Heterogeneity in Serum 25‐Hydroxy‐Vitamin D Response to Cholecalciferol in Elderly Women with Secondary Hyperparathyroidism and Vitamin D Deficiency

OBJECTIVES: To compare the effects on parathyroid hormone (PTH) and 25‐hydroxy‐vitamin D (25(OH)D) of two dosing regimens of cholecalciferol in women with secondary hyperparathyroidism (sHPTH) and hypovitaminosis D and to investigate variables affecting 25(OH)D response to cholecalciferol. DESIGN: Randomized‐controlled trial with 6‐month follow‐up. SETTING: Two osteoporosis centers in northern Italy. PARTICIPANTS: Sixty community‐dwelling women aged 65 and older with sHPTH and hypovitaminosis D, creatinine clearance greater than 65 mL/min and without diseases or drugs known to influence bone and vitamin D metabolism. INTERVENTION: Cholecalciferol 300,000 IU every 3 months, once at baseline and once at 3 months (intermittent D₃ group) or cholecalciferol 1,000 IU/day (daily D₃ group). MEASUREMENTS: Serum PTH, 25(OH)D, calcium, bone‐specific alkaline phosphatase, β‐C‐terminal telopeptide of type I collagen, phosphate, 24‐hour urinary calcium excretion. RESULTS: The two groups had similar baseline characteristics. All participants had vitamin D deficiency [25(OH)D<20 ng/mL)], and 36 subjects (60%) had severe deficiency (<10 ng/mL), with no difference between the groups (severe deficiency: intermittent D₃ group, n=18; daily D₃ group, n=18). After 3 and 6 months, both groups had a significant increase in 25(OH)D and a reduction in PTH. Mean absolute increase±standard deviation of 25(OH)D at 6 months was higher in the intermittent D₃ group (22.7±11.8 ng/mL) than in the daily D₃ group (13.7±6.7 ng/mL, P<.001), with a higher proportion of participants in the intermittent D₃ group reaching desirable serum concentration of 25(OH)D ≥ 30 ng/mL (55% in the intermittent D₃ group vs 20% in the daily D₃ group, P<.001). Mean percentage decrease of PTH in the two groups was comparable, and at 6 months, a similar proportion of participants reached normal PTH values. 25(OH)D response to cholecalciferol showed a wide variability. In a logistic regression analysis, body mass index and type of treatment appeared to be significantly associated with normalization of 25(OH)D values. CONCLUSION: Cholecalciferol 300,000 IU every 3 months was more effective than 1,000 IU daily in correcting vitamin D deficiency, although the two groups achieved similar effects on PTH at 6 months. Only 55% of the higher‐dose intermittent group reached desirable concentrations of 25(OH)D, suggesting that yet‐higher doses will be required for adequate vitamin D repletion.     

Short and long-term variations in serum calciotropic hormones after a single very large dose of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) in the elderly

CONTEXT: In humans, few studies have compared the potencies of ergocalciferol and cholecalciferol in improving and maintaining vitamin D status. OBJECTIVE: Our objective was to evaluate the effects of a single very large dose of both calciferols on serum changes of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], ionized calcium, and parathyroid hormone (PTH) at baseline, and at 3, 7, 30, and 60 d. DESIGN: This was a prospective randomized intervention study. SETTING: The study was performed in a nursing home residence. PARTICIPANTS: A total of 32 elderly female patients (age range 66-97 yr), with vitamin D deficiency was included in the study. INTERVENTION: Participants were randomized into four groups of eight to receive a single dose of 300,000 IU ergocalciferol or cholecalciferol by oral (os) or im route. RESULTS: 25(OH)D levels sharply increased at d 3 only when vitamins were given os. The 30-d basal difference in serum 25(OH)D was significantly greater after cholecalciferol os administration (47.8 +/- 7.3 ng/ml) compared with other forms (D(3) im: 15.9 +/- 11.3; D(2) os: 17.3 +/- 4.7; D(2) im: 5 +/- 4.4; all P < 0.001). The area under the curve (AUC) of the serum 25(OH)D against time (AUC(60)) was: D(3) os, 3193 +/- 759 ng x d/ml vs. D(2) os, 1820 +/- 512, P < 0.001; and D(3) im, 1361 +/- 492 vs. D(2) im, 728 +/- 195, P < 0.01. 25(OH)D significantly influences PTH levels at 3 (P < 0.03), 7 (P < 0.01), 30 (P < 0.01), and 60 d (P < 0.05). At 60 d, the form of vitamin (cholecalciferol) significantly lowers PTH levels (P = 0.037). CONCLUSIONS: Cholecalciferol is almost twice as potent as ergocalciferol in increasing serum 25(OH)D, when administered either by mouth or im. 25(OH)D plays a role in modulating serum PTH.     

Effects of a Single,High Oral Dose of 25‐Hydroxycholecalciferol on the Mineral Metabolism Markers in Hemodialysis Patients

Vitamin D deficiency is common in dialysis patients with chronic kidney disease. Low levels have been associated with increased cardiovascular risk and mortality. We evaluated the administration of a high, single oral dose of 25‐OH cholecalciferol (3 mg of Hidroferol, 180 000 IU) in patients on chronic hemodialysis. The 94 chronic hemodialysis patients with vitamin D deficiency 25 (OH)D <30 ng/mL included in the study were randomized into two groups. Follow‐up time was 16 weeks. Neither the usual treatment for controlling Ca/P levels nor the dialysis bath (calcium of 2.5 mEq/L) were modified. Of the 86 patients who finished the study, 42 were in the treated group and 44 in the control group. An increase in 25(OH)D levels was observed in the treated group that persisted after 16 weeks and was associated with a significant decrease in parathyroid hormone (PTH) levels during the 8 weeks post‐treatment. Baseline 1,25(OH)₂D levels of the treated group increased two weeks after treatment (5.9 vs. 21.9 pg/mL, P < 0.001) but gradually reduced to 8.4 at week 16. The administration of a single 3 mg dose of 25‐OH cholecalciferol seems safe in patients on hemodialysis and maintains sufficient levels of 25(OH)D with a decrease in PTH for 3 months.     

Third F. Raymond Keating, Jr., Memorial Symposium--parathyroid hormone, calcitonin and vitamin D: clinical considerations. II. Vitamin D--1973

The recent advances in our understanding of the functional metabolism of vitamin D to 25-hydroxyvitamin D (25-(OH)D) and subsequently to 1,25-dihydroxyvitamin D (1,25-(OH)₂D) are presented with a review of current views on the regulation of vitamin D metabolism at the 25-hydroxylation and 1-hydroxylation stages. It seems clear that, physiologically, the latter regulation is governed by parathyroid hormone (PTH) under conditions of hypocalcemia and by serum inorganic phosphorus levels under conditions from normal to hypercalcemia. The molecular mechanism of the regulation of the renal hydroxylations remains unknown.The metabolism of 25-(OH)D₃ to 24,25-(OH)₂D₃ and further to 1,24,25-(OH)₃D₃ has been established. The significance of these reactions is unknown, but 1,24,25-(OH)₃D₃ preferentially stimulates intestinal calcium transport.The mechanism whereby 1,25-(OH)₂D₃ stimulates intestinal calcium transport and the receptors of this metabolite in intestine are discussed. In addition, the application of the metabolites of vitamin D to clinical problems has been considered and 1α-(OH)D₃, an important analog of 1,25-(OH)₂D₃, has been introduced as a potentially important therapeutic compound.     

Long-term 1,25(OH)2 vitamin D therapy increases bone mineral density in osteopenic women. Comparison with the effect of plain vitamin D

BACKGROUND AND AIMS: Although the bone protective effect of vitamin D has been studied intensively, the usefulness of 1,25(OH)2D3 in treating osteoporosis is still questionable. The aim of the present prospective study was to evaluate the effect of a standard pharmacological dose of 1,25(OH)2D3 in postmenopausal unsubstituted women. METHODS: Our study group comprised 52 post-menopausal women with low normal or osteopenic values of bone mineral density (BMD). Thirty-two of them were treated with 1,25(OH)2D3 for 3 years. In parallel, another group of women was treated with cholecalciferol (n=20). Vitamin D adequacy before administration of 1,25(OH)2D3 and compliance with treatment were checked by serum PTH levels, which were assessed at the start and three times in the course of treatment. RESULTS: Increase in BMD at the spine at the end of the 1st, 2nd and 3rd years of treatment with 1,25(OH)2D3 (expressed as a percentage of the value before treatment) was higher, but did not significantly differ from the effect of plain vitamin D. A significant increase in BMD at the hip at the end of the 3rd (but not the 1st and 2nd) year of treatment with 1,25(OH)2D3 was found (p<0.05, compared with the effect of plain vitamin D). The protective effect of cholecalciferol was found only on spine but not hip BMD. CONCLUSION: The study supports the hypothesis that long-term administration of 1,25(OH)2D3 is effective in treating low bone mass in postmenopausal women.     

Opposite effects of pravastatin and atorvastatin on insulin sensitivity in the rat: role of vitamin D metabolites

ObjectiveRecent studies indicate that pravastatin improves whereas other statins impair glucose homeostasis in humans, but the underlying mechanisms are not clear. We examined the effect of pravastatin and atorvastatin on insulin sensitivity in a rat model.MethodsPravastatin (40 mg/kg/day) or atorvastatin (20 mg/kg/day) were administered for 3 weeks and insulin sensitivity was assessed by measuring fasting plasma insulin, HOMA-IR, non-esterified fatty acids (NEFA) and glycerol levels, as well as by the hyperinsulinemic euglycemic clamp.ResultsPravastatin had no effect on fasting insulin and HOMA-IR but significantly reduced plasma NEFA and glycerol levels and increased glucose infusion rate (GIR) during the hyperinsulinemic clamp. Increase in GIR induced by pravastatin was not abolished by NO synthase inhibitor, l-NAME, indicating that this effect did not result from the improvement of endothelial function. Atorvastatin increased fasting insulin, HOM-IR, NEFA and glycerol levels as well as reduced GIR. Statins had no effect on leptin, HMW adiponectin, resistin, visfatin, interleukin-6 and TNF-α. Pravastatin increased plasma concentrations of 25-hydroxy- and 1,25-dyhydroxyvitamin D₃ (25-OH-D₃ and 1,25-(OH)₂-D₃), and its effect on insulin sensitivity was mimicked by exogenous 1,25-(OH)₂-D₃. Atorvastatin reduced plasma 25-OH-D₃ but had no effect on 1,25-(OH)₂-D₃. Decrease in insulin sensitivity induced by atorvastatin was not corrected by supplementation of vitamin D₃ despite normalization of plasma 25-OH-D₃ level.ConclusionsPravastatin and atorvastatin have opposite effects on insulin sensitivity and vitamin D₃ status. Pravastatin-induced increase in insulin sensitivity is mediated by elevation of 1,25-(OH)₂-D₃. In contrast, atorvastatin-induced decrease in insulin sensitivity is independent of lowering 25-OH-D₃.     

Cholecalciferol supplementation in chronic kidney disease: restoration of vitamin d status and impact on parathyroid hormone

Background/Aims: Hypovitaminosis D is highly prevalent among patients with chronic kidney disease (CKD) and has been associated with poor outcome. We aimed to test the effect of a protocol of cholecalciferol supplementation on the restoration of vitamin D status and on parathyroid hormone (PTH) levels in patients with CKD. Methods: This was a prospective interventional study of 6 months. Forty-five CKD patients (stages 3 and 4) with 25-hydroxyvitamin D deficiency [25(OH)D <15 ng/ml] were included. Patients received a weekly dose of 50,000 IU of cholecalciferol during 3 months, and 50,000 IU/month thereafter for those who had achieved 25(OH)D ≥30 ng/ml. Results: At 3 months, 78% of the patients restored their vitamin D status. At 6 months, only 43% of those patients maintained adequate vitamin D status. PTH decreased at 3 months (p = 0.02) but returned to baseline levels after 6 months. Fibroblast growth factor 23 increased at 3 months (p = 0.001) and returned to initial levels at 6 months. No changes were found in serum 1,25(OH)(2)D, ionized calcium and phosphorus. Conclusions: A weekly dose of 50,000 IU of cholecalciferol for 3 months restored the vitamin D status of most patients and led to a reduction in PTH. The monthly dose of 50,000 IU appears not to be sufficient to maintain the levels of 25(OH)D.     

Decreased expression of vitamin D receptor may contribute to the hyperimmune status of patients with acquired aplastic anemia

Acquired aplastic anemia (AA) is an immune‐mediated bone marrow failure syndrome. 1α,25‐Dihydroxyvitamin D₃ [1,25(OH)₂D₃], the biologically active metabolite of vitamin D, is a critical modulator of immune response via binding with vitamin D receptor (VDR). Previous studies have established that 1,25(OH)₂D₃ and VDR were involved in the pathogenesis of some autoimmune diseases. In this study, we evaluated the involvement of 1,25(OH)₂D₃ and VDR on T‐cell responses in AA. Plasma 25(OH)D₃ levels were comparable between patients with AA and healthy controls. Surprisingly, VDR mRNA was significantly lower in untreated patients with AA than in healthy controls. Subsequent in vitro experiments revealed that 1,25(OH)₂D₃ treatment suppressed the proliferation of lymphocytes and inhibited the secretion of interferon‐γ, tumor necrosis factor‐α, and interleukin‐17A, meanwhile promoting the production of transforming growth factor‐β1 in patients with AA. Moreover, 1,25(OH)₂D₃ inhibited the differentiation of type 1 and Th17 cells but induced the differentiation of type 2 and regulatory T cells. Interestingly, VDR mRNA was elevated in healthy controls after 1,25(OH)₂D₃ treatment, but not in patients with AA. In conclusion, decreased expression of VDR might contribute to the hyperimmune status of AA and appropriate vitamin D supplementation could partly correct the immune dysfunction by strengthening signal transduction through VDR in patients with AA.     

Plasma vitamin D metabolite levels in phosphorus deficient rats during the development of vitamin D deficient rickets

Plasma levels of the vitamin D metabolites were related to changes in bone morphology during the development of rickets in rats deprived of phosphorus and vitamin D. Weanling rats were studied at 1, 3, and 5 wk after onset of diets deficient in phosphorus or in both phosphorus and vitamin D. Bone histology and morphometry were carried out and measurements were made of ⁴⁵Ca and ³²P absorption, serum Ca and P, and plasma 25(OH)D₃, 24,25 (OH)₂D₃ and 1,25 (OH)₂D₃. After 1 wk of vitamin D restriction, the plasma levels of 25(OH)D₃ and 24,25(OH)₂D₃ were non-detectable (<0.5 and <0.8 ng/ml). The plasma 1,25(OH)₂D₃ level was elevated at 1 wk (105.5 pg/ml) and fell to 19 pg/ml by 5 wk. At 1 wk mild rachitic lesions in epiphyseal cartilage were observed despite the elevated 1,25(OH)D₃ level. Serum Ca and P levels and values for ⁴⁵Ca and ³²P absorption decreased and the severity of the rickets increased with the fall in plasma levels of 1,25(OH)₂D₃. In vitamin D replete, phosphate deficient rats the epiphyseal cartilage was normal throughout the 5 wk study peroid. Our results provide further evidence that physiological levels of 1,25 (OH)₂D₃ will not prevent rickets without adequate plasma concentrations of either 25(OH)D₃ or 24,25(OH)₂D₃.     

Changes in vitamin D levels in patients with systemic lupus erythematosus: Effects on fatigue,disease activity,and damage

Objective

To analyze whether changes in serum 25‐hydroxyvitamin D (25[OH]D) levels affect activity, irreversible organ damage, and fatigue in systemic lupus erythematosus (SLE).

Methods

We performed an observational study of 80 patients with SLE included in a previous cross‐sectional study of 25(OH)D, reassessed 2 years later. Oral vitamin D₃ was recommended in those with low baseline 25(OH)D levels. The relationship between changes in 25(OH)D levels from baseline and changes in fatigue (measured by a 0–10 visual analog scale [VAS]), SLE activity (measured by the Systemic Lupus Erythematosus Disease Activity Index [SLEDAI]), and irreversible organ damage (measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]) were analyzed.

Results

Sixty patients took vitamin D₃. Mean 25(OH)D levels increased among all treated patients (P = 0.044), in those with baseline vitamin D levels <30 ng/ml (P < 0.001), and in those with baseline vitamin D levels <10 ng/ml (P = 0.005). Fifty‐seven patients (71%) still had 25(OH)D levels <30 ng/ml and 5 (6%) had 25(OH)D levels <10 ng/ml. Inverse significant correlations between 25(OH)D levels and the VAS (P = 0.001) and between changes in 25(OH)D levels and changes in the VAS in patients with baseline 25(OH)D levels <30 ng/ml (P = 0.017) were found. No significant correlations were seen between the variation of the SLEDAI or SDI values and the variation in 25(OH)D levels (P = 0.87 and P = 0.63, respectively).

Conclusion

Increasing 25(OH)D levels may have a beneficial effect on fatigue. Our results do not support any effects of increasing 25(OH)D levels on SLE severity, although they are limited by the insufficient 25(OH)D response to the recommended regimen of oral vitamin D₃ replacement.     

The effect of a combined oral calcium and vitamin D supplement for treating mild to moderate vitamin D deficiency in postmenopausal women

Objective

To evaluate the efficacy of a combined calcium and vitamin D (Ca-D3) supplement for vitamin D deficiency in a small group of postmenopausal women.

Methods

A prospective open label 3 month-study.

Participants

23 postmenopausal women (mean age 61.2 yrs) with vitamin D deficiency were given a combined oral Ca-D3 supplement called “Osteoblast”. The supplement comprises 500 mg elemental calcium and 500 IU of cholecalciferol. The dosing regimen comprised a loading dose of 1000 IU of cholecalciferol per day for one month (two tablets) and thereafter a maintenance dose of 500 IU of cholecalciferol per day for 2 months (one tablet).

Outcome measure

Serum was collected for calcium, 25 hydroxyvitamin D3 (25OHD3), and PTH measurements, as well as early morning 2-hour urine calcium/creatinine excretion index (Uca/creat). Specimens were collected at baseline and after 3 months of therapy. Data are reported as mean ± 1 standard error and 95% confidence intervals.

Results

Data was available for the 21 subjects who completed the study. Two subjects (9%) withdrew because of gastrointestinal intolerance. There were 3 subjects with moderate (12.5–24 nmol/L) and 18 with mild (25–49 nmol/L) vitamin D deficiency. Ten subjects (48%) had secondary hyperparathyroidism. Following the oral Ca-D3 combination, serum 25OHD3 levels normalised in all subjects with 18 (86%) subjects achieving values of greater than 70 nmol/L. Serum 25OHD3 levels increased from 36 (31–41) to 91 (79–102) nmol/L (p = 0.0001), increasing by an average of 152% over the 3-month period. There was a corresponding 38% decrease in serum PTH concentrations at 3 months (5.1 + 0.6 pmol/L), compared with baseline (8.0 + 1 pmol/L) (p = 0.001). No subject developed hypercalcemia, but an elevated Uca/creat excretion index occurred in one subjects.

Conclusions

A combined oral Ca-D3 product (Osteoblast) is effective for treating vitamin D deficiency and is adequately tolerated.     

Hormonal control of skeletal and mineral homeostasis

The interactions of parathyroid hormone (PTH), calcitonin (CT) and vitamin D in mineral and skeletal homeostasis are discussed. Evidence is presented that not only does PTH control the renal synthesis of 1,25-dihydroxyvitamin D₃ (1,25-(OH)₂D₃), the biologically active form of vitamin D₃, but also that 1,25-(OH)₂D₃ acts as a feedback inhibitor of PTH secretion. Thus, the plasma concentrations of both 1,25-(OH)₂D₃ and calcium are controlled by the actions of PTH, and both of these metabolites operate as feedback inhibitors of PTH secretion. At the level of bone cell function, present evidence indicates that both PTH and CT influence the size of the osteoclast and osteoblast cell pools and the respective activities of the cells in these pools: PTH increases the size of the osteoclast pool and the activity of the cells in this pool; CT has the opposite effects; and 1,25-(OH)₂D₃ seems to increase the activity of these cells as well as those in the osteoblast pool without altering the size of these pools. These different effects are interpreted in terms of the actions of these three hormonal agents on the concentration of three second messengers, cyclic adenosine monophosphate (AMP), calcium ion and monohydrogen phosphate, within the cell.     

Vitamin D metabolites and skeletal consequences in primary hyperparathyroidism

Background Primary hyperparathyroidism (PHPT) is associated with reduced bone mineral density (BMD) mainly at sites rich in cortical bone. However, successful parathyroidectomy causes an increase in BMD especially at sites rich in trabecular bone. Plasma 25‐hydroxyvitamin D (25OHD) levels are typically reduced and plasma 1,25‐dihydroxyvitamin D [1,25(OH)₂D] slightly increased in PHPT. These variations in vitamin D metabolites may influence variations in BMD and fracture risk. Aim To investigate relations between preoperative vitamin D metabolites and skeletal consequences in patients with untreated PHPT and to appraise the influence of preoperative vitamin D metabolites on postoperative changes in BMD. Design Cross‐sectional and cohort study. Materials Two hundred and forty‐six consecutive Caucasian PHPT patients aged 19–91 years. (median 63, 87% females). Results BMD was reduced at the femoral neck (P < 0·001) and forearm (P < 0·001), but normal at the lumbar spine (P = 0·11). Levels of biochemical bone markers were associated with high plasma PTH, high plasma 1,25(OH)₂D and low plasma levels of 25OHD. Moreover, low plasma 25OHD was associated with low levels of BMD at the femoral neck (r_p = 0·23), the forearm (r_p = 0·19) and the whole body (r_p = 0·30), whereas plasma 1,25(OH)₂D was inversely associated with BMD at all regional sites and the whole body. Plasma PTH only showed an inverse association with BMD at the forearm (r_p = –0·21). No association was observed between biochemical variables and prevalent spinal fractures, all peripheral fractures or osteoporotic peripheral fractures. The annual increase in spinal BMD after surgery was positively associated with preoperative plasma PTH (r_p = 0·40), whereas the annual increase in whole body BMD was inversely associated with plasma 25OHD (r_p = –0·32). No change in BMD at the femoral neck and forearm was observed 1 year after surgery. Conclusion Low vitamin D status and high plasma 1,25(OH)₂D are associated with increased bone turnover and decreased BMD in patients with PHPT.     

Vitamin D3 metabolism in patients with rheumatic diseases: Low serum levels of 25-hydroxyvitamin D3 in patients with systemic lupus erythematosus

Summary 1,25-dihydroxyvitamin D₃ (1,25(OH)₂ D₃) has been shown to modulate lymphocyte activation in vitro. Through binding to specific receptors 1,25(OH)₂ D₃ inhibits proliferation, immunoglobulin production and the release of cytokines. Moreover, 1,25-(OH)₂ D₃ is efficiently produced by activated monocytes. These findings suggest that 1,25-(OH)₂ D₃ may play a role as a regulator of immunological activation. Consequently, we found it of interest to study the serum levels of the two major metabolites of vitamin D₃ in patients with systemic lupus erythematosus (SLE) (n=21), rheumatoid arthritis (RA) (n=29) and osteoarthritis (n=12). In patients with SLE the levels of 25-OH D₃ were below those of the healthy controls (p=0.0008) and OA (p=0.0168). The levels 1,25-(OH)₂ D₃ corresponded to normal levels. There were no significant correlations between 25-OH D₃ levels and clinical or paraclinical disease manifestations. Further, the phenotypic distribution of Gc-globulin, which binds vitamin D₃ metabolites in circulation, was normal. The serum concentrations of 1,25-(OH)₂ D₃ and 25-OH D₃ in patients with RA and OA corresponded to those of the controls. Although the cause of the reduced 25-OH D₃ levels in SLE patients is unclear, possible beneficial effects of administration of vitamin D to these patients should be considered.     

1,25‐dihydroxyvitamin D3 modulates Th17 polarization and interleukin‐22 expression by memory T cells from patients with early rheumatoid arthritis

Objective

To examine the immunologic mechanism by which 1,25‐dihydroxyvitamin D₃ (1,25[OH]₂D₃) may prevent corticosteroid‐induced osteoporosis in patients with early rheumatoid arthritis (RA), with a focus on T cell biology.

Methods

Peripheral blood mononuclear cells (PBMCs) and CD4+CD45RO+ (memory) and CD4+CD45RO− (non‐memory) T cells separated by fluorescence‐activated cell sorting (FACS) from treatment‐naive patients with early RA were stimulated with anti‐CD3/anti‐CD28 in the absence or presence of various concentrations of 1,25(OH)₂D₃, dexamethasone (DEX), and 1,25(OH)₂D₃ and DEX combined. Levels of T cell cytokines were determined by enzyme‐linked immunosorbent assay and flow cytometry.

Results

The presence of 1,25(OH)₂D₃ reduced interleukin‐17A (IL‐17A) and interferon‐γ levels and increased IL‐4 levels in stimulated PBMCs from treatment‐naive patients with early RA. In addition, 1,25(OH)₂D₃ had favorable effects on tumor necrosis factor α (TNFα):IL‐4 and IL‐17A:IL‐4 ratios and prevented the unfavorable effects of DEX on these ratios. Enhanced percentages of IL‐17A– and IL‐22–expressing CD4+ T cells and IL‐17A–expressing memory T cells were observed in PBMCs from treatment‐naive patients with early RA as compared with healthy controls. Of note, we found no difference in the percentage of CD45RO+ and CD45RO− cells between these 2 groups. Interestingly, 1,25(OH)₂D₃, in contrast to DEX, directly modulated human Th17 polarization, accompanied by suppression of IL‐17A, IL‐17F, TNFα, and IL‐22 production by memory T cells sorted by FACS from patients with early RA.

Conclusion

These data indicate that 1,25(OH)₂D₃ may contribute its bone‐sparing effects in RA patients taking corticosteroids by the modulation of Th17 polarization, inhibition of Th17 cytokines, and stimulation of IL‐4.

     

Decreased Conversion of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3 Following Cholecalciferol Therapy in Patients with CKD

Background and objectives

Elevated concentrations of fibroblast growth factor 23 (FGF23) are postulated to promote 25-hydroxyvitamin D (25[OH]D) insufficiency in CKD by stimulating 24-hydroxylation of this metabolite, leading to its subsequent degradation; however, prospective human studies testing this relationship are lacking.

Design, setting, participants, & measurements

An open-label prospective study was conducted from October 2010 through July 2012 to compare the effect of 8 weeks of oral cholecalciferol therapy (50,000 IU twice weekly) on the production of 24,25(OH)₂D₃ in vitamin D–insufficient patients with CKD (n=15) and controls with normal kidney function (n=15). Vitamin D metabolites were comprehensively profiled at baseline and after treatment, along with FGF23 and other mineral metabolism parameters.

Results

Vitamin D₃ and 25(OH)D₃ concentrations increased equivalently in the CKD and control groups following cholecalciferol treatment (median D₃ change, 8.6 ng/ml [interquartile range, 3.9–25.6 ng/ml] for controls versus 12.6 ng/ml [6.9–41.2 ng/ml] for CKD [P=0.15]; 25(OH)D₃ change, 39.2 ng/ml [30.9–47.2 ng/ml] for controls versus 39.9 ng/ml [31.5–44.1 ng/ml] for CKD [P=0.58]). Likewise, the absolute increase in 1α,25(OH)₂D₃ was similar between CKD participants and controls (change, 111.2 pg/ml [64.3–141.6 pg/ml] for controls versus 101.1 pg/ml [74.2–123.1 pg/ml] for CKD; P=0.38). Baseline and post-treatment 24,25(OH)₂D₃ concentrations were lower in the CKD group; moreover, the absolute increase in 24,25(OH)₂D₃ after therapy was markedly smaller in patients with CKD (change, 2.8 ng/ml [2.3–3.5 ng/ml] for controls versus 1.2 ng/ml [0.6–1.9 ng/ml] for patients with CKD; P<0.001). Furthermore, higher baseline FGF23 concentrations were associated with smaller increments in 24,25(OH)₂D₃ for individuals with CKD; this association was negated after adjustment for eGFR by multivariate analysis.

Conclusions

Patients with CKD exhibit an altered ability to increase serum 24,25(OH)₂D₃ after cholecalciferol therapy, suggesting decreased 24-hydroxylase activity in CKD. The observed relationship between baseline FGF23 and increments in 24,25(OH)₂D₃ further refutes the idea that FGF23 directly contributes to 25(OH)D insufficiency in CKD through stimulation of 24-hydroxylase activity.     

The effect of different doses of vitamin D3 on markers of vascular health in patients with type 2 diabetes: a randomised controlled trial

Aims/hypothesis

Low 25-hydroxyvitamin D levels predict future cardiovascular events and are common in patients with type 2 diabetes. We compared the effect of 100,000 and 200,000 IU doses of vitamin D₃ on endothelial function, blood pressure and markers of glycaemic control in patients with type 2 diabetes.

Methods

This was a randomised, parallel group, placebo-controlled trial. Patients with type 2 diabetes and baseline 25-hydroxyvitamin D levels <100 nmol/l were enrolled from community and hospital-based diabetes clinics. Participants were assessed in a university department of clinical pharmacology and received a single oral dose of placebo or vitamin D₃ (100,000 IU or 200,000 IU) at baseline, randomly allocated via numbered bottles prepared offsite; participants and investigators were both blinded to treatment allocation. Endothelial function, office blood pressure, B-type natriuretic peptide, insulin resistance and glycosylated haemoglobin were measured at baseline, and at 8 and 16 weeks.

Results

We randomised 61 participants to the three groups (placebo 22, 100,000 IU vitamin D₃ 19, 200,000 IU vitamin D₃ 20). There was no significant difference in the primary outcome of endothelial function at 8 weeks (placebo 5.2%, n?=?22; 100,000 IU 4.3%, n?=?19; 200,000 IU 4.9%, n?=?17) or at 16 weeks. Insulin resistance and glycosylated haemoglobin did not improve with either dose of vitamin D₃. On covariate analysis, systolic blood pressure was significantly lower in both treatment arms than in the placebo group at 8 weeks (placebo 146.4 mmHg, 100,000 IU 141.4 mmHg [p?=?0.04 vs placebo], 200,000 IU 136.8 mmHg [p?=?0.03 vs placebo]). B-type natriuretic peptide levels were significantly lower in the 200,000 IU group by 16 weeks (placebo 34 pg/ml, 200,000 IU 21 pg/ml, p?=?0.02). No significant excess of adverse effects was noted in the treatment arms.

Conclusions/interpretation

High-dose vitamin D₃ improved systolic blood pressure and B-type natriuretic peptide levels, but not endothelial function, insulin resistance or glycosylated haemoglobin in patients with type 2 diabetes.

Trial registration

ISRCTN50587697 (www.controlled-trials.com)

Funding

Diabetes UK, grant number 06/0003429. M. D. Witham is funded by a Scottish Government NES/CSO Clinician Scientist Award.     

Elevated serum parathormone levels are associated with myocardial iron overload in patients with β‐thalassaemia major

Objectives: Despite advances in conventional treatment, iron‐induced cardiomyopathy is still the most frequent cause of death among patients with β‐thalassaemia major. Recent studies have correlated increased myocardial iron content to decreased levels of vitamin D in thalassaemic patients. The aim of this study was to measure parathormone (PTH) and metabolites of vitamin D and consequently to investigate whether these parameters predispose to myocardial iron overload in patients with β‐thalassaemia major. Methods: In 62 patients (29 M and 33 F, mean age: 22.79 ± 6.18 yr) with β‐thalassaemia major levels of intact parathormone (iPTH) and vitamin D metabolites [25(ΟH)D₃ and 1,25(ΟH)₂D₃] were measured in serum. Additionally, estimation of myocardial iron content was performed by magnetic resonance imaging, whereas mean serum ferritin concentrations were calculated for 1 yr prior to the study. Results: Results showed markedly decreased levels of serum 25(OH)D₃ in 37 patients (60%), whereas 7 patients (11%) had borderline 25(OH)D₃ levels (between 50 and 75 nmol/L). Serum iPTH levels were significantly higher in patients having increased myocardial iron compared to those having normal myocardial iron (44.04 ± 22.09 pg/mL vs. 31.39 ± 14.30 pg/mL, P = 0.017). Multivariant regression analysis identified PTH levels as the major predictor of increased myocardial iron.     

Pancreatic secretion in man with subclinical vitamin D deficiency

Summary The effects of subclinical vitamin D deficiency and vitamin D supplementation on oral glucose tolerance and secretion of pancreatic hormones were studied in 10 diphenyl-hydantoin-treated epileptic patients and 15 geriatric patients. Their mean serum concentrations of 25-hydroxyvitamin D₃ and 1,25-dihydroxyvitamin D₃ decreased markedly, but returned to normal within 2 weeks of oral supplementation with 25-hydroxyvitamin D₃. The serum concentration of ionized calcium was within the normal range before treatment, and remained unchanged. Serum parathyroid hormone was increased during vitamin D deficiency, but decreased significantly (p < 0.05) afterwards. In vitamin D-deficient epileptic and geriatric patients, the 2- and 3-h insulin levels after glucose ingestion were increased when compared with control values, and glucagon secretion was not suppressed by glucose. Oral glucose tolerance of both groups of patients did not change after 25-hydroxyvitamin D₃ supplementation. Insulin secretion remained unchanged in geriatric patients, but was reduced to normal values in epileptic patients. Glucagon suppressibility by glucose was partly restored after vitamin D supplementation in epileptic patients but not in geriatric patients. In contrast to that observed in severely vitamin D-deficient rats or rabbits, correction of subclinical vitamin D deficiency failed to enhance insulin secretion or to improve glucose tolerance in man.