A pilot-randomized, double-blind crossover trial to evaluate the pharmacokinetics of orally administered 25-hydroxyvitamin D3 and vitamin D3 in healthy adults with differing BMI and in adults with intestinal malabsorption.

BACKGROUND: Obese and malabsorptive patients have difficulty increasing serum 25-hydroxyvitamin D [25(OH)D] after taking vitamin D supplementation. Since 25(OH)D is more hydrophilic than vitamin D, we hypothesized that oral 25(OH)D supplementation is more effective in increasing serum 25(OH)D concentrations in these patients. OBJECTIVES: We aimed to investigate the pharmacokinetics of oral 25-hydroxyvitamin D3 [25(OH)D3] and oral vitamin D3 in healthy participants with differing BMI and malabsorptive patients. METHODS: A randomized, double-blind crossover trial was performed in 6 malabsorptive patients and 10 healthy participants who were given 900 µg of either vitamin D3 or 25(OH)D3 orally followed by a pharmacokinetic study (PKS). After ≥28 d from the first dosing, each participant returned to receive the other form of vitamin D and undergo another PKS. For each PKS, serum vitamin D3 and 25(OH)D3 were measured at baseline and at 2, 4, 6, 8, and 12 h and days 1, 2, 3, 7, and 14. Pharmacokinetic parameters were calculated. RESULTS: Data were expressed as means ± SEMs. The PKS of 900 µg vitamin D3 revealed that malabsorptive patients had 64% lower AUC than healthy participants (1177 ± 425 vs. 3258 ± 496 ng · h/mL; P < 0.05). AUCs of 900 µg 25(OH)D3 were not significantly different between the 2 groups (P = 0.540). The 10 healthy participants were ranked by BMI and categorized into higher/lower BMI groups (5/group). The PKS of 900 µg vitamin D3 showed that the higher BMI group had 53% lower AUC than the lower BMI group (2089 ± 490 vs. 4427 ± 313 ng · h/mL; P < 0.05), whereas AUCs of 900 µg 25(OH)D3 were not significantly different between the 2 groups (P = 0.500). CONCLUSIONS: Oral 25(OH)D3 may be a good choice for managing vitamin D deficiency in malabsorption and obesity. This trial was registered at clinicaltrials.gov as (NCT03401541.

Reduction in Bone Loss from 5 to 20 Weeks Postpartum in Adolescents Supplemented with Calcium Plus Vitamin D during Pregnancy Is Not Sustained at 1 Year Postpartum: Follow-up Study of a Randomized Controlled Trial.

BACKGROUND: Calcium plus vitamin D supplementation of pregnant Brazilian adolescents with habitually low calcium intake (∼600 mg/d) reduced bone loss during the first 20 wk postpartum. OBJECTIVE: We investigated maternal bone mass changes during the first year postpartum as a follow-up of the clinical trial. METHODS: Pregnant adolescents (14-19 y) received calcium (600 mg/d) plus cholecalciferol (200 IU/d) supplementation (n = 30) or placebo (n = 26) from 26 wk of gestation until parturition. Bone area and bone mineral content and bone mineral density (BMD) at total body, lumbar spine, and hip (total and femoral neck) were assessed by DXA at 3 time points postpartum (5 wk, 20 wk, and 56 wk). Intervention group, time postpartum, and group × time interaction effects were tested by repeated-measures mixed-effects models adjusting for calcium intake, return of menses, breastfeeding practices, and body weight. RESULTS: Time (P < 0.05) but not group affected several absolute bone measurements. There was a group × time interaction for femoral neck BMD (P = 0.045). Mean ± SE values (g/cm2) at 5 wk, 20 wk, and 56 wk were, respectively, 1.025 ± 0.026, 0.980 ± 0.026, and 1.022 ± 0.027 for the placebo group and 1.057 ± 0.025, 1.030 ± 0.024, and 1.055 ± 0.025 for the supplemented group. An interaction also was observed for percentage change in femoral neck BMD relative to 5 wk (P = 0.049), with a more pronounced decrease in the placebo group (-4.58 ± 0.42%) than in the supplemented group (-3.15% ± 0.42%) at 20 wk (P = 0.019), and no difference between groups at 56 wk (-0.44% ± 0.71% in the placebo and -0.76% ± 0.62% in the supplemented group; P = 0.65). CONCLUSIONS: Calcium plus vitamin D supplementation of the adolescent mothers reduces the magnitude of bone loss at the femoral neck from 5 to 20 wk postpartum without an effect on bone changes after 1 y postpartum, indicating that there is no sustained effect of the supplement tested.

The joint effect of energy reduction with calcium supplementation on the risk factors of type 2 diabetes in the overweight population: a two-year randomized controlled trial.

Both excessive energy intake and low calcium intake are inversely associated with the aging-related diseases, particularly for type 2 diabetes mellitus(T2DM). This study examined whether energy reduction coupled with calcium supplementation aided in the prevention of T2DM among the overweight population. A randomized controlled trial(RCT) of 1021 overweight participants was performed, in which participants were randomly assigned to 4 groups: 1) energy-reduction group(ERG), 2) calcium supplementation group(CSG), 3) energy-reduction with calcium supplementation group(ER-CSG), 4) control group(CG). Nutritional habits, anthropometric and diabetes-related indicators were measured at baseline and each follow-up time. To analyze the separate effects of dietary energy reduction and calcium supplementation, ERG and ER-CSG were integrated into ERGs. Similarly, CSG and ER-CSG were integrated into CSGs. Compared to the non-energy-reduction groups(NERGs), ERGs had lower values of ΔBMI(-0.9kg/m2), ΔFSG (-0.34mmol/L), ΔHbA1c(0.16%), and ΔHOMA-IR(-0.13), and higher value of ΔGutt index(-5.82). Compared to the non-calcium supplementation groups(NCSGs), the ΔGutt index(-5.46) in CSGs showed a significant decrease. Moreover, these risk factors for T2DM were most effectively ameliorated in ER-CSG group with the decreased values of ΔFSG(-0.42mmol/L), ΔGutt index(-0.73), and the slowest increasing rate value of Δ2h-glucose(0.37mmol/L). This RCT demonstrated that energy-reduction with calcium supplementation was a useful dietary intervention strategy for preventing the development of T2DM in the overweight population.

Effect of 1-year oral cholecalciferol on a metabolic profile and blood pressure in poor-controlled type 2 diabetes mellitus: an open-label randomized controlled pilot study.

PURPOSE: Hypovitaminosis D has been associated with many cardio-metabolic disorders, although their pathogenetic link still remains unclear. Our aim was to evaluate whether 1-year vitamin D (D) supplementation could improve glycemic control, lipid profile, systolic (SBP) and diastolic (DBP) blood pressure levels and body composition. METHODS: In an open-label randomized-controlled pilot study, thirty poor-controlled (HbA1c > 59 mmol/mol) type 2 diabetic patients (age 71.5 ± 3.2 years, M/F 21/9, BMI 29.8 ± 3.6 kg/m2) with hypovitaminosis D (25OHD 22.0 ± 11.3 nmol/l) were randomized to cholecalciferol supplementation (500 UI/kg p.o. weekly, + D) or observation (- D) for one year. Changes in parameters of glucose, lipid and blood pressure control at 3, 6, 9 and 12 months vs. baseline were assessed. RESULTS: One-year D supplementation restored D status and had a beneficial effect on fasting glucose (FG, mean percentage changes ± SD, - 1.8% ± 23.1 vs. + 18.8% ± 30.0), glycosylated haemoglobin (HbA1c, - 13.7% ± 14.5 vs. - 4.2% ± 14.1), SBP (- 13.4% ± 8.5 vs. - 2.4% ± 12.6) and HDL-cholesterol levels (- 2.1% ± 14.0 vs. - 10.9% ± 12.9; p < 0.05 for all comparisons) in + D vs. - D patients, respectively. In the former, a reduction in HBA1c, SBP and DBP levels, BMI, fat mass index (FMI) and ratio (FMR) was observed after 1 year (p < 0.05 for all comparisons vs. baseline). We noticed a relationship between 1-year mean percentage changes of serum 25OHD and SBP levels (R = - 0.36, p < 0.05). CONCLUSION: One-year cholecalciferol supplementation, able to restore D status, significantly improves FG, HbA1c, SBP and HDL-cholesterol levels in patients with poor-controlled type 2 diabetes mellitus and D deficiency.

[Iatrogenic non uremic calciphylaxis: A case report]. / Calciphylaxie non urémique iatrogène : une nouvelle observation.

Calciphylaxis is a rare and severe condition, characterized by calcification and thrombosis of small vessels, mainly affecting the skin. It is most often described in patients with end-stage renal disease on dialysis. Rarer cases of non-uremic calciphylaxis are reported. The prognosis is grim and the treatment is not well codified. Sodium thiosulfate has been used for more than a decade in the treatment of uremic calciphylaxis and has been shown to be effective. Its use in non-uremic cases has been reported in a few rare observations. Rheopheresis is a technique very recently used as an adjuvant treatment in uremic calciphylaxis. We describe a case of non-uremic calciphylaxis in a patient with normal renal function and with calcium supplementation. Sodium thiosulfate was introduced, then discontinued due to the patient's poor tolerance for this treatment. Rheopheresis was then used and allowed the acceleration of healing process and a significant reduction in pain. These two treatments are promising, larger studies are needed to establish their effectiveness in non-uremic calciphylaxis.

Neuromuscular tetanic hyperexcitability syndrome associated to a heterozygous Kv1.1 N255D mutation with normal serum magnesium levels.

Mutations of the main voltage-gated K channel members Kv1.1 are linked to several clinical conditions, such as periodic ataxia type 1, myokymia and seizure disorders. Due to their role in active magnesium reabsorption through the renal distal convoluted tubule segment, mutations in the KCNA1 gene encoding for Kv1.1 has been associated with hypomagnesemia with myokymia and tetanic crises. Here we describe a case of a young female patient who came to our attention for a history of muscular spasms, tetanic episodes and muscle weakness, initially misdiagnosed for fibromyalgia. After a genetic screening she was found to be carrier of the c.736A > G (p.Asn255Asp) mutation in KCNA1, previously described in a family with autosomal dominant hypomagnesemia with muscular spasms, myokymia and tetanic episodes. However, our patient has always presented normal serum and urinary magnesium values, whereas she was affected by hypocalcemia. Calcium supplementation gave only partial clinical benefit, with an improvement on tetanic episodes yet without a clinical remission of her spasms, whereas magnesium supplementation worsened her muscular symptomatology.

Exploring the effect of vitamin D3 supplementation on surrogate biomarkers of cholesterol absorption and endogenous synthesis in patients with type 2 diabetes-randomized controlled trial.

BACKGROUND: Inverse associations have been reported between serum 25-hydroxyvitamin D [25(OH)D] and circulating cholesterol concentrations in observational studies. Postulated mechanisms include reduced bioavailability of intestinal cholesterol and alterations in endogenous cholesterol synthesis. OBJECTIVE: To explore the effect of daily supplementation with 4000 IU/d vitamin D3 for 24 wk on surrogate biomarkers of cholesterol absorption (campesterol and ß-sitosterol) and endogenous synthesis (lathosterol and desmosterol). METHODS: Ancillary study of The Vitamin D for Established Type 2 Diabetes (DDM2) trial. Patients with established type 2 diabetes (N = 127, 25-75 y, BMI 23-42 kg/m2) were randomly assigned to receive either 4000 IU vitamin D3 or placebo daily for 24 wk. Of participants without changes in cholesterol-lowering medications (n = 114), plasma surrogate cholesterol absorption and endogenous synthesis biomarker concentrations were measured and merged with available measures of serum LDL cholesterol and HDL cholesterol concentrations. RESULTS: At week 24, vitamin D3 supplementation significantly increased 25(OH)D concentrations (+21.5 ± 13.4 ng/mL) but not insulin secretion rates (primary outcome of the parent study) as reported previously. In this ancillary study there was no significant effect of vitamin D3 supplementation on serum cholesterol profile or surrogate biomarkers of cholesterol absorption and endogenous synthesis. Compared with participants not treated with cholesterol-lowering medications, those who were treated exhibited a greater reduction in plasma campesterol concentrations in the vitamin D3 but not placebo group (P-interaction = 0.011). Analyzing the data on the basis of cholesterol absorption status (hypo- versus hyperabsorbers) or cholesterol synthesis status (hypo- versus hypersynthesizers) did not alter these results. CONCLUSIONS: Vitamin D3 supplementation for 24 wk had no significant effect on surrogate biomarkers of cholesterol absorption or endogenous synthesis, consistent with the lack of effect on serum cholesterol profile. Vitamin D3 supplementation resulted in greater reduction in campesterol concentrations in participants not using compared with those using cholesterol-lowering medications. Further studies are required.This trial was registered at clinicaltrials.gov as NCT01736865.

[Cholecalciferol supplementation improves secondary hyperparathyroidism control in hemodialysis patients].

Introduction: Vitamin D deficiency is common among hemodialysis (HD) patients and is an important component in the pathogenesis of secondary hyperparathyroidism (SHPT). We herein report our experience on the impact of cholecalciferol supplementation on PTH levels in a group of HD patients. Patients and methods: We selected 122 HD patients. The main selection criteria were 25- hydroxyvitamin D (25(OH)D) levels ≤30 ng/mL and SHPT defined as PTH levels >300 pg/mL or PTH levels between 150-300 pg/mL during therapy with cinacalcet or paricalcitol. 82 patients agreed to receive cholecalciferol at the fixed dose of 25,000 IU per week orally for 12 months, while the remaining 40 represented the control group. The main endopoints of the study were the reduction in PTH levels ≥30% compared to baseline values and the increase of 25(OH)D levels to values >30 ng/mL. Results: At follow-up PTH levels decreased in the supplemented group from 476 ±293 to 296 ± 207 pg/mL (p<0.001), 25(OH)D levels increased from 10.3 ± 5.7 to 33.5 ± 11.2 ng/mL (p<0.001), serum calcium increased from 8.6 ± 0.5 to 8.8 ± 0.6 mg/dL (p<0.05) while serum phosphorus did not change. In this group the mean doses of paricalcitol were significantly reduced, from 8.7 ± 4.0 to 6.1 ± 3.9 µg/week (p<0.001). Moreover, in this group there were a significant increase of hemoglobin levels, from 11.6 ± 1.3 to 12.2 ± 1.1 g/dL (p <0.01) and a significant reduction of erythropoietin doses (p<0.05). In the control group the 25(OH)D and PTH levels did not change, while cinacalcet doses increased from 21 ±14 to 43 ± 17 mg/d (p<0.01). Conclusions: Vitamin deficiency is very common in HD patients. Cholecalciferol treatment significantly increased serum 25(OH)D levels, significantly decreased PTH levels and paricalcitol doses, concurrently entailing a better control of anemia.

Flash Fabrication of Orally Targeted Nanocomplexes for Improved Transport of Salmon Calcitonin across the Intestine.

Salmon calcitonin (sCT) is a potent calcium-regulating peptide hormone and widely applied for the treatment of some bone diseases clinically. However, the therapeutic usefulness of sCT is hindered by the frequent injection required, owing to its short plasma half-life and therapeutic need for a high dose. Oral delivery is a popular modality of administration for patients because of its convenience to self-administration and high patient compliance, while orally administered sCT remains a great challenge currently due to the existence of multiple barriers in the gastrointestinal (GI) tract. Here, we introduced an orally targeted delivery system to increase the transport of sCT across the intestine through both the paracellular permeation route and the bile acid pathway. In this system, sCT-based glycol chitosan-taurocholic acid conjugate (GC-T)/dextran sulfate (DS) ternary nanocomplexes (NC-T) were produced by a flash nanocomplexation (FNC) process in a kinetically controlled mode. The optimized NC-T exhibited well-controlled properties with a uniform and sub-60 nm hydrodynamic diameter, high batch-to-batch reproducibility, good physical or chemical stability, as well as sustained drug release behaviors. The studies revealed that NC-T could effectively improve the intestinal uptake and permeability, owing to its surface functionalization with the taurocholic acid ligand. In the rat model, orally administered NC-T showed an obvious hypocalcemia effect and a relative oral bioavailability of 10.9%. An in vivo assay also demonstrated that NC-T induced no observable side effect after long-term oral administration. As a result, the orally targeted nanocomplex might be a promising candidate for improving the oral transport of therapeutic peptides.

Intermittent cholecalciferol supplementation in children and teenagers followed in pediatric nephrology: data from a prospective single-center single-arm open trial.

Vitamin D deficiency is frequent in pediatric nephrology. The 2017 European guidelines recommend keeping 25OH vitamin D (25-D) levels within the 75-120 nmol/L range, ideally with daily supplementation. Intermittent supplementation with D3 has also been proposed. We aimed to assess the influence of our local protocol of intermittent vitamin D supplementation on the evolution of 25-D levels between baseline and 2 months. VITATOL is a prospective single-center study performed in our tertiary unit in children and teenagers followed for chronic kidney disease (CKD), kidney transplantation, or stable chronic nephrotic syndrome with 25-D levels below 75 nmol/L. Intermittent oral cholecalciferol (100,000 IU) was administered depending on baseline vitamin D levels and body weight. The primary outcome was the change in 25-D levels between baseline and 2 months. Secondary outcomes were the evolution of the main mineral biomarkers. Thirty-seven patients were included. Two months after beginning supplementation, corresponding to a median(min-max) of 46 (14-79) days after the last dose of vitamin D, 25-D levels increased from 50 to 76 nmol/L (p < 0.001), 18 patients having 25-D levels within the target range and 2 above. All patients displayed 25-D levels above 50 nmol/L. There were no significant changes in phosphate, PTH, alkaline phosphatase, and FGF23 levels before and after supplementation. Calcium levels increased from 2.39 to 2.44 mmol/L (p = 0.017), but no differences in calciuria and urinary calcium/creatinine ratio were observed.Conclusion: This vitamin D supplementation protocol using intermittent moderate doses of cholecalciferol seems efficient in 54% of cases, with neither significant overdose nor hypercalciuria. What is Known: • Vitamin D deficiency is frequent in pediatric nephrology. • The 2017 European guidelines recommend keeping 25OH vitamin D levels within the 75-120 nmol/L range ideally with daily supplementation, but intermittent supplementation with D3 has also been proposed. What is New: • We assessed the influence of a local protocol of intermittent vitamin D supplementation on the evolution of 25-D levels between baseline and 2 months in children and teenagers followed in pediatric nephrology. • The intermittent cholecalciferol supplementation protocol seems efficient in 54% of cases, with neither significant overdose nor hypercalciuria.

Comparison of fracture risk using different supplemental doses of vitamin D, calcium or their combination: a network meta-analysis of randomised controlled trials.

OBJECTIVE: Inconsistent findings in regard to association between different concentrations of vitamin D, calcium or their combination and the risk of fracture have been reported during the past decade in community-dwelling older people. This study was designed to compare the fracture risk using different concentrations of vitamin D, calcium or their combination. DESIGN: A systematic review and network meta-analysis. DATA SOURCES: Randomised controlled trials in PubMed, Cochrane library and Embase databases were systematically searched from the inception dates to 31 December 2017. OUTCOMES: Total fracture was defined as the primary outcome. Secondary outcomes were hip fracture and vertebral fracture. Due to the consistency of the original studies, a consistency model was adopted. RESULTS: A total of 25 randomised controlled trials involving 43 510 participants fulfilled the inclusion criteria. There was no evidence that the risk of total fracture was reduced using different concentrations of vitamin D, calcium or their combination compared with placebo or no treatment. No significant associations were found between calcium, vitamin D, or combined calcium and vitamin D supplements and the incidence of hip or vertebral fractures. CONCLUSIONS: The use of supplements that included calcium, vitamin D or both was not found to be better than placebo or no treatment in terms of risk of fractures among community-dwelling older adults. It means the routine use of these supplements in community-dwelling older people should be treated more carefully. PROSPERO REGISTRATION NUMBER: CRD42017079624.

Experience of intravenous calcium treatment and long-term responses to treatment in a patient with hereditary vitamin D-resistant rickets resulting from a novel mutation.

Background Vitamin D resistant rickets (HVDRR), is a rare autosomal recessive disorder caused by vitamin D receptor (VDR) gene mutations. There is no standard treatment in HVDRR. Case report The patient was a 3-year-old girl presenting with short stature, genu varum deformity, waddling gait and alopecia. She had hypocalcemia, hypophosphatemia, hyperparathyroidism and normal 1.25-(OH)2D levels. The patient was initially treated with calcitriol and high-dose oral calcium (Ca) for 22 months. The patient was treated with continuous high dose intravenous (i.v.) Ca therapy for 4 months, following initial lack of response to oral Ca and calsitriol. At the end of the 4 months, rickets was dramatically improved and did not recur for 3 years after i.v. Ca therapy. DNA sequence analyses of the VDR gene showed a homozygous novel mutation. Conclusions We identified a novel VDR gene mutation, and we concluded that i.v. Ca therapy from the central catheter is a safe treatment in HVDRR.

Preclinical Prevention Trial of Calcitriol: Impact of Stage of Intervention and Duration of Treatment on Oral Carcinogenesis.

The anticancer activity of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3 or calcitriol) has been widely reported in preclinical models. However, systematic investigation into the chemopreventive potential of calcitriol against the spectrum of oral carcinogenesis has not been performed. To address this gap in knowledge, we conducted a preclinical prevention trial of calcitriol in the 4-nitroquinoline-1-oxide (4NQO) oral carcinogenesis model. C57BL/6 mice were exposed to the carcinogen 4NQO in drinking water for 16 weeks and randomized to control (4NQO only) or calcitriol arms. Calcitriol (0.1 µg i.p, Monday, Wednesday, and Friday) was administered for (i) 16 weeks concurrently with 4NQO exposure, (ii) 10 weeks post completion of 4NQO exposure, and, (iii) a period of 26 weeks concurrent with and following 4NQO exposure. Longitudinal magnetic resonance imaging (MRI) was performed to monitor disease progression until end point (week 26). Correlative histopathology of tongue sections was performed to determine incidence and multiplicity of oral dysplastic lesions and squamous cell carcinomas (SCC). Vitamin D metabolites and calcium were measured in the serum using liquid chromatography-mass spectrometry (LC-MS/MS) and colorimetric assay, respectively. Renal CYP24A1 (24-hydroxylase) and CYP27B1 (1α-hydroxylase) expression was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Immunostaining of tongue sections for vitamin D receptor (VDR), CYP24A1, and Ki67 was also performed. Non-invasive MRI enabled longitudinal assessment of lesions in the oral cavity. Calcitriol administered concurrently with 4NQO for 16 weeks significantly (P < .001) decreased the number of premalignant lesions by 57% compared to 4NQO only controls. Mice treated with calcitriol for 26 weeks showed highest renal CYP24A1, lowest serum 1,25(OH)2D3 levels and highest incidence of invasive SCC. Immunohistochemistry revealed increased VDR, CYP24A1 and Ki67 staining in dysplastic epithelia compared to normal epithelium, in all four groups. Collectively, our results show that the effects of calcitriol on oral carcinogenesis are critically influenced by the stage of intervention and duration of exposure and provide the basis for exploring the potential of calcitriol for prevention of OSCC in the clinical setting.

Pharmacokinetics of a New Pharmaceutical Form of Vitamin D3 100,000 IU in Soft Capsule.

Vitamin D deficiency is frequent in the general population and both subjects and health professionals could benefit from a broader range of vitamin D3 formulations. We conducted a single-dose, open-label, parallel-group, randomized bioequivalence study to compare a single dose of a newly developed vitamin D3 100,000 IU in a soft capsule (Group 1) with the reference drug vitamin D3 100,000 IU oral solution in ampoule (Group 2) in healthy volunteers over a four-month period. The primary endpoint was the area under the curve (AUC) of serum 25-hydroxyvitamin-D (25(OH)D) concentrations on Day 112. This study was conducted in France from February to June 2014 in 53 young adults with a mean age of 26.9 years. At baseline, low mean serum 25(OH)D levels were observed in both groups (10.6 ng/mL in Group 1 and 9.0 ng/mL in Group 2). On Day 112, the AUC of serum 25(OH)D concentration was 2499.4 ± 463.8 nmol/mL (7.8 ± 0.2 for LogAUC) for Group 1 and 2152.3 ± 479.8 nmol/mL (7.6 ± 0.2 for LogAUC) for Group 2. Bioequivalence of the two treatments was not demonstrated. Superiority of vitamin D3 100,000 IU soft capsule was observed with p = 0.029 for AUC and p = 0.03 for LogAUC using a non-parametric Wilcoxon test. The profile of the serum 25(OH)D concentration showed a significant difference in favor of Group 1 on Days 1, 3, 7, 14 and 90. Mean serum 25(OH)D concentrations in Group 1 were between 20 and 30 ng/mL during the four-month period and under 20 ng/mL throughout the study in Group 2, except on Day 112. Mean Cmax for Group 1 was significantly higher (p = 0.002). Fourteen days were needed to reach Tmax by more than half the subjects in Group 1 compared to 45 days in Group 2. Both treatments were well tolerated, with no severe or related adverse events reported. In conclusion, the pharmacokinetic profile of the new formulation of vitamin D3 100,000 IU soft capsule is superior to that of the oral solution in ampoule. The new formulation increased serum 25(OH)D levels to above 20 ng/mL and maintained levels from 20 ng/mL to 30 ng/mL for four months in late winter and spring.

Single injection of PTH improves osteoclastic parameters of remodeling at a stress fracture site in rats.

Stress fractures (SFx) result from repetitive cyclical loading of bone. They are frequent athletic injuries and underlie atypical femoral fractures following long-term bisphosphonate (BP) therapy. We investigated the effect of a single PTH injection on the healing of SFx in the rat ulna. SFx was induced in 120 female Wistar rats (300 ± 15 g) during a single loading session. A single PTH (8 µg.100g-1 ) or vehicle (VEH) saline injection was administered 24 h after loading. Rats were divided into four groups (n = 15) and ulnae were examined 1, 2, 6, or 10 weeks following SFx. Two Toluidine Blue and TRAP-stained sections of the SFx were examined for histomorphometric analysis using Osteomeasure™ software. An increase in osteoclast number (N.Oc) and perimeter (Oc.Pm) was observed two weeks following PTH treatment (p < 0.01). At 6 weeks, bone formation was the main activity in BMUs. At 10 weeks, the proportion of healing along the SFx line remained 50% greater in PTH groups (p = 0.839), leading to a 43% reduction in the porosity area of BMU (p = 0.703). The main effect of time was a significant variable along the entire SFx remodeling cycle, with significant interactions between time and treatment type affecting (N.Oc) (p = 0.047) and (Oc.Pm) (p = 0.002). We conclude that a single PTH injection increases osteoclastogenesis by the second week of the remodeling cycle in a SFx in vivo. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.

Vitamin D and health in the Mediterranean countries.

Vitamin D, traditionally well known for its role in maintaining optimal health through its contribution to calcium metabolism and skeletal health, has received increased attention over the past two decades, with considerable focus being placed on its nonskeletal benefits. This paper is a narrative review of the nonskeletal health benefits of vitamin D, of particular interest to inhabitants of Mediterranean countries, namely, autism, cancer, cardiovascular disease, chronic obstructive pulmonary disease, dental caries, diabetes mellitus, erectile dysfunction, hypertension, metabolic syndrome, respiratory tract infections, all-cause mortality, and pregnancy and birth outcomes, because of the relatively high incidence and/or prevalence of these disorders in this region. Currently, the best evidence is coming out of observational studies related to serum 25-hydroxyvitamin D [25(OH)D] concentrations. Vitamin D clinical trials have generally been poorly designed and conducted, usually being based on vitamin D dose rather than 25(OH)D concentration. The optimal 25(OH)D concentration is above 75 nmol/l (30 ng/ml), with even better health outcomes in the range of 100-150 nmol/l. Achieving these concentrations with vitamin D3 supplements will require 1000-4000 IU/day of vitamin D3. Sensible sun exposure should also be encouraged. Countries should also consider fortifying grain and dairy products with vitamin D3.

The role of vitamin D in the pathogenesis and treatment of diabetes mellitus: a narrative review.

Diabetes mellitus, a metabolic disorder associated with chronic complications, is traditionally classified into two main subtypes. Type 1 diabetes mellitus (T1DM) results from gradual pancreatic islet ß cell autoimmune destruction, extending over months or years. Type 2 diabetes mellitus (T2DM) is a heterogeneous disorder, with both insulin resistance and impairment in insulin secretion contributing to its pathogenesis. Vitamin D is a fat-soluble vitamin with an established role in calcium metabolism. Recently, several studies have provided evidence suggesting a role for it in various non-skeletal metabolic conditions, including both types of diabetes mellitus. Preclinical studies of vitamin D action on insulin secretion, insulin action, inflammatory processes, and immune regulation, along with evidence of an increase of hypovitaminosis D worldwide, have prompted several epidemiological, observational, and supplementation clinical studies investigating a potential biological interaction between hypovitaminosis D and diabetes. This narrative review aims to summarize current knowledge on the effect of vitamin D on T1DM and T2DM pathogenesis, prevention, and treatment, as well as on micro- and macrovascular complications of the disease. Furthermore, on the basis of current existing evidence, we aim to highlight areas for potential future research.

Presumptive Glucocorticoid-Induced Refractory Hypocalcemia in a Dog with Idiopathic Immune-Mediated Hypoparathyroidism, Thrombocytopenia, and Hemolytic Anemia.

Clinically relevant hypocalcemia is a well-documented complication of glucocorticoid administration in people with hypoparathyroidism. The current report describes the phenomenon in a dog. A 7 yr old neutered male Pomeranian was diagnosed with immune-mediated thrombocytopenia, immune-mediated hemolytic anemia, and primary hypoparathyroidism. This dog required long-term parenteral calcium gluconate to prevent clinical hypocalcemia despite appropriate doses of oral calcitriol and calcium carbonate. This is the first description of clinically significant presumptive glucocorticoid induced hypocalcemia in a dog with primary hypoparathyroidism.

Calcitriol loading before total parathyroidectomy with autotransplant in patients with end-stage kidney disease: does it prevent postoperative hypocalcaemia?

BACKGROUND: Hungry bone syndrome (HBS) is one of the most serious complications following parathyroidectomy for severe hyperparathyroidism. There is a lack of literature informing the treatment and risk factors for this condition and the ideal pre-operative strategy for prevention. AIMS: The primary aims were to examine the incidence of HBS with pre-operative calcitriol loading for 10 days and to determine the risk factors for HBS. The secondary aims were to determine the rate of intravenous calcium replacement in those with HBS and to assess whether cinacalcet removal has increased rates of parathyroidectomy in the end-stage kidney disease population. METHODS: We performed a retrospective study from 2011 to 2018 on 45 patients with end-stage kidney disease undergoing total parathyroidectomy with autotransplantation for severe hyperparathyroidism. This was based at the John Hunter and Newcastle Private Hospitals in New South Wales. RESULTS: 28.3% of patients with calcitriol loading undergoing parathyroidectomy fulfilled criteria for HBS. Pre-operative variables that were associated with HBS were elevated parathyroid hormone (P = 0.028) and longer duration of renal replacement therapy (P = 0.033). Rates of total parathyroidectomy were higher after the removal of calcimimetics from the Pharmaceutical Benefits Scheme (P = 0.0024). CONCLUSIONS: HBS remains a common complication of parathyroidectomy, even with prolonged high-dose calcitriol loading. This emphasises the need for further trials investigating other targeted therapies, such as bisphosphonates, to prevent HBS. Those most at risk of HBS are patients with high bone turnover and prolonged renal replacement therapy.

The Effect of Nordic Walking Training Combined with Vitamin D Supplementation on Postural Control and Muscle Strength in Elderly People-A Randomized Controlled Trial.

Nordic Walking (NW) and Vitamin D concentration (Vit D) alone have been shown to contribute to the health and performance of elderly people. However, the interaction between these two factors has yet to be explored. In this study 42 women over 60 years of age (69.02 ± 5.56 years) were recruited and divided in two NW groups: a high-intensity interval training group (HI-NW) and a moderate-intensity continuous training group (MI-NW). Individuals from each group completed a 12-week NW training program (3 times a week/2 hours) combined with randomized Vitamin D supplementation (HD = high dose: 4000 IU/day or LD = low dose: 800 IU/day). Body composition, postural control, muscle strength and Vitamin D serum concentration were measured twice; before and after the intervention. To investigate the interaction between supplementation and training a mixed-design analysis of variance (ANOVA) was performed. The HI-NW group, regardless of supplementation dose, increased their Vit D and elbow torque performance. On the other hand, in the MI-NW group the same Vit D outcome was seen only with HD supplementation and was also associated with increased leg muscle mass. In conclusion, beneficial effects of both HI-NW and MI-NW training regimes were seen. The impact of the dose supplementation on Vit D and body composition was related to the type of NW training.