferol y calcio 1 g mínimo /día, o calcidiol 16.000 UI/3 semanas y el mismo aporte de calcio a diario) durante un año. A los 3,6 y 12 meses se realizaron controles analíticos. Resultados. Se incluyeron en el estudio 129 pacientes con una edad media de 72,4 [10] años. El valor medio de 25-OHD3 basal fue de 16 [5] ng/ml y el de PTHi 76 [42]. El 52% de los pacientes presentaba hiperparatiroidismo secundario. Tras el tratamiento inicial se observó normalización de los niveles de 25-OHD3 en 124 casos (96%) e hiperparatiroidismo secundario en 15 pacientes (19%). Ambos tratamientos mantuvieron unos niveles séricos de 25-OHD3 en la normalidad, pero significativamente más elevados con calcidiol (p < 0,001 a los 3, 6 y 12 meses). En un porcentaje de pacientes el tratamiento fue insuficiente para mantener los niveles de 25-OHD3, sobre todo en el grupo de colecalciferol (19% frente a 4% a los 6 meses; p= 0,04, y 18% frente a 0% a los 12 meses; p= 0,006). Conclusiones. Una pauta de 16.000 UI semanales de calcidiol, durante 4 semanas, es sumamente útil para normalizar los niveles séricos de 25-OHD3 y de PTH en pacientes con déficit de vitamina D. Calcidiol y colecalciferol son metabolitos eficaces para mantener normalizados los niveles de 25-OHD3 y de PTHi

Introduction. Hypovitaminosis D is frequent among the population of our country. Vitamin D deficiency replacement treatment may be done with cholecalciferol or with calcidiol but it is not known if these two metabolites have an equivalent efficacy. In this study, we propose the following objectives: first, evaluate the efficacy of a calcidiol regimen to correct a vitamin D deficiency in the short-term and compensate the secondary hyperparathyroidism in patients with hypovitaminosis D, and second, compare the efficacy of the two regimes, one with calcidiol and the other with cholecalciferol, to maintain serum levels of vitamin D normal and maintain the secondary hyperparathyroidism compensated in patients with levels of 25-OHD3 that have already been normalized. Patients and methods. Prospective study with consecutive enrolment of all the patients with vitamin D deficiency of outpatient rheumotology clinic. At the onset, and for one month, patients recieved calcidiol (16.000 IU orally in a single weekly dose and for 4 weeks) to normalized levels of 25-OHD3. Serum (calcium, phosphorus, alkaline phosphatase, 25-OHD3 and PTHi), and in urine (24-hour calciuria) analysis were performed at the onset and after the completion of treatment. Patients who normalized levels of 25-OHD3 were enrolled in a randomized prospective protocol to maintain levels of 25-OHD3, (with 800 IU of cholecalciferol plus calcium 1 g minimum/day or calcidiol 16.000 IU /3 weeks and the same daily suplementation of calcium), for one year. Laboratory controls were conducted at 3, 6 and 12 months. Results. 129 patients with a mean age of 72.4 [10] years were included in the study. The mean value of baseline 25-OHD3 was 16 [5] ng/ml and PTHi 76 [42]. 52% of the patients had secondary hyperparathyroidism. After the initial treatment, normalization of 25-OHD3 levels was observed in 124 cases (96%) and secondary hyperparathyroidism in 15 patients (19%). Both treatments maintained serum levels of 25-OHD3 within the nomal range, but they were significantly more elevated with calcidiol (p < 0.001 at 3, 6 and 12 months). Treatment was ineffective to maintain 25-OHD3 levels in some patients, mainly, in the cholecalciferol group (19% vs 4% at 6 months, p = 0.04, and 18% vs 0% at 12 months, p = 0.006). Conclusions. A regimen of 16.000 IU weekly of calcidiol for 4 weeks is very useful to normalize serum levels of 25-OHD3 and of PTH in patients with vitamin D deficiency. Both calcidiol and cholecalciferol are effective to maintain normalized levels of 25-OHD3 and PTHi

Biological actions of extra-renal 25-hydroxyvitamin D-1alpha-hydroxylase and implications for chemoprevention and treatment.

The Vitamin D-activating enzyme 25-hydroxyvitamin D-1alpha-hydroxylase (1alpha-hydroxylase) is now known to be expressed in a much wider range of tissues that previously thought, suggesting a role for 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), which is more in keeping with a cytokine than a hormone. In this capacity, the function of 1alpha-hydroxylase in tumors is far from clear. Studies from several groups including ours have shown altered expression of 1alpha-hydroxylase in different types of neoplasm including breast, prostate and colon cancers. However, functional analysis of Vitamin D metabolism in cancer is complicated by the heterogenous composition of tumors. Immunohistochemical analysis of breast tumors has shown that 1alpha-hydroxylase is expressed by both epithelial cells and by tumor-infiltrating macrophages, suggesting an immunomodulatory component to 1,25(OH)(2)D(3) production in some types of cancer. The demonstration of 1alpha-hydroxylase activity in tumors and their equivalent normal tissues has implications for both the treatment and prevention of cancers. For example, in tumors chemotherapy options may include the use of non-1alpha-hydroxylated Vitamin D analogs to increase local concentrations of active metabolites without systemic side-effects. The role of 1alpha-hydroxylase in protection against cancer is likely to be more complicated and may involve anti-tumor immune responses.

Altered mineral metabolism in glucocorticoid-induced osteopenia. Effect of 25-hydroxyvitamin D administration.

Parameters of mineral and bone metabolism were studied in 17 patients treated chronically with supraphysiologic doses of glucocorticoids. When compared to 15 matched normal subjects, the patient group exhibited similar serum 25-hydroxyvitamin D (25-OHD) levels, decreased intestinal 47Ca absorption, increased serum immunoreactive parathyroid hormone, and decreased forearm bone mass. Iliac crest bone biopsies revealed a decreased bone formation rate and increased osteoclast number. Treatment with 25-OHD (mean dose 4.03 micrograms/d) and calcium (500 mg/d) in nine patients produced a 46% increase in 47Ca absorption (P less than 0.001) and a 54% decrease in serum immunoreactive parathyroid hormone (P less than 0.001) by 3 mo. In addition, by 12 mo the treatment group exhibited (a) a 13.2 +/- 5.1% increase in metaphyseal (P less than 0.001) and a 2.1 +/- 0.4% increase in diaphyseal (P less than 0.05) forearm bone mass, and (b) significant decreases in cortical and endosteal osteoclast number. Biochemical and bone mass changes persisted through 18 mo. No significant changes in any parameter occurred in eight control patients administered calcium 100 mg/d. It is concluded that treatment with 25-OHD and calcium can significantly improve parameters of mineral and bone metabolism in patients with glucocorticoid-induced osteopenia.

[Hypocalcemic vitamin D-dependent renal rickets]. / Raquitismo renal hipocalcémico dependiente de vitamina D

Two siblings, female 10 years old, and male 15 years old, with the diagnosis of vitamin D-dependent rickets were studied. Another sibling, also with the same diagnosis, died of bronchopnemonia at about 7 months of age. Both patients developed rachitic manifestations since the first year of life, which persisted despite the administration of massive doses of vitamin D intermitently. Severe hypocalcemia, moderate hypophosphatemia and elevated serum alkaline phosphatase were the most characteristic biochemical findings. Both patients showed diminished renal tubular reabsorption of amino acids and phosphates. These alterations were reversible during I.V. calcium gluconate administration. The clinical biochemical and X-ray manifestations disappeared completely after one year of treatment with dihydrotaquisterol. Vitamin D-dependent rickets is an autosomal recessive disease, characterized by a hydroxylation defect of 25 hydroxycholecalciferol at the carbon 1 level, due to abscence of 25 hydroxy-D1-hydroxylase. Thus 1-25 Dihydroxycholecalciferol, the active form of vitamin D3 is not formed, resulting in depression of intestinal calcium absorption and reabsorption from the bones.