Nonskeletal and skeletal effects of high doses versus low doses of vitamin D3 in renal transplant recipients: Results of the VITALE (VITamin D supplementation in renAL transplant recipients) study, a randomized clinical trial.

Vitamin D sufficiency is associated with a reduced risk of fractures, diabetes mellitus, cardiovascular events, and cancers, which are frequent complications after renal transplantation. The VITALE (VITamin D supplementation in renAL transplant recipients) study is a multicenter double-blind randomized trial, including nondiabetic adult renal transplant recipients with serum 25-hydroxy vitamin D (25(OH) vitamin D) levels of <30 ng/mL, which is randomized 12 to 48 months after transplantation to receive high (100 000 IU) or low doses (12 000 IU) of cholecalciferol every 2 weeks for 2 months and then monthly for 22 months. The primary outcome was a composite endpoint, including diabetes mellitus, major cardiovascular events, cancer, and death. Of 536 inclusions (50.8 [13.7] years, 335 men), 269 and 267 inclusions were in the high-dose and low-dose groups, respectively. The serum 25(OH) vitamin D levels increased by 23 versus 6 ng/mL in the high-dose and low-dose groups, respectively (P < .0001). In the intent-to-treat analysis, 15% versus 16% of the patients in the high-dose and low-dose groups, respectively, experienced a first event of the composite endpoint (hazard ratio, 0.94 [0.60-1.48]; P = .78), whereas 1% and 4% of patients in the high-dose and low-dose groups, respectively, experienced an incident symptomatic fracture (odds ratio, 0.24 [0.07-0.86], P = .03). The incidence of adverse events was similar between the groups. After renal transplantation, high doses of cholecalciferol are safe but do not reduce extraskeletal complications (trial registration: ClinicalTrials.gov; identifier: NCT01431430).

Vitamin D3 Prevents Calcium-Induced Progression of Early-Stage Prostate Tumors by Counteracting TRPC6 and Calcium Sensing Receptor Upregulation.

Active surveillance has emerged as an alternative to immediate treatment for men with low-risk prostate cancer. Accordingly, identification of environmental factors that facilitate progression to more aggressive stages is critical for disease prevention. Although calcium-enriched diets have been speculated to increase prostate cancer risk, their impact on early-stage tumors remains unexplored. In this study, we addressed this issue with a large interventional animal study. Mouse models of fully penetrant and slowly evolving prostate tumorigenesis showed that a high calcium diet dramatically accelerated the progression of prostate intraepithelial neoplasia, by promoting cell proliferation, micro-invasion, tissue inflammation, and expression of acknowledged prostate cancer markers. Strikingly, dietary vitamin D prevented these calcium-triggered tumorigenic effects. Expression profiling and in vitro mechanistic studies showed that stimulation of PC-3 cells with extracellular Ca2+ resulted in an increase in cell proliferation rate, store-operated calcium entry (SOCE) amplitude, cationic channel TRPC6, and calcium sensing receptor (CaSR) expression. Notably, administration of the active vitamin D metabolite calcitriol reversed all these effects. Silencing CaSR or TRPC6 expression in calcium-stimulated PC3 cells decreased cell proliferation and SOCE. Overall, our results demonstrate the protective effects of vitamin D supplementation in blocking the progression of early-stage prostate lesions induced by a calcium-rich diet. Cancer Res; 77(2); 355-65. ©2016 AACR.

Anti-inflammatory properties of Lipidosterolic extract of Serenoa repens (Permixon®) in a mouse model of prostate hyperplasia.

BACKGROUND: Permixon®, the hexanic lipidosterolic extract of saw palmetto Serenoa repens (LSESr), has shown properties that highlight its benefit in the management of benign prostate hyperplasia (BPH). To address its actual anti-inflammatory potency, we used a unique pro-inflammatory mouse model of prostate hyperplasia involving prostate-specific over-expression of prolactin transgene (Pb-Prl). METHODS: Six month-old Pb-Prl males were administered with Permixon® per os at the daily dose of 100 mg/kg for 28 days. Body and prostate weights were measured weekly and at sacrifice, respectively. Prostate histology was carefully assessed by a pathologist and detailed quantifications of epithelial and stromal compartments were performed using image analysis software. Luminal cell proliferation index was determined using Ki-67 immunostaining, and apoptosis using Bax/Bcl2 mRNA ratio. Tissue inflammation and fibrosis were assessed by histological analyses then quantified using CD45 immunostaining and picrosirius staining, respectively. Expression profiling of selected pro-inflammatory cytokines, chemokines, and chemokine receptors was performed by quantitative RT-PCR. RESULTS: In this model, Permixon® significantly decreased tissue weight and proliferation index specifically in the ventral lobe. Although treatment had no noticeable effect on epithelial histology of any lobe, it markedly reduced the histological hallmarks of inflammation in all lobes. This was confirmed by the global down-regulation of prostate pro-inflammatory cytokine profile, with significant reduction of CCR7, CXCL6, IL-6, and IL-17 expression. CONCLUSIONS: In this mouse model of prostate hyperplasia, Permixon® exerted potent anti-inflammatory properties in the whole prostate while anti-androgenic effects were lobe-specific, suggesting that distinct LSESr components may be involved in these effects. Our results support the beneficial role of Permixon® treatment for BPH. The relevance of CCR7, CXCL6, IL-6, and IL-17 as potential biomarkers to follow up BPH inflammatory status needs to be assessed.

Determination of optimal vitamin D3 dosing regimens in HIV-infected paediatric patients using a population pharmacokinetic approach.

AIMS: To investigate 25-hydroxycholecalciferol [25(OH)D] population pharmacokinetics in children and adolescents, to establish factors that influence 25(OH)D pharmacokinetics and to assess different vitamin D3 dosing schemes to reach sufficient 25(OH)D concentrations (>30 ng ml(-1) ). METHODS: This monocentric prospective study included 91 young HIV-infected patients aged 3 to 24 years. Patients received a 100 000 IU vitamin D3 supplementation. A total of 171 25(OH)D concentrations were used to perform a population pharmacokinetic analysis. RESULTS: At baseline 28% of patients had 25(OH)D concentrations below 10 ng ml(-1) , 69% between 10 and 30 ng ml(-1) and 3% above 30 ng ml(-1) . 25(OH)D pharmacokinetics were best described by a one compartment model with an additional production parameter reflecting the input from diet and sun exposure. The effects of skin phototype and bodyweight were significant on 25(OH)D production before any supplementation. The basal level was 27% lower in non-white skin phototype patients and was slightly decreased with bodyweight. No significant differences in 25(OH)D concentrations were related to antiretroviral drugs. To obtain concentrations between 30 and 80 ng ml(-1) , patients with baseline concentrations between 10 and 30 ng ml(-1) should receive 100 000 IU per 3 months. However, vitamin D deficient patients (<10 ng ml(-1) ) would need an intensive phase of 100 000 IU per 2 weeks (two times) followed 2 weeks later by a maintenance phase of 100 000 IU per 3 months. CONCLUSIONS: Skin phototype and bodyweight had an influence on the basal production of 25(OH)D. According to 25(OH)D baseline concentrations, dosing schemes to reach sufficient concentrations are proposed.

Determination of optimal cholecalciferol treatment in renal transplant recipients using a population pharmacokinetic approach.

PURPOSE: No information on optimal cholecalciferol dosing in kidney transplant patients is currently available because the time-course of serum 25-hydroxy vitamin D [25(OH)D] concentration has never been investigated. The aim of this study was to investigate 25(OH)D pharmacokinetics in renal transplant recipients and to determine the optimal dosage scheme allowing 25(OH)D concentrations to be maintained between 30-80 ng/mL during the first year post-transplantation. METHODS: Four months after renal transplantation, 49 patients received four oral doses of 100,000 IU cholecalciferol every 2 weeks (intensive phase), then every 2 months until 1 year after transplantation (maintenance phase). A control group of 47 transplanted patients was not supplemented but underwent blood sampling. In the treated group, 74 samples were collected before the first cholecalciferol administration and 119 thereafter. Two blood samples per patient were collected in the control group. Serum 25(OH)D concentrations were analyzed using a population approach. The turnover of 25(OH)D was modeled using a one-compartment-model with first-order formation and elimination and basal concentration. RESULTS: The mean population parameter estimates and the associated between-subject variability were: formation rate constant (k(f)), 0.11 day(-1); clearance (CL/F), 2.5 L/day (0.42); central volume of distribution (V(C)/F), 237 L; basal concentration (C(0)),12.82 ng/mL (0.41). Based on these values, in order to maintain 25(OH)D concentrations between 30 and 80 ng/mL, cholecalciferol dosing should be six successive administrations of 100,000 IU at 2-week intervals, followed by 100,000 IU once a month until the end of the first year. CONCLUSIONS: We present here the first pharmacokinetic model describing the time-course of 25(OH)D. We propose an optimal and practical scheme for the treatment of vitamin D insufficiency after renal transplantation. Taking into account the numerous effects of vitamin D on health, this scheme could help clinicians improve the care of kidney recipients.

Relationship between vitamin D deficiency and bone fragility in sickle cell disease: a cohort study of 56 adults.

BACKGROUND: Recent studies suggest that patients with sickle cell disease (SCD) have profound vitamin D (VD) deficiency. Limited data exist on the effect of VD deficiency on bone fragility in these patients. OBJECTIVES: To assess the prevalence of VD deficiency in adults with SCD and its consequences on bone metabolism and fragility. METHODS: This prospective study included 56 SCD adult patients (mean age 29.8 ± 9.5 years), in a clinically steady state. Clinical and laboratory data were recorded. Bone mineral density (BMD) was measured using dual X-ray absorptiometry. Fracture history, BMD, avascular osteonecrosis, H-shaped vertebra and markers of mineral metabolism were compared between two groups of patients presenting very low (≤ 6 ng/mL, n=26) (group 1) and low (>6 ng/mL, n=26) (group 2) 25(OH)D concentration, respectively. RESULTS: Median 25(OH)D concentration was 6 ng/mL. VD deficiency (25(OH)D <10 ng/mL) was found in 42 out of 56 patients (75%) and secondary hyperparathyroidism in 40 (71.4%). History of fracture was documented in 17 patients (30.3%), osteopenia and/or osteoporosis in 39.6% of patients. Overall, patients of group 1 were more likely to have sustained a fracture (42.8%) compared to patients of group 2 (17.8%) (p=0.04). These patients had also lower body mass index and significantly higher parathyroid hormone, C-terminal telopeptides of type I-collagen and bone-specific alkaline phosphatase serum levels. There was no difference between group for BMD, avascular osteonecrosis history, H-shaped vertebra, and disease severity markers. CONCLUSION: This study suggests that VD deficiency is a key feature in SCD-bone disease. It is highly prevalent and associated with hyperparathyroidism, bone resorption markers, and history of fracture. The optimal supplementation regimen remains to be determined.

Vitamin D and primary hyperparathyroidism (PHPT).

Vitamin D deficiency and PHPT are two common conditions, especially in postmenopausal women. Vitamin D deficiency is said to be even more frequent in PHPT patients than in the general population due to an accelerated conversion of 25OHD into calcitriol or 24-hydroxylated compounds. Although several studies have reported worsening of PHPT phenotype (larger tumours, higher PTH levels, more severe bone disease) when vitamin D deficiency coexists whereas vitamin D supplementation in PHPT patients with a serum calcium level<3 mmol/L has been shown to be safe (no increase in serum or urinary calcium) and to decrease serum PTH concentration, that many physicians are afraid to give vitamin D to already hypercalcemic PHPT patients. On the other hand, it is possible that, in some patients, a persistent vitamin D deficiency induces, in the long-term, an autonomous secretion of PTH (i.e. tertiary hyperparathyroidism). The mechanism by which this could occur is unclear however. Finally, as many, otherwise normal, subjects with vitamin D insufficiency may have an increased serum PTH level we believe that those with vitamin D insufficiency should be excluded from a reference population for serum PTH levels. By doing that, we found that the upper normal limit for serum PTH was 25-30% lower than in the whole population.

Effects of vitamin D supplementation on the calcium-phosphate balance in renal transplant patients.

Low serum levels of 25-hydroxy vitamin D frequently occur after renal transplantation, but few studies have evaluated the effects of normalizing this on serum parathyroid hormone and calcium levels or urinary calcium excretion. To determine this we compared the outcomes of 94 renal transplant patients with low 25-hydroxy vitamin D and normal serum calcium levels who were either treated or not with cholecalciferol every 2 weeks for 2 months (intensive phase) followed by an every other month maintenance phase. The biological characteristics of the two equally divided patient groups did not differ before treatment. After the intensive phase, serum 25-hydroxy vitamin D levels were normalized in all but 3 patients and the serum parathyroid hormone decreased and calcium levels increased with no severe adverse effects. During the maintenance phase, the serum 25-hydroxy vitamin D level decreased but remained significantly higher than in controls. In the control group, the serum 25-hydroxy vitamin D concentration increased slightly but became normal in only three patients. Serum 25-hydroxy vitamin D levels were significantly higher and parathyroid hormone levels were lower in treated patients compared to controls one year following transplant. Hence, cholecalciferol treatment significantly increased serum 25-hydroxy vitamin D and decreased parathyroid hormone levels with no adverse effects in 25-hydroxy vitamin D-deficient renal transplant patients.

Evaluating vitamin D status. Implications for preventing and managing osteoporosis and other chronic diseases.

Recent studies have added new dimensions to the fund of knowledge on vitamin D. In addition to the classic role of vitamin D in preventing rickets and osteomalacia, a preventive effect against osteoporotic fractures has been convincingly established, and abundant evidence suggests a role in preventing malignancies and autoimmune diseases. Serum 25-OH-vitamin D assay is a simple test for evaluating vitamin D status. However, recent review articles indicate that current reference ranges for serum 25-OH-vitamin D are too low. An appropriate lower normal limit may be between 50-100 nmol/l (20-40 ng/ml). Standard supplement dosages may fail to provide concentrations above this range.