Plasma 25OHD Research Articles

Instrumental Variable Estimation of the Causal Effect of Plasma 25-Hydroxy-Vitamin D on Colorectal Cancer Risk: A Mendelian Randomization Analysis

Vitamin D deficiency has been associated with several common diseases, including cancer and is being investigated as a possible risk factor for these conditions. We reported the striking prevalence of vitamin D deficiency in Scotland. Previous epidemiological studies have reported an association between low dietary vitamin D and colorectal cancer (CRC). Using a case-control study design, we tested the association between plasma 25-hydroxy-vitamin D (25-OHD) and CRC (2,001 cases, 2,237 controls). To determine whether plasma 25-OHD levels are causally linked to CRC risk, we applied the control function instrumental variable (IV) method of the Mendelian randomization (MR) approach using four single nucleotide polymorphisms (rs2282679, rs12785878, rs10741657, rs6013897) previously shown to be associated with plasma 25-OHD. Low plasma 25-OHD levels were associated with CRC risk in the crude model (odds ratio (OR): 0.76, 95% Confidence Interval (CI): 0.71, 0.81, p: 1.4×10−14) and after adjusting for age, sex and other confounding factors. Using an allele score that combined all four SNPs as the IV, the estimated causal effect was OR 1.16 (95% CI 0.60, 2.23), whilst it was 0.94 (95% CI 0.46, 1.91) and 0.93 (0.53, 1.63) when using an upstream (rs12785878, rs10741657) and a downstream allele score (rs2282679, rs6013897), respectively. 25-OHD levels were inversely associated with CRC risk, in agreement with recent meta-analyses. The fact that this finding was not replicated when the MR approach was employed might be due to weak instruments, giving low power to demonstrate an effect (<0.35). The prevalence and degree of vitamin D deficiency amongst individuals living in northerly latitudes is of considerable importance because of its relationship to disease. To elucidate the effect of vitamin D on CRC cancer risk, additional large studies of vitamin D and CRC risk are required and/or the application of alternative methods that are less sensitive to weak instrument restrictions.

Feeding 25-hydroxycholecalciferol improves gilt reproductive performance and fetal vitamin D status1

Little information is available regarding the effects of vitamin D and its metabolites on reproduction in swine. To investigate the effects of feeding the circulating metabolite of vitamin D, 25-hydroxycholecalciferol (25OHD3, ROVIMIX Hy • D, DSM Nutritional Products, Basel, Switzerland) on maternal and fetal circulating 25OHD3 concentration and gilt reproductive performance, a total of 40 PIC Camborough-22 gilts (BW on d -6 = 138 kg) in 4 replicates were randomly assigned to 1 of 2 corn-soybean meal-based diets. The control diet (CTL) was formulated to contain 2,500 IU D3/kg diet, and the experimental diet (25OHD3) was formulated to contain 500 IU D3/kg diet + 50 μg 25OHD3/kg diet. Gilts were fed 2.7 kg of their assigned diet once daily beginning 43 d before breeding. Gilt BW were measured on gestational d -6 and d 90. Gilts were artificially inseminated with PIC 337-G semen 12 h and 24 h after showing signs of estrus. Blood samples were collected from the jugular vein on gestational d -43, -13, 46, and 89 for analysis of circulating 25OHD3 plasma concentration and overall vitamin D status of the gilts. At gestational d 90 ± 1, gilts were harvested and reproductive tracts were removed. Fetal weight, sex, crown-to-rump length (CRL), as well as the number of mummified fetuses were recorded. As expected, circulating plasma concentrations of 25OHD3 were not different among treatment groups at d -43 (CTL = 53.8 ng/mL, 25OHD3 = 57.4 ng/mL; P = 0.66). However, gilts fed 25OHD3 had greater (P < 0.001) circulating plasma concentrations of 25OHD3 on d -13 (89.7 vs. 56.7 ng/mL), d 46 (95.8 vs. 55.7 ng/mL), and d 89 (92.8 vs. 58.2 ng/mL) of gestation compared with CTL-fed gilts. Circulating 25OHD3 was also greater in fetuses from 25OHD3-fed gilts on d 90 (P < 0.001). A 23% increase in pregnancy rate was observed in 25OHD3-fed gilts compared with CTL (78% vs. 55%, respectively; P = 0.21). Maternal BW gain (without conceptus), number of mummified fetuses, mean fetal weight, and mean fetal CRL were similar among treatments (P > 0.05). However, litter size was larger (CTL = 10.2; 25OHD3 = 12.7; P = 0.04) in 25OHD3-fed gilts compared with CTL-fed gilts. Notably, mean fetal weight was not decreased in 25OHD3-fed gilts as frequently occurs when litter size is increased. Overall, feeding 25OHD3 to first-service gilts before and during gestation improved both maternal and fetal vitamin D status and improved maternal reproductive performance.

Peripheral quantitative computed tomography (pQCT) in nine month old infants: Relations to gender and to maternal and infant plasma 25OHD and PTH levels

Peripheral quantitative computed tomography (pQCT) in nine month old infants: Relations to gender and to maternal and infant plasma 25OHD and PTH levels

The Hydroxylation of Vitamin D on C25 in Thyrotoxicosis The Role of the Activity of Microsomal Liver Enzymes

Vitamin D3 after its entrance in the organism undergoes hydroxylation on C-25 carbon atom by the action of microsomal liver enzymes giving the metabolite 25 hydroxyvitamin D3 (25OHD3). The function of microsomal liver enzymes is influenced in some specified states by hormones or drugs. It has approved that thyroxin is a potent stimulator of these enzymes while allopurinol suppresses their function. The aim of this issue is to examine 25OHD3 plasma levels in thyrotoxic subjects and in those pretreated with allopurinol on the base of the afford mentioned data. In a first phase 25OHD3 plasma levels were estimated in thyrotoxic subjects against euthytoid healthy controls. In a second phase lmg vitamin D3 was injected intravenously (i.v.) in thyrotoxic subjects and in healthy euthyroid controls. 25OHD3 plasma levels were measured before and in post injection period in six hours intervals for 48 hours. In a third phase a couple of subjects one thyrotoxic and one euthyroid healthy control pretreated both with allopurinol injected lmg of vitamin D3 i.v. In all studied subjects 25OHD3 plasma levels were measured before and in post injection period in six hours intervals for 48 hours. The pre and post injection 25OHD3 plasma levels measured the size of activity of liver enzyme responsible for bioactivation of vitamin D3. In the first phase was indicated that 25OHD3 plasma levels were lower in thyrotoxic subjects comparing with that of euthyroid healthy controls (p 3 in thyrotoxic subjects was 2,5 to 8 times faster comparing with euthyroid healthy controls. In the third phase was shown that allopurinol decreases the activity of liver enzymes function as regard the bioactivation of vitamin D3. The bioactivation of vitamin D3 is accelerated in thyrotoxicosis compared with that in euthyroid state. This phenomenon produces low 25OHD3 plasma levels in thyrotoxic subjects which initially may be normal or slightly increased depended from the vitamin D3 status in the thyrotoxic subjects. By continuous stimulatory action of increased thyroid hormones on liver enzymes the 25OHD3 plasma levels earlier or later decline in levels of hypo-or avitaminosis D3. The previously described biological events may explain the decreased intestinal calcium absorption of vitamin D3 and the osteomalacic component found in a percentage of thyrotoxic bone histology. For the blocking effects of allopurinol on liver enzymes function and possibly of other pharmaceutical products in relation to vitamin D3 bioactivation, available data are still lacking.

Type of Dietary Fat Is Associated with the 25-Hydroxyvitamin D3 Increment in Response to Vitamin D Supplementation

Mono- and polyunsaturated fats may have opposing effects on vitamin D absorption. The purpose of this study was to determine whether intakes of different dietary fats are associated with the increase in serum 25-hydroxyvitamin D (25OHD) after supplementation with vitamin D(3). This analysis was conducted in the active treatment arm of a randomized, double-blind, placebo-controlled trial of vitamin D and calcium supplementation to prevent bone loss and fracture. Subjects included 152 healthy men and women age 65 and older who were assigned to 700 IU/d vitamin D(3) and 500 mg/d calcium. Intakes of monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), and saturated fatty acids (SFA) were estimated by food frequency questionnaire. The change in plasma 25OHD during 2 yr vitamin D and calcium supplementation was assessed. The change in plasma 25OHD (nanograms per milliliter) during vitamin D supplementation was positively associated with MUFA, (β = 0.94; P = 0.016), negatively associated with PUFA, (β = -0.93; P = 0.038), and positively associated with the MUFA/PUFA ratio (β = 6.46; P = 0.014). The fat composition of the diet may influence the 25OHD response to supplemental vitamin D(3). Diets rich in MUFA may improve and those rich in PUFA may reduce the effectiveness of vitamin D(3) supplements in healthy older adults. More studies are needed to confirm these findings.

Diet, Environmental Factors, and Lifestyle Underlie the High Prevalence of Vitamin D Deficiency in Healthy Adults in Scotland, and Supplementation Reduces the Proportion That Are Severely Deficient

Vitamin D deficiency has recently been implicated as a possible risk factor in the etiology of numerous diseases, including nonskeletal conditions. In humans, skin synthesis following exposure to UVB is a potent source of vitamin D, but in regions with low UVB, individuals are at risk of vitamin D deficiency. Our objectives were to describe the prevalence of vitamin D deficiency and to investigate determinants of plasma 25-hydroxyvitamin D (25-OHD) concentrations in a high northern latitude country. Detailed dietary, lifestyle, and demographic data were collected for 2235 healthy adults (21–82 y) from Scotland. Plasma 25-OHD was measured by liquid chromatography-tandem MS. Among study participants, 34.5% were severely deficient (25-OHD <25 nmol/L) and 28.9% were at high risk of deficiency (25–40 nmol/L). Only 36.6% of participants were at low risk of vitamin D deficiency or had adequate levels (>40 nmol/L). Among participants who were taking supplements, 21.3% had a May-standardized 25-OHD concentration >50 nmol/L, 54.2% had 25–50 nmol/L, and 24.5% had <25 nmol/L, whereas this was 15.6, 43.3, and 41%, respectively, among those who did not take supplements (P < 0.0001). The most important sources of vitamin D were supplements and fish consumption. Vitamin D deficiency in Scotland is highly prevalent due to a combination of insufficient exposure to UVB and insufficient dietary intake. Higher dietary vitamin D intake modestly improved the plasma 25-OHD concentration (P =0.02) and reduced the proportion of severely deficient individuals (P < 0.0001). In regions with low UVB exposure, dietary and supplement intake may be much more important than previously thought and consideration should be given to increasing the current recommended dietary allowance of 0–10µg/d for adults in Scotland.

Cord Blood Vitamin D Deficiency Is Associated With Respiratory Syncytial Virus Bronchiolitis

Respiratory syncytial virus (RSV) is the most important pathogen causing severe lower respiratory tract infection (LRTI) in infants. Epidemiologic and basic studies suggest that vitamin D may protect against RSV LRTI. To determine the association between plasma vitamin D concentrations at birth and the subsequent risk of RSV LRTI. A prospective birth cohort study was performed in healthy term neonates. Concentrations of 25-hydroxyvitamin D (25-OHD) in cord blood plasma were related to RSV LRTI in the first year of life, defined as parent-reported LRTI symptoms in a daily log and simultaneous presence of RSV RNA in a nose-throat specimen. The study population included 156 neonates. Eighteen (12%) developed RSV LRTI. The mean plasma 25-OHD concentration was 82 nmol/L. Overall, 27% of neonates had 25-OHD concentrations < 50 nmol/L, 27% had 50-74 nmol/L and only 46% had 25-OHD 75 nmol/L. Cord blood 25-OHD concentrations were strongly associated with maternal vitamin D3 supplementation during pregnancy. Concentrations of 25-OHD were lower in neonates who subsequently developed RSV LRTI compared with those who did not (65 nmol/L versus 84 nmol/L, P = .009). Neonates born with 25-OHD concentrations <50 nmol/L had a sixfold (95% confidence interval: 1.6-24.9; P = .01) increased risk of RSV LRTI in the first year of life compared with those with 25-OHD concentrations ≥ 75 nmol/L. Vitamin D deficiency in healthy neonates is associated with increased risk of RSV LRTI in the first year of life. Intensified routine vitamin D supplementation during pregnancy may be a useful strategy to prevent RSV LRTI during infancy.

Plasma 25‐hydroxyvitamin D to parathyroid hormone ratio is associated with glucose tolerance and insulin sensitivity in older adults

Purpose To assess the relationships between plasma 25-hydroxyvitamin D (25OHD), plasma parathyroid hormone (PTH), and oral glucose tolerance (OGT) in older adults before and after a dietary protein and resistance training (RT) regimen. Methods 16 males (BMI 27.2 ± 4.2 kg/m2) and 19 females (BMI 25.5 ± 3.0 kg/m2) aged 50–80 y performed RT 3x/wk for 12 wk while consuming diets with either 0.9 or 1.2 g protein · kg BW−1· d−1. Results RT had no effect on body weight, plasma 25OHD or plasma PTH but reduced fat mass and increased lean body mass and strength independent of protein intake. OGT improved after RT (i.e. decreased area under the glucose curve (AUC) and 2-h plasma glucose) (all changes P<0.05). Using non-parametric statistics, at baseline, 25OHD to PTH ratio was correlated inversely with HOMA (Rho = −0.398, Prob > |Rho| = 0.03) and 2-h glucose (Rho = −0.463, Prob > |Rho| = 0.01) and positively with insulin sensitivity index (Rho = 0.406, Prob > |Rho| = 0.02). Similar results were found post intervention and AUC and 2-h glucose were lower in subjects with 25OHD ≥ 30 ng/mL versus subjects with 25OHD ≤ 20 ng/mL (P<0.05). Mean (average of pre & post) 25OHD, PTH, and 25OHD/PTH ratio were not correlated to the response of OGT-related parameters to RT. Conclusion Vitamin D status and the 25OHD to PTH ratio may impact glucose tolerance in older adults regardless of resistance training. Support: Amer. Egg Board; NIH UL 1 RR025761; Purdue Univ. Grant Funding Source: American Egg Board, NIH UL 1 RR025761, Purdue University

Vitamin D Deficiency and Seasonal and Inter-day Variation in Circulating 25-hydroxyvitamin D and Parathyroid Hormone Levels in Indoor Daytime Workers: A Longitudinal Study

Seasonal variation in circulating 25-hydroxyvitamin D (25OHD) levels related to seasonal and inter-day fluctuation in sunlight ultraviolet irradiation, may lead to misjudgments concerning 25OHD status in individual workers around threshold levels. Here, to examine seasonal and inter-day variations in plasma 25OHD, we conducted a longitudinal study involving indoor daytime workers. Subjects were four male indoor daytime workers aged 32-57 yr working in Kawasaki City, Japan. Blood samples were obtained on six days within two two-week periods in February and October, 2008. Plasma 25OHD, serum intact parathyroid hormone (PTH) and 1α,25-dihydroxyvitamin D [1α,25(OH)(2)D] were measured. Individual monthly mean 25OHD levels were 16-56% higher in October than in February (p=0.03), while individual monthly mean intact PTH levels were 15-41% lower in October (p=0.09). No seasonal change was observed in 1α,25(OH)(2)D (p=0.62). Notably, nearly all measured 25OHD levels in February were lower than the reference value of 20 ng/ml. Our study identified the occurrence of seasonal variation in circulating 25OHD and intact PTH levels, even after accounting for inter-day variability, and hypovitaminosis D in wintertime in indoor daytime male workers in Japan. Due to this variability, single spot measurements of 25OHD may lead to misjudgment of workers' vitamin D status.

The correlation between third-trimester maternal and newborn-serum 25-hydroxy-vitamin D in a selected South Australian group of newborn samples

BackgroundAlthough vitamin D insufficiency is prevalent in the community, only a few population-based studies have measured serum 25-hydroxy-vitamin D (25OHD) levels during pregnancy and in newborns. Maternal vitamin D deficiency...

Increased Fracture Risk in Normocalcemic Postmenopausal Women with High Parathyroid Hormone Levels: A 16-Year Follow-Up Study

High PTH levels increase bone turnover and decrease bone mineral density (BMD). Low plasma 25-hydroxyvitamin D (25OHD) levels cause secondary hyperparathyroidism, but the relative contribution of low 25OHD and high PTH levels on risk of fracture is largely unknown. Within the cohort of women (n = 2,016) included in the Danish Osteoporosis Prevention Study (DOPS), we studied risk of fracture according to parathyroid status. Analyses were performed on effects of high PTH levels (i.e., in the upper tertile, ≥4.5 pmol/L) on risk of incident fractures at different 25OHD levels during 16 years of follow-up. Incident fractures were assessed using a nationwide hospital discharge register. In addition, effects of high PTH levels on BMD and vertebral fractures were assessed by DXA scans and spinal X-ray examination after 10 years of follow-up. High PTH levels were associated with a decreased body mass index, adjusted BMD, and an increased risk of any fracture (HR = 1.41, 95% CI 1.11-1.79) as well as an increased risk of osteoporotic fractures (HR = 1.59, 95% CI 1.20-2.10). Plasma 25OHD levels per se did not affect fracture risk, but high PTH levels were associated with an increased fracture risk only at 25OHD levels <50 nmol/L and 50-80 nmol/L. High PTH levels did not increase risk of fracture at 25OHD levels >80 nmol/L. In conclusion, PTH levels in the upper part or above the upper level of the reference interval increase risk of fracture in the presence of low vitamin D levels.

Determinants of plasma PTH and their implication for defining a reference interval

To improve the diagnostic sensitivity of PTH measurements, more data on the upper limit of the reference interval for PTH levels were requested at a recent international consensus conference. As PTH levels vary inversely with plasma 25-hydroxyvitamin D (25OHD) levels and as vitamin D insufficiency is widespread, particular attention should be given to the influence of low vitamin D levels on the PTH reference interval. AIM, DESIGN AND METHODS: In a cross-sectional design, including 2316 women aged 17-84, we determined 95% reference interval using a nonparametric approach and studied the effects of potential predictors on plasma PTH levels. PTH was a positive function of age, body weight and BMI and inversely associated with total daily calcium intake, smoking, plasma calcium levels and 25OHD levels, all of which explained 16% of the variability in plasma PTH levels. The threshold value for 25OHD levels below which PTH levels started to rise was 82 nmol/l. Plasma PTH levels varied inversely with the seasonal variations in 25OHD levels. Mean PTH level was 4·1 pmol/l with a reference interval equal to 2·0-8·6 pmol/l. Restricting the population in whom the reference interval was calculated to only women with 25OHD levels above 30 or 100 nmol/l lowered the upper limit of the reference interval to 8·4 and 7·1 pmol/l, respectively. Similar, stratification according to age, body mass index, smoking and calcium intake had only minor impact on the reference interval. Indices with known effects on plasma PTH levels have only a minor impact on the upper levels of the normative reference interval in women with intact renal function.

Vitamin D and cognition in the elderly

The understanding of the role of vitamin D in maintaining good health has considerably increased in the recent years. There is a growing evidence that vitamin D has not only a beneficial effect to prevent osteoporosis and the risk of falls in the elderly, but also may reduce incidence of cancers, infections, autoimmune, cardiovascular and neurologic diseases, and psychiatric disorders. Laboratory studies yield a biological plausibility for a positive contribution of vitamin D to brain functions: vitamin D receptor and 1,α-hydroxylase, the terminal calcitriol-activating enzyme, are widely distributed in both the fetal and adult brain. Vitamin D may be involved in neuroprotection, control of proinflammatory cytokine induced cognitive dysfunction and synthesis of calcium-binding proteins and neurotransmitter acetylcholine. However, the observational studies conducted in humans are still inconclusive, given the various tests of the cognitive functions that have been used, the performance of the studies either in patients or in healthy subjects, and different designs and/or confounding factors. The role of the vitamin D receptor in the pathophysiology of cognitive decline, incidence of Alzheimer's disease or vascular dementia and/or cognitive decline with respect to previous plasma 25OHD concentration, and the effect on cognition of vitamin D supplementation should be explored in further studies.

Effects of vitamin D on muscle function and performance: a review of evidence from randomized controlled trials

Vitamin D insufficiency is frequent in the general population. Meta-analyses of randomized controlled trials (RCTs) have shown a decreased risk of falls in elderly treated with vitamin D supplements, which may be due to an improved neuromuscular function in vitamin D-replete subjects. In most observational studies, vitamin D status correlates positively with muscle strength and postural stability. However, as physical activity is associated with vitamin D status as well as muscle strength, effects of vitamin D status on muscular health can only be assessed properly in RCTs. A systematic search was performed and 16 RCTs on the effects of treatment with vitamin D on muscle function were identified. All except one of the studies were performed in subjects above 50 years of age. Baseline 25-hydroxyvitmin D (25OHD) levels were below 50 nmol/l in 11 studies. Plasma 25OHD levels increased significantly in all studies. In seven studies, a beneficial effect of vitamin D treatment was documented on muscle strength of the lower legs, body sway, and/or physical performance. Identified studies were heterogeneous with regard to most aspects including indices measured. No obvious characteristics delineated studies showing beneficial effects from studies showing no effects. Only a few investigators reported the statistical power of measurements performed. In conclusion, evidence from RCTs do support an effect of vitamin D supplements on muscle strength and function in the elderly, but more studies showing a lack of an effect have been published than studies showing beneficial effects. There is a major lack of data on possible effects in younger subjects.

Plasma 25-Hydroxyvitamin D Concentration and Risk of Incident Type 2 Diabetes in Women

OBJECTIVETo determine the association between 25-hydroxyvitamin D (25-OHD) concentration and risk of incident type 2 diabetes.RESEARCH DESIGN AND METHODSIn a nested case-control study conducted among 608 women with newly diagnosed type 2 diabetes and 559 control subjects in the Nurses' Health Study, we measured the association between baseline plasma 25-OHD concentration and risk of incident diabetes.RESULTSAfter adjusting for matching factors and diabetes risk factors, including BMI, higher levels of plasma 25-OHD were associated with a lower risk for type 2 diabetes. The odds ratio for incident type 2 diabetes in the top (median 25-OHD, 33.4 ng/ml) versus the bottom (median 25-OHD, 14.4 ng/ml) quartile was 0.52 (95% CI 0.33–0.83). The associations were consistent across subgroups of baseline BMI, age, and calcium intake.CONCLUSIONSPlasma 25-OHD concentration was associated with lower risk of incident type 2 diabetes in women.

Plasma vitamin D and cytokines in periodontal disease and postmenopausal osteoporosis

Osteoporosis and periodontal disease are chronic diseases, in the pathogenesis of which plasma osteoprotogerin (OPG) and RANKL are important. The study aimed to investigate the relationship between periodontal disease and plasma cytokines, vitamin D and bone mineral density in postmenopausal women with and without osteoporosis. One hundred and eighty-five postmenopausal women with osteoporosis and 185 age- and sex-matched control subjects were recruited. Periodontal disease was subdivided into active or past periodontal disease. Osteoprotegerin, RANKL, 25-hydroxyvitamin D₃ (25OHD), biochemical markers of bone turnover (serum C-terminal telopeptide, CTX), anthropometry and bone mineral density were measured. A significantly higher proportion of the women with osteoporosis had active or past periodontal disease or both compared with control subjects (87.6 vs. 37.8%, p < 0.001). Plasma 25OHD was significantly lower (p < 0.001) and RANKL and OPG significantly higher in the women with osteoporosis than in control subjects (p < 0.0001). RANKL, OPG and CTX were significantly higher in women with active periodontal disease than in those without (p < 0.001), as were OPG and CTX in past periodontal disease (p < 0.001). In active and past periodontal disease, 25OHD was significantly lower (p < 0.001). Multiple logistic regression analysis showed that periodontal disease was best predicted by RANKL, 25OHD, C-terminal telopeptide and weight, r² = 10.4%. Periodontal disease is more common in women with osteoporosis and is associated with lower vitamin D and higher concentrations of RANKL and OPG. Raised cytokines may provide the underlying mechanism that links these two conditions.

Determinants of plasma PTH and their implication for defining a reference interval

Summary Background To improve the diagnostic sensitivity of PTH measurements, more data on the upper limit of the reference interval for PTH levels were requested at a recent international consensus conference. As PTH levels vary inversely with plasma 25-hydroxyvitamin D (25OHD) levels and as vitamin D insufficiency is widespread, particular attention should be given to the influence of low vitamin D levels on the PTH reference interval. Aim, design and methods In a cross-sectional design, including 2316 women aged 17–84, we determined 95% reference interval using a nonparametric approach and studied the effects of potential predictors on plasma PTH levels. Results PTH was a positive function of age, body weight and BMI and inversely associated with total daily calcium intake, smoking, plasma calcium levels and 25OHD levels, all of which explained 16% of the variability in plasma PTH levels. The threshold value for 25OHD levels below which PTH levels started to rise was 82 nmol/l. Plasma PTH levels varied inversely with the seasonal variations in 25OHD levels. Mean PTH level was 4·1 pmol/l with a reference interval equal to 2·0–8·6 pmol/l. Restricting the population in whom the reference interval was calculated to only women with 25OHD levels above 30 or 100 nmol/l lowered the upper limit of the reference interval to 8·4 and 7·1 pmol/l, respectively. Similar, stratification according to age, body mass index, smoking and calcium intake had only minor impact on the reference interval. Conclusion Indices with known effects on plasma PTH levels have only a minor impact on the upper levels of the normative reference interval in women with intact renal function.

Plasma 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol concentrations are decreased in hind limb unloaded Dahl salt-sensitive female rats

Plasma 1,25-dihydroxyvitamin D (1,25-(OH) 2D) concentration was shown to decrease during bed rest in several studies when baseline plasma 25-hydroxyvitamin D (25-OHD) concentration was sub-optimal. Dahl salt-sensitive female (S) rats, but not Dahl salt-resistant female (R) rats, demonstrated a 50% decrease in plasma 1,25-dihydroxycholecalciferol (1,25-(OH) 2D 3) concentration after 28 days of hind limb unloading (HU, disuse model) during low salt intake (0.3%). We tested the vitamin D endocrine system response of female S rats to hind limb unloading during high salt intake (2%, twice that of standard rat chow to mimic salt intake in the USA). Hind limb unloading resulted in lower plasma 25-OHD 3 concentrations in S-HU rats than in R-HU rats ( P < 0.05) and greater urinary loss of 25-OHD 3 by S-HU rats than by S rats ( P < 0.05). Plasma 1,25-(OH) 2D 3 concentration of S-HU rats was half that of S rats, but was unchanged in R-HU rats. The association of low plasma 25-OHD concentration with decrease in plasma 1,25-(OH) 2D concentration of hind limb unloaded rats and of bed rest participants (published studies) suggests that low vitamin D status might be a risk factor for decrease in plasma vitamin D hormone concentration during long-term immobilization or bed rest.

Skeletal consequences of familial hypocalciuric hypercalcaemia vs. primary hyperparathyroidism

Bone metabolism is only superficially described in familiar hypocalciuric hypercalcaemia (FHH). We describe and compare biochemical and osteodensitometric variables in FHH and primary hyperparathyroidism (PHPT) and assess whether they can improve the diagnostic discrimination between the groups. Cross-sectional. Sixty-six FHH patients with known calcium-sensing receptor (CASR) gene mutations and 147 PHPT patients. We determined calcium, creatinine, phosphate, magnesium, parathyroid hormone (PTH), 25OHD, 1,25(OH)(2) D and alkaline phosphatase (AP) in plasma, NTx/creatinine ratio in urine and calculated the calcium/creatinine clearance ratio (CCCR). We performed dual energy X-ray absorptiometry at the lumbar spine, hip, forearm and whole body. When compared with normal controls, the FHH patients had increased levels of PTH and AP with normal U-NTx and regional Z-scores. Increased phenotypic expression of CASR mutations in terms of hypercalcaemia was associated with higher lumbar spine bone mineral density, but not with bone markers. FHH were younger and leaner than the PHPT patients. They had comparable plasma Ca(2+) and 25OHD, but lower levels of PTH, 1,25(OH)(2) D, AP and U-NTx. They had higher Z-scores in the hip and in the forearm. We achieved the best discrimination between groups by multiplying CCCR with AP, 1,25(OH)(2) D and PTH, but the difference between the area under the curves by receiver operating characteristic analysis remained insignificant. Familiar hypocalciuric hypercalcaemia is associated with increased PTH and AP compared to normal controls, but not with bone loss irrespective of the severity of the CASR mutations. A multiplicative model including CCCR, AP, 1,25(OH)(2) D and PTH insignificantly improved the power of the CCCR to differentiate between FHH and PHPT. However, we still recommend CASR gene analysis in patients with a CCCR <0.020.

Reduced Prediagnostic 25-Hydroxyvitamin D Levels in Women with Breast Cancer: A Nested Case-Control Study

Vitamin D status may affect risk of cancer. In a cross-sectional study with a nested case-control analysis, we determined whether risk of breast cancer is associated with prediagnostic plasma 25-hydroxyvitamin D (25OHD) levels and the effects of lifestyle characteristics known to influence vitamin D status on risk of breast cancer. We studied women without a prior history of breast cancer referred to a diagnostic mammography examination (n = 2,465). Cases were women diagnosed with an incident breast cancer (n = 142). Controls were women not diagnosed with a breast cancer matched to cases on age, menopausal status, and time of year of blood sampling (n = 420). Characteristics of cases and controls were assessed by a self-administrated questionnaire. Blood samples were collected prior to the diagnostic mammography examination. Cases had lower plasma 25OHD levels than controls. Compared with the lowest tertile of 25OHD levels, risk of breast cancer was significantly reduced among women in the highest tertile (relative risk, 0.52; 95% confidence interval, 0.32-0.85). Risk estimates were similar in women with an estrogen receptor-positive and estrogen receptor-negative breast cancer. Use of vitamin D supplements, sunbathing frequency, and fish intake was associated with 25OHD levels, but did not affect the risk of breast cancer. Accordingly, risk of breast cancer was inversely associated with 25OHD levels. Randomized controlled trials are warranted in order to assess whether a causal relationship exists.