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Calcifediol Treatment and COVID-19-Related Outcomes.
Nogues, X, Ovejero, D, Pineda-Moncusí, M, Bouillon, R, Arenas, D, Pascual, J, Ribes, A, Guerri-Fernandez, R, Villar-Garcia, J, Rial, A, et al
The Journal of clinical endocrinology and metabolism. 2021;(10):e4017-e4027
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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.
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Bone Matrix Mineralization in Patients With Gain-of-Function Calcium-Sensing Receptor Mutations Is Distinctly Different From that in Postsurgical Hypoparathyroidism.
Ovejero, D, Misof, BM, Gafni, RI, Dempster, D, Zhou, H, Klaushofer, K, Collins, MT, Roschger, P
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2019;(4):661-668
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The role of the calcium-sensing receptor (CaSR) as a regulator of parathyroid hormone secretion is well established, but its function in bone is less well defined. In an effort to elucidate the CaSR's skeletal role, bone tissue and material characteristics from patients with autosomal dominant hypocalcemia (ADH), a genetic form of primary hypoparathyroidism caused by CASR gain-of-function mutations, were compared to patients with postsurgical hypoparathyroidism (PSH). Bone structure and formation/resorption indices and mineralization density distribution (BMDD), were examined in transiliac biopsy samples from PSH (n = 13) and ADH (n = 6) patients by histomorphometry and quantitative backscatter electron imaging, respectively. Bone mineral density (BMD by DXA) and biochemical characteristics were measured at the time of the biopsy. Because both study groups comprised children and adults, all measured biopsy parameters and BMD outcomes were converted to Z-scores for comparison. Histomorphometric indices were normal and not different between ADH and PSH, with the exception of mineral apposition rate Z-score, which was higher in the ADH group. Similarly, average BMD Z-scores were normal and not different between ADH and PSH. Significant differences were observed for the BMDD average Z-scores of mean and typical degree of mineralization (CaMean, CaPeak, respectively) were lower (p = 0.02 and p = 0.03, respectively), whereas the heterogeneity of mineralization (CaWidth) and percentage of lower mineralized areas (CaLow) were increased in ADH versus PSH (p = 0.01 and p = 0.002, respectively). The BMDD outcomes point toward a direct, PTH-independent role of the CaSR in the regulation of bone mineralization. © 2018 American Society for Bone and Mineral Research.
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Octreotide Is Ineffective in Treating Tumor-Induced Osteomalacia: Results of a Short-Term Therapy.
Ovejero, D, El-Maouche, D, Brillante, BA, Khosravi, A, Gafni, RI, Collins, MT
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2017;(8):1667-1671
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Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which unregulated hypersecretion of fibroblast growth factor 23 (FGF23) by phosphaturic mesenchymal tumors (PMT) causes renal phosphate wasting, hypophosphatemia, and osteomalacia. The resulting mineral homeostasis abnormalities and skeletal manifestations can be reversed with surgical resection of the tumor. Unfortunately, PMTs are often difficult to locate, and medical treatment with oral phosphate and vitamin D analogues is either insufficient to manage the disease or not tolerated. Octreotide has been proposed as a potential treatment for TIO due to the presence of somatostatin receptors (SSTR) on PMTs; however, the role of somatostatin signaling in PMTs and the efficacy of treatment of TIOs with somatostatin analogues is not clear. In an effort to evaluate the efficacy of octreotide therapy in TIO, five subjects with TIO were treated with octreotide for 3 days. Blood intact FGF23, phosphate, and 1,25(OH)2 D3 , and tubular reabsorption of phosphate (TRP) were measured at frequent time points during treatment. Octreotide's effects were assessed by comparing group means of the biochemical parameters at each time-point to mean baseline values. There were no significant changes in blood phosphate, FGF23, 1,25(OH)2 D3 , or TRP during octreotide treatment, consistent with a lack of efficacy of octreotide in treating TIO. © 2017 American Society for Bone and Mineral Research.
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Cutaneous skeletal hypophosphatemia syndrome: clinical spectrum, natural history, and treatment.
Ovejero, D, Lim, YH, Boyce, AM, Gafni, RI, McCarthy, E, Nguyen, TA, Eichenfield, LF, DeKlotz, CM, Guthrie, LC, Tosi, LL, et al
Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2016;(12):3615-3626
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UNLABELLED Cutaneous skeletal hypophosphatemia syndrome (CSHS), caused by somatic RAS mutations, features excess fibroblast growth factor-23 (FGF23) and skeletal dysplasia. Records from 56 individuals were reviewed and demonstrated fractures, scoliosis, and non-congenital hypophosphatemia that in some cases were resolved. Phosphate and calcitriol, but not skin lesion removal, were effective at controlling hypophosphatemia. No skeletal malignancies were found. PURPOSE CSHS is a disorder defined by the association of epidermal and/or melanocytic nevi, a mosaic skeletal dysplasia, and an FGF23-mediated hypophosphatemia. To date, somatic RAS mutations have been identified in all patients whose affected tissue has undergone DNA sequencing. However, the clinical spectrum and treatment are poorly defined in CSHS. The purpose of this study is to determine the spectrum of the phenotype, natural history of the disease, and response to treatment of hypophosphatemia. METHODS Five CSHS subjects underwent prospective data collection at clinical research centers. A review of the literature identified 45 reports that included a total of 51 additional patients, in whom the findings were compatible with CSHS. Data on nevi subtypes, bone histology, mineral and skeletal disorders, abnormalities in other tissues, and response to treatment of hypophosphatemia were analyzed. RESULTS Fractures, limb deformities, and scoliosis affected most CSHS subjects. Hypophosphatemia was not present at birth. Histology revealed severe osteomalacia but no other abnormalities. Skeletal dysplasia was reported in all anatomical compartments, though less frequently in the spine; there was no clear correlation between the location of nevi and the skeletal lesions. Phosphate and calcitriol supplementation was the most effective therapy for rickets. Convincing data that nevi removal improved blood phosphate levels was lacking. An age-dependent improvement in mineral abnormalities was observed. A spectrum of extra-osseous/extra-cutaneous manifestations that included both benign and malignant neoplasms was present in many subjects, though osteosarcoma remains unreported. CONCLUSION An understanding of the spectrum, natural history, and efficacy of treatment of hypophosphatemia in CSHS may improve the care of these patients.