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Clinical characteristics associated with bone mineral density improvement after 1-year alendronate/vitamin d3 or calcitriol treatment: Exploratory results from a phase 3, randomized, controlled trial on postmenopausal osteoporotic women in China.
Liao, EY, Zhang, ZL, Xia, WB, Lin, H, Cheng, Q, Wang, L, Hao, YQ, Chen, DC, Tang, H, Peng, YD, et al
Medicine. 2018;(31):e11694
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Abstract
Baseline and on-treatment characteristics, including age, obesity, calcium intake, and bone turnover markers, may predict the bone mineral density (BMD) response in women with postmenopausal osteoporosis (PMO) to 1 to 2 years of antiresorptive therapy and/or vitamin D supplementation. This study aimed to explore clinical characteristics associated with 12-month BMD improvement in Chinese women with postmenopausal osteoporosis (PMO).In this post hoc analysis of a previous phase 3 multicenter, randomized controlled trial, Chinese PMO women who were treated with once weekly alendronate 70 mg/vitamin D3 5600 IU (ALN/D5600) or once daily calcitriol 0.25 mcg, and had measurements of 1-year lumbar spine BMD (LS-BMD) and on-treatment bone turnover markers (BTMs) were included in the analysis.In Chinese PMO patients on ALN/D5600, 1-year LS-BMD change was negatively correlated with age (β = -0.00084, P < .01), dietary calcium (β = -0.0017, P = .07), and procollagen type 1 N-terminal propeptide (P1NP) change at month 6 (β = -0.000469, P = .0016), but positively with body mass index (BMI) (β = 0.00128, P = .08); baseline P1NP above the median was associated with a significantly greater BMD percentage change at the lumbar spine (P = .02) and the total hip (P = .0001). In the calcitriol group, a significant 1-year LS-BMD increase was associated with BMI (β = 0.0023, P = .02), baseline P1NP (β = 0.00035, P = .0067), history of prior vertebral fracture(s) (β = 0.034, P < .0001) and baseline serum 25(OH)D level (β = -0.00083, P = .02).The presented findings from Chinese postmenopausal osteoporotic women suggested clinically meaningful baseline and on-treatment characteristics predicting BMD improvement after 1 year of ALN/D5600 treatment, which differed from calcitriol treatment with baseline identifiable associations. The study remained exploratory and further accumulation of evidence is needed.
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The D-vitamin metabolite 1,25(OH)2 D in serum is associated with disease activity and Anti-Citrullinated Protein Antibodies in active and treatment naïve, early Rheumatoid Arthritis Patients.
Herly, M, Stengaard-Pedersen, K, Vestergaard, P, Østergaard, M, Junker, P, Hetland, ML, Hørslev-Petersen, K, Ellingsen, T
Scandinavian journal of immunology. 2018;(3):e12704
Abstract
RATIONALE Sufficient levels of vitamin D seem to be essential for proper immune function, and low levels might be associated to disease activity in Rheumatoid Arthritis (RA). Most studies investigate only 25OHD and not the physiologically active vitamin D metabolite, 1,25(OH)2 D. OBJECTIVE To investigate associations between serum level of vitamin D metabolites and disease activity parameters in 160 inflammatory active and treatment naïve early RA patients. Serum level of vitamin D metabolites (25OHD2 , 25OHD3 and 1,25(OH)2 D) was measured by isotope dilution mass spectrometry and radio-immunoassays at baseline. Disease characteristics were gender, number of tender joints, number of swollen joints, DAS28-CRP, HAQ, VAS-scores, CRP, erosive status (Total Sharp Score; TSS), ACPA and IgM-RF-status. Associations were evaluated using Spearman's and Wilcoxon rank-sum tests. The study was registered in clinical trials; trial registration number: NCT00209859. FINDINGS Statistically significant inverse associations were found between the active metabolite 1,25(OH)2 D and DAS28-CRP (P = 0.004, rho = -0.23), HAQ (P = 0.005, rho = -0.22), CRP (P = 0.001, rho = -0.25), VASpatient-pain (P = 0.008, rho = -0.21), and a positive association was found to ACPA-status (P = 0.04). CONCLUSION The vitamin D metabolite 1,25(OH)2 D was inversely associated with disease activity and positively associated with ACPA in treatment naïve and inflammatory active early RA. The results indicate that in RA, both the degree of inflammatory activity, and the diagnostic sensitivity and specificity might affect-or might be affected by the level of vitamin 1,25(OH)2 D.
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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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Abstract
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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25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 exert distinct effects on human skeletal muscle function and gene expression.
Hassan-Smith, ZK, Jenkinson, C, Smith, DJ, Hernandez, I, Morgan, SA, Crabtree, NJ, Gittoes, NJ, Keevil, BG, Stewart, PM, Hewison, M
PloS one. 2017;(2):e0170665
Abstract
Age-associated decline in muscle function represents a significant public health burden. Vitamin D-deficiency is also prevalent in aging subjects, and has been linked to loss of muscle mass and strength (sarcopenia), but the precise role of specific vitamin D metabolites in determining muscle phenotype and function is still unclear. To address this we quantified serum concentrations of multiple vitamin D metabolites, and assessed the impact of these metabolites on body composition/muscle function parameters, and muscle biopsy gene expression in a retrospective study of a cohort of healthy volunteers. Active serum 1,25-dihydroxyvitamin D3 (1α,25(OH)2D3), but not inactive 25-hydroxyvitamin D3 (25OHD3), correlated positively with measures of lower limb strength including power (rho = 0.42, p = 0.02), velocity (Vmax, rho = 0.40, p = 0.02) and jump height (rho = 0.36, p = 0.04). Lean mass correlated positively with 1α,25(OH)2D3 (rho = 0.47, p = 0.02), in women. Serum 25OHD3 and inactive 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) had an inverse relationship with body fat (rho = -0.30, p = 0.02 and rho = -0.33, p = 0.01, respectively). Serum 25OHD3 and 24,25(OH)2D3 were also correlated with urinary steroid metabolites, suggesting a link with glucocorticoid metabolism. PCR array analysis of 92 muscle genes identified vitamin D receptor (VDR) mRNA in all muscle biopsies, with this expression being negatively correlated with serum 25OHD3, and Vmax, and positively correlated with fat mass. Of the other 91 muscle genes analysed by PCR array, 24 were positively correlated with 25OHD3, but only 4 were correlated with active 1α,25(OH)2D3. These data show that although 25OHD3 has potent actions on muscle gene expression, the circulating concentrations of this metabolite are more closely linked to body fat mass, suggesting that 25OHD3 can influence muscle function via indirect effects on adipose tissue. By contrast, serum 1α,25(OH)2D3 has limited effects on muscle gene expression, but is associated with increased muscle strength and lean mass in women. These pleiotropic effects of the vitamin D 'metabolome' on muscle function indicate that future supplementation studies should not be restricted to conventional analysis of the major circulating form of vitamin D, 25OHD3.
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Associations between circulating 1,25(OH)₂D concentration and odds of metachronous colorectal adenoma.
Hibler, EA, Molmenti, CL, Lance, P, Jurutka, PW, Jacobs, ET
Cancer causes & control : CCC. 2014;(7):809-17
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Abstract
Cellular-level studies demonstrate that the availability of the secosteroid hormone 1α,25-dihydroxyvitamin D [1,25(OH)2D] to colon cells promotes anti-carcinogenic activities. Although epidemiological data are relatively sparse, suggestive inverse trends have been reported between circulating 1,25(OH)2D concentration and colorectal neoplasia. We therefore sought to evaluate the relationship between circulating 1,25(OH)2D concentrations and odds for metachronous colorectal adenomas among 1,151 participants from a randomized trial of ursodeoxycholic acid for colorectal adenoma prevention. No relationship between 1,25(OH)2D and overall odds for metachronous lesions was observed, with ORs (95% CIs) of 0.80 (0.60-1.07) and 0.81 (0.60-1.10) for participants in the second and third tertiles, respectively, compared with those in the lowest (p-trend = 0.17). However, a statistically significant inverse association was observed between circulating 1,25(OH)2D concentration and odds of proximal metachronous adenoma, with an OR (95% CI) of 0.71 (0.52-0.98) for individuals in the highest tertile of 1,25(OH)2D compared with those in the lowest (p-trend = 0.04). While there was no relationship overall between 1,25(OH)2D and metachronous distal lesions, there was a significantly reduced odds for women, but not men, in the highest 1,25(OH)2D tertile compared with the lowest (OR 0.53; 95% CI 0.27-1.03; p-trend = 0.05; p-interaction = 0.08). The observed differences in associations with proximal and distal adenomas could indicate that delivery and activity of vitamin D metabolites in different anatomic sites in the colorectum varies, particularly by gender. These results identify novel associations between 1,25(OH)2D and metachronous proximal and distal colorectal adenoma, and suggest that future studies are needed to ascertain potential mechanistic differences in 1,25(OH)2D action in the colorectum.
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Regulation of CYP27B1 and CYP24A1 hydroxylases limits cell-autonomous activation of vitamin D in dendritic cells.
Kundu, R, Chain, BM, Coussens, AK, Khoo, B, Noursadeghi, M
European journal of immunology. 2014;(6):1781-90
Abstract
The active vitamin D metabolite 1α,25-dihydroxyvitamin D (1,25[OH]₂ D) potently inhibits DC priming of T-cell activation, suggesting that it mediates a homeostatic role in this context. Therefore, careful regulation of 1,25[OH]₂ D levels is necessary to avoid inappropriate inhibition of T-cell activation. Cell-autonomous control of vitamin D activity can be modulated by the action of the vitamin D-activating and -inactivating hydroxylases, CYP27B1, and CYP24A1, respectively. We show that in comparison to macrophages, human monocyte-derived DCs exhibit significantly less activation of 25-dihydroxyvitamin D to 1,25[OH]₂ D, and that DCs predominantly express a truncated CYP27B1 transcript that may contribute to the deficiency in activation of vitamin D. Furthermore, in response to stimulation with 1,25[OH]₂ D, upregulation of the inactivating enzyme CYP24A1 curtailed the functional effects of vitamin D in DCs, but not macrophages. Production of 1,25[OH]₂ D by macrophages was adequate to induce expression of vitamin D-responsive genes by DCs, inhibit DC maturation in response to innate immune stimulation and DC-dependent T-cell responses. Our data suggest that in comparison to macrophages, differential regulation of hydroxylases limits autocrine vitamin D activity in DCs, and that paracrine activation of vitamin D exerts a more potent mechanism for homeostatic control of DC function.
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Serum 1,25-dihydroxyvitamin d and the development of kidney dysfunction in a Japanese community.
Izumaru, K, Ninomiya, T, Nagata, M, Usui, T, Yoshida, D, Yonemoto, K, Fukuhara, M, Tsuruya, K, Kitazono, T, Kiyohara, Y
Circulation journal : official journal of the Japanese Circulation Society. 2014;(3):732-7
Abstract
BACKGROUND Recent evidence indicates that vitamin D deficiency is associated with an increased risk of renal impairment, but studies addressing the influence of vitamin D deficiency on the development of chronic kidney disease (CKD) in the general Asian population have been few. METHODS AND RESULTS A total of 2,417 community-dwelling individuals without CKD stage 3-5 aged ≥40 years were followed for 5 years (mean age, 60 years; women, 59.1%). The cumulative incidence of CKD stage 3-5, defined as estimated glomerular filtration rate (eGFR) <60ml·min(-1)·1.73m(-2), and the rate of decline in eGFR according to quartile of serum 1,25-dihydroxyvitamin D (1,25(OH)2D), were estimated. During follow-up, 378 subjects experienced CKD stage 3-5. The age- and sex-adjusted incidence of CKD stage 3-5 increased significantly with decreasing serum 1,25(OH)2D (P for trend <0.001). Compared with the highest quartile, the multivariate-adjusted odds ratio for the development of CKD stage 3-5 was 1.90 in the lowest quartile and 1.74 in the second lowest quartile, after adjusting for confounding factors. Additionally, lower serum 1,25(OH)2D was significantly associated with a greater change in eGFR (-0.10ml·min(-1)·1.73m(-2)·year(-1) per 10-pg/ml decrement in serum 1,25(OH)2D). CONCLUSIONS Lower serum 1,25(OH)2D is a significant risk factor for the development of CKD stage 3-5 in the general Asian population.
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Individualized therapy to prevent bone mineral density loss after kidney and kidney-pancreas transplantation.
Mainra, R, Elder, GJ
Clinical journal of the American Society of Nephrology : CJASN. 2010;(1):117-24
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Abstract
BACKGROUND AND OBJECTIVES Most patients who undergo kidney or kidney-pancreas transplantation have renal osteodystrophy, and immediately after transplantation bone mineral density (BMD) commonly falls. Together, these abnormalities predispose to an increased fracture incidence. Bisphosphonate or calcitriol therapy can preserve BMD after transplantation, but although bisphosphonates may be more effective, they pose potential risks for adynamic bone. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 153 kidney (61%) and kidney-pancreas (39%) transplant recipients were allocated to bisphosphonate (62%) or calcitriol (38%) therapy using an algorithm that incorporated BMD, prevalent vertebral fracture, biomarkers of bone turnover, and risk factor assessment. Patients received cholecalciferol and calcium as appropriate and were followed for 12 mo. RESULTS Patients who were treated with bisphosphonates had lower BMD at the lumbar spine and femoral neck and longer time on dialysis. Age and gender were similar between the groups. At 12 mo, bisphosphonate-treated patients had significant BMD increases at the lumber spine and femoral neck and a negative trend at the wrist. Patients who were allocated to calcitriol, who were assessed to have lower baseline fracture risk, had no significant change in BMD at any site. At 1 yr, mean levels of bone turnover marker and intact parathyroid hormone normalized in both groups. Incident fracture rates did not differ significantly. CONCLUSIONS With targeted treatment, BMD levels were stable or improved and bone turnover markers normalized. This algorithm provides a guide to targeting therapy after transplantation that avoids BMD loss and may reduce suppression of bone turnover.
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Treatment of X-linked hypophosphatemia with calcitriol and phosphate increases circulating fibroblast growth factor 23 concentrations.
Imel, EA, DiMeglio, LA, Hui, SL, Carpenter, TO, Econs, MJ
The Journal of clinical endocrinology and metabolism. 2010;(4):1846-50
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Abstract
CONTEXT X-Linked hypophosphatemia (XLH) is characterized by renal phosphate wasting, with inappropriately low or normal serum 1,25-dihydroxyvitamin D concentrations causing rickets and osteomalacia. Mutations in PHEX result in increased fibroblast growth factor 23 (FGF23) expression, elevating circulating FGF23 concentrations. Treating XLH with phosphate and calcitriol may further increase FGF23 concentrations, based on in vitro and in vivo models. OBJECTIVE The aim of the study was to investigate whether current standard XLH therapies increase circulating FGF23 concentrations. DESIGN AND SETTING We conducted a prospective observational study of XLH subjects during routine clinical management at two tertiary referral centers. PATIENTS The study included 10 XLH patients (seven children, three adults; age, 2-30 yr) initiating therapy and five XLH patients (age, 18-41 yr) electing not to undergo therapy. INTERVENTION(S): Oral calcitriol and phosphate were administered. MAIN OUTCOME MEASURES We measured circulating intact FGF23 concentrations. RESULTS Baseline circulating FGF23 concentrations were elevated in 14 of 15 subjects, increasing after treatment in most subjects. Follow-up was 14.4 +/- 11.7 months (treatment cohort) and 25 +/- 32 months (nontreatment cohort). FGF23 concentrations increased 132.7 +/- 202.4% from pretreatment to peak during therapy but did not change significantly over time in the nontreatment cohort. FGF23 concentrations were related to phosphate doses (P = 0.04) and nonsignificantly to calcitriol doses (P = 0.06). CONCLUSIONS Treating XLH with phosphate and calcitriol was associated with concurrent increases in circulating FGF23 concentrations, which may diminish therapeutic effect or contribute to complications of therapy. Because it is unknown whether the degree of FGF23 elevation correlates with disease severity in XLH, further study is needed to determine whether adjusting therapy to minimize effects on FGF23 concentration is warranted.
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The effects of increasing serum calcitriol on energy and fat metabolism and gene expression.
Boon, N, Hul, GB, Sicard, A, Kole, E, Van Den Berg, ER, Viguerie, N, Langin, D, Saris, WH
Obesity (Silver Spring, Md.). 2006;(10):1739-46
Abstract
OBJECTIVE Evidence from a number of investigations indicates that calcium intake could be inversely related to body weight through alterations in the 1,25-OH(2)-D(3) metabolism. The objective of this study was to test whether energy and substrate metabolism and adipose tissue enzyme mRNA expression can be altered by changes in serum 1,25-OH(2)-D(3) through oral cholecalciferol supplementation in non-obese human subjects. RESEARCH METHODS AND PROCEDURES An intervention study was used with a treatment period of 7 days. During this intervention, energy expenditure (EE) and substrate metabolism were measured using indirect calorimetry at t = 0, 1, 3, and 7 days, and blood samples were obtained at t = -1, 0, 1, 2, 3, 5 and 7 days. Fat biopsies were obtained at t = 0 and 7 days for determination of expression of genes involved in lipolytic and lipogenic pathways. Subjects from the general community were studied in an ambulatory setting at a university hospital. Ten healthy young men (age, 28 +/- 3 years; BMI, 25.5 +/- 0.5 kg/m(2)) were recruited by local announcement, and all completed the study. All subjects received 2000 IU cholecalciferol/d for 7 days, and they were instructed to consume a low-cholecalciferol, low-calcium diet. EE, fat oxidation, and adipose tissue enzyme mRNA were the main outcome measures. RESULTS Despite a significant increase in serum 1,25-OH(2)-D(3) concentration at t = 5 and 7 days, no significant differences in substrate and energy metabolism nor mRNA concentrations of different lipid metabolism-related proteins were observed. DISCUSSION Seven-day supplementation with 2000 IU cholecalciferol/d together with a decrease in dietary calcium intake does not affect EE or substrate metabolism nor gene expression of proteins related to fat metabolism, despite a significant increase in serum 1,25-OH(2)-D(3) concentration.