Vitamin D supplementation: when and how?

The multiple effects of vitamin D on skeletal and extra-skeletal tissues increased the attention of scientists and public to the possible relationship between hypovitaminosis D and a variety of acute and chronic diseases. However, several points are still largely debated. In particular, the definition of optimal vitamin D status [as assessed by the circulating levels of 25-hydroxyvitamin D (25(OH)D)] remains controversial, and experts still disagree about several related outcomes: how to estimate the prevalence of vitamin D deficiency, when to start treatment, how to reach optimal 25(OH)D levels, which type of vitamin is preferable for supplementation, which dosing strategy is the better option. In this context, a matter of major debate is represented by the measurement of circulating level of 25(OH)D, whose determination is affected by the lack of standardization and by several technical problems. It has been recently hypothesized that free and bio-available, rather than total 25(OH)D, mostly determine its biological action. However, further evaluation of directly measured free 25(OH)D levels is needed, in order to establish its role in research and clinical practice. Finally, it is not yet defined if a threshold of optimal vitamin D status for reducing the risk of extra-skeletal diseases exists. Actually, it is plausible that the desired 25(OH)D level may vary widely, depending on the health outcome in question. However, this topic is uncertain, partly due to the lack of randomized controlled trials assessing the effect of vitamin D supplementation on extra-skeletal end-points.

Six-year follow-up of a characteristic osteolytic lesion in a patient with tumor-induced osteomalacia.

OBJECTIVE: Tumor-induced osteomalacia is a rare paraneoplastic syndrome characterized by hypophosphatemia and inappropriately normal or low 1,25-dihydroxyvitamin D. CLINICAL CASE: Here, we report a 6-year postoperative follow-up of a patient with oncogenic osteomalacia with a distinctive skeletal manifestation. The latter was characterized by an almost linear lytic lesion of a few millimeters with irregular borders, mainly involving the trabecular compartment but extending into cortical shell, located in the middle third of the right fibula. Six years after tumor resection, a sclerotic repair with a complete recovery was observed. Furthermore, we monitored a striking increase in bone mineral density throughout the observation period, reaching a peak of 73% over basal values at lumbar spine after 2 years; at total femur and radius, the peak was 47.5 and 4.6% respectively, after 4 years from tumor resection. CONCLUSIONS: We report for the first time that an osteolytic lesion may be part of the skeletal involvement in tumor-induced osteomalacia.

Management of endocrine disease: value and limitations of assessing vitamin D nutritional status and advised levels of vitamin D supplementation.

The growing attention to the role of vitamin D in skeletal and extra-skeletal diseases over the last decade induced an increased demand for vitamin D determination as well as a dramatic rise of sales of vitamin D supplement. However, several critical points in this field remain to be clarified. We lack a clear consensus about the definition of vitamin D deficiency, insufficiency, and sufficiency. The identification of different thresholds defining vitamin D status has relevant implications in clinical practice. In fact, the worldwide prevalence of low vitamin D status is highly varying according to the level of 25(OH)D utilized to define sufficiency. Therefore, the assessment of 25-hydroxyvitamin D levels may have a critical role, but a number of different technical problems associated with its determination may interfere in interpreting the results. The hydrophobic nature of vitamin D and the tight binding to its carrier (vitamin D binding protein), the different forms circulating in blood, and the issue of standardization are among the most important factors influencing the measurement of this metabolite. Another controversial point relies on the conflicting guidance on prevention and treatment of vitamin D deficiency endorsed by different medical and scientific communities. In particular, uncertainty exists about how to replete vitamin D stores, how to maintain normal 25(OH)D levels after repletion, which form of vitamin D is preferable for supplementation, and which route of administration and dosing regimens are advisable. Finally, concerns have been raised regarding vitamin D toxicity and its adverse effects.

Long-term bioavailability after a single oral or intramuscular administration of 600,000 IU of ergocalciferol or cholecalciferol: implications for treatment and prophylaxis.

CONTEXT: We previously showed that a single high dose of oral (po) cholecalciferol (D3) sharply increases serum 25-hydroxyvitamin D [25(OH)D]. OBJECTIVE: We evaluated the long-term bioavailability and metabolism of a single po or intramuscular (im) high dose of ergocalciferol (D2) or D3. DESIGN: This was a prospective intervention study. SETTING: The study was conducted in an ambulatory care setting. PATIENTS: Participants were 24 subjects with hypovitaminosis D. INTERVENTIONS: A single dose of 600,000 IU of po or im D2 or D3 was administered. MAIN OUTCOME MEASURES: Serum 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)2D] were measured at baseline and at days 30, 60, 90, and 120 by RIA. Serum 1,25(OH)2D2, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], 24,25-hydroxyvitamin D2 [24,25(OH)D2], and 24,25-hydroxyvitamin D3 [24,25(OH)D3] were measured by liquid chromatography-tandem mass spectrometry in a subgroup of patients receiving the po formulations. RESULTS: The areas under the curve of 25(OH)D after D3 were significantly higher than those after D2 (P < .0001). Serum 25(OH)D basal difference significantly increased at day 30 with po D2 and D3 (P < .01 and P < .0001) and up to day 90 with po D3 (P < .01). The im formulations produced a slow increased, and values peaked at day 120 relative to the other time points (P < .0001). We found a decrease in 1,25(OH)2D at day 30 (P < .05) and up to day 120 (P < .001) and an increase in 1,25(OH)2D2 at day 30 (P < .01) and up to day 120 (P < .01) after po D2. Oral D2 and D3 produced increases in 24,25(OH)D2 and 24,25(OH)D3, respectively, at day 30 (P < .001). CONCLUSIONS: A po dose of 600,000 IU of D2 or D3 is initially more effective in increasing serum 25(OH)D than the equivalent im dose and is rapidly metabolized. Our RIA assay for 1,25(OH)2D may not recognize 1,25(OH)2D2.

Effects of strontium ranelate administration on calcium metabolism in female patients with postmenopausal osteoporosis and primary hyperparathyroidism.

We investigated possible changes of parameters of calcium metabolism induced by strontium ranelate (SR). Twenty-three patients with postmenopausal osteoporosis (PO) and 14 with primary hyperparathyroidism (PHPT) were studied while taking 2 g/day of SR. Women with PO and 10 healthy age-matched control women were also daily supplemented with 1,000 mg calcium and 800 IU vitamin D. All subjects were studied at baseline and after 7 and 30 days; PO women and controls were also investigated at 180 and 360 days of treatment. Serum ionized calcium (iCa), phosphate (sP), magnesium, creatinine, 25-hydroxycholecalciferol (25[OH]D), 1,25-dihydroxycholecalciferol (1,25[OH](2)D), serum parathyroid hormone (PTH) were measured. In spot urine, we assessed calcium and phosphate over creatinine ratios (uCa/Cr, uP/Cr), calcium excretion (Ca ex) and renal phosphate threshold (TmP/GFR); in 24-h urine, calcium and magnesium over creatinine clearance ratios (CaCl/CrCl and MgCl/CrCl). In PO, SR administration was associated with a significant decrease of PTH and 1,25(OH)(2)D levels but an increase of sP (p < 0.001). SR also significantly increased Ca/Cr, Ca ex, and TmP/GFR in spot urine and CaCl/CrCl in both spot and 24-h urine (p = 0.004 to <0.001). In PHPT, SR significantly decreased iCa and increased sP, slightly modifying PTH, 25(OH)D, and 1,25(OH)(2)D values. Also in PHPT, Ca ex and CaCl/CrCl of spot and 24-h urine, as TmP/GFR, significantly increased (all p < 0.02). SR influenced the main parameters of calcium homeostasis, probably through the calcium-sensing receptor.

Metabolic changes following 500 µg monthly administration of calcidiol: a study in normal females.

This study was performed to investigate the effect of monthly oral administration of 500 µg of calcidiol (25-hydroxyvitamin D(3)) for 4 months on both serum vitamin D levels and sequential changes of parameters of calcium metabolism; 18 normal women aged 24-72 years were investigated. There was a significant increase of serum 25(OH)D after the first administration; thereafter all values persisted significantly higher compared to the basal value (P < 0.001). Mean 1,25(OH)(2)D serum levels peaked at day 3 and then tended to stabilize following day 30. During the first month, all mean values observed following the initial administration were significantly higher than basal values. The first calcidiol dose produced a significant reduction of serum PTH levels (P < 0.001), which then remained constant over time. Concerning serum calcium and phosphorus, we were not able to demonstrate any significant change during the entire observation period. Considering the single values for both serum ionized and total calcium, the values of Ca(2+) exceeded upper limits of normal on only two occasions. Regarding biochemical markers of bone remodeling, mean changes of serum bone isoenzyme of alkaline phosphatase activity showed a significant trend to decrease, starting at day 30. No significant changes of serum CTX values were noted. Overall, 24-h urinary excretion of calcium did not change, seven values exceeding the threshold of 4 mg/kg body weight. Monthly administration of 500 µg of 25-hydroxyvitamin D(3) may be considered an alternative for vitamin D repletion, without any detrimental effect.

Acute and chronic effects of hypercalcaemia on cortical excitability as studied by 5 Hz repetitive transcranial magnetic stimulation.

We designed the present study to disclose changes in cortical excitability in humans with hypercalcaemia, by delivering repetitive transcranial magnetic stimulation (rTMS) over the primary motor area (M1). In 22 patients with chronic hypercalcaemia related to primary hyperparathyroidism and 22 age-matched healthy subjects 5 Hz-rTMS was delivered at rest and during a sustained voluntary contraction of the target muscle. Changes in the resting motor threshold (RMT), motor evoked potential (MEP) amplitudes and cortical silent period (CSP) duration were measured and compared in patients and healthy controls. Two of the 22 patients were re-tested after parathyroidectomy when serum calcium had normalized. In a subgroup of healthy subjects, changes in the rTMS parameters were tested before and after acute hypercalcaemia. No significant difference between healthy normocalcaemic subjects and chronic hypercalcaemic patients was found in the RMT values and MEP amplitude and CSP duration evoked by the first stimulus of the trains. During the course of 5 Hz-rTMS trains, MEP size increased significantly less in patients with chronic hypercalcaemia than in healthy subjects, whereas the CSP duration lengthened to a similar extent in both groups. In the two patients studied after parathyroidectomy, rTMS elicited a normal MEP amplitude facilitation. Our findings indicate that acute hypercalcaemia significantly decreased the MEP amplitude facilitation. Given that 5 Hz-rTMS modulates cortical excitability through mechanisms resembling short-term synaptic enhancement, the reduction of MEP amplitude facilitation by hypercalcaemia may be related to Ca2+-dependent changes in synaptic plasticity.

The effects of alendronate treatment in osteoporotic patients affected by monoclonal gammopathy of undetermined significance.

In patients with monoclonal gammopathy of undetermined significance (MGUS) the increase of bone turnover rate can increase the risk of fracture. Thus, a treatment normalizing this negative balance could be of benefit in these patients. We studied 100 patients affected by MGUS, grouped according to the presence (group A, 50 patients) or absence (group B) of vertebral fractures and/or osteoporosis. Group A was treated with alendronate (70 mg/weekly) plus calcium and cholecalciferol for 18 months, and group B was treated with calcium and cholecalciferol. After 18 months, the mean bone mineral density (BMD) of the lumbar spine and total femur had increased by 6.1% and 1.5%, respectively, in group A. In the nine patients of this group not taking alendronate, BMD values of the lumbar spine and total femur decreased by 1.6% (P < or = 0.001 ) and 1.3% (P < or = 0.01), respectively. In patients of group B, BMD increased by 1.2% at the lumbar spine and decreased by 1.2% at the total femur. Corresponding figures of those patients in the same group not taking calcium and vitamin D supplementation were -0.1% and -1.2%, respectively. At 18 months we observed significant decreases of serum bone markers: the difference between the groups was -23.2 (P < or = 0.01) for bone alkaline phosphatase, -23.6 for osteocalcin (P < or = 0.01), -35.1 for C-terminal telopeptides of collagen type I (P < or = 0.001), and -0.47 for bone sialoprotein (P = nonsignificant). Treatment with alendronate could lead to a significant reduction in fracture risk in MGUS patients with skeletal fragility.

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.