Effect of Vitamin D Receptor Genotypes on Calcium Absorption,Duodenal Vitamin D Receptor Concentration,and Serum 1,25 Dihydroxyvitamin D Levels in Normal Women

It is well established that bone mineral density is under strong genetic control. Recently it was reported that the Bsm I restriction fragment length polymorphism of the vitamin D receptor (VDR) gene could account for up to 75% of the genetic variance in bone mineral density. However, the physiological basis for such an effect has not been established. The VDR gene codes for the vitamin D receptor protein which regulates intestinal calcium absorption. In order to assess the biochemical basis we studied the effect of common allelic variation of the VDR gene on intestinal VDR protein concentration, calcium absorption, and serum 1,25 dihydroxyvitamin D (1,25(OH)₂D). Ninety-two Caucasian women were genotyped for Bsm I and Taq I polymorphism at the VDR gene locus. From these we compared 49 young women aged 25–35 years and 43 elderly women aged 65–83 years, who had all three measurements performed. There were no significant differences in intestinal VDR protein concentration, serum 1,25(OH)₂D, or radioactive calcium absorption among VDR genotype groups. Therefore, the small intestine does not seem to be a target for VDR gene polymorphism. Received: 12 August 1996 / Accepted: 3 January 1997     

Vitamin D Receptor Genotypes and Intestinal Calcium Absorption in Postmenopausal Women

Several studies have shown that bone mass and bone turnover are genetically determined. This genetic component is thought to be mediated in part by polymorphisms at the vitamin D receptor (VDR) locus, even though the underlying molecular mechanisms are still unknown. To evaluate a possible site of differential action of the VDR gene alleles we examined their correlation with intestinal calcium absorption in 120 Caucasian postmenopausal women (aged 61 ± 0.6 years). VDR gene polymorphisms for Apa I, Bsm I, and Taq I restriction endonucleases were assessed by Southern blotting analysis. The most common genotypes observed in our population were AaBbTt (37%), AABBtt (20%), aabbTT (15%), AabbTT (15%), and AABbTt (9%). Although there was some evidence of 13% higher lumbar BMD values in aabbTT genotype with respect to AABBtt genotype, this difference of approximately 0.1 g/cm² did not reach statistical significance, possibly because of the limited number of observations. On the contrary, no relationship was found between genotypes and femoral neck BMD values. Intestinal calcium absorption was significantly lower in BB and tt genotypes than, in bb and TT genotypes, respectively, and in AABBtt genotype than in either aabbTT or AaBbTt genotypes (P= 0.0015 ANOVA). No significant differences in intact PTH, alkaline phosphatase, 25OHD₃, and 1,25(OH)₂D₃ were found among subjects with different VDR genotypes. These results are consistent with a possible role of VDR alleles on intestinal calcium absorption.     

Treatment of Glucocorticoid-Induced Osteoporosis with Alfacalcidol/Calcium Versus Vitamin D/Calcium

Vitamin D/calcium substitution is generally regarded as an effective first step treatment for glucocorticoid-induced osteoporosis (GIOP). The aim of our study was to evaluate the efficacy of the active vitamin D metabolite alfacalcidol (1α) compared with the native vitamin D₃ in patients with established GIOP with or without vertebral fractures. Patients on long-term corticoid therapy were given either 1 μg alfacalcidol plus 500 mg calcium per day (group A, n = 43) or 1000 IU vitamin D₃ plus 500 mg calcium (group B, n = 42). The two groups were alike in age range, sex ratio, percentages of underlying diseases, average initial bone density values (lumbar spine: mean T-score −3.28 and −3.25, respectively), and rates of vertebral and nonvertebral fractures. During the 3-year study we found a small but significant increase of lumbar spine density in group 1α (+2.0%, P < 0.0001) and no significant changes at the femoral neck. In the D₃ group, there were no significant changes at both sites. At the end of the study, 12 new vertebral fractures had occurred in 10 patients of the group 1α and 21 in 17 patients of the D₃ group. In accordance with the observed fracture rates, the alfacalcidol group showed a significant decrease in back pain (P < 0.0001) whereas no change was seen in the vitamin D group. We conclude that with the doses used in this trial, alfacalcidol is superior to vitamin D in the treatment of established GIOP.     

Effect of Vitamin E on Ruminal Fermentation In Vitro

The effects of vitamin E on pH value, total protozoa counts, volatile fatty acid (VFA), ammonia nitrogen and lactate levels were examined using an in vitro ruminal incubation system. The ruminal fluid (100 ml) of the first and second group was supplemented with 0.4 mg or 0.8 mg of vitamin E, respectively. Samples were taken immediately before and following 3, 6, 12 and 24 h of incubation at 39°C and analysed for the total protozoa counts, the pH and the levels of ammonia nitrogen, lactate and VFA. Levels of propionate at 24 h and ammonia nitrogen at 12 and 24 h were significantly higher in the second group than in the control. In contrast, the levels of butyrate at 6, 12 and 24 h and lactate at 6, 12 and 24 h were lower in the second group than in the control. Propionate at 24 h, acetate levels at 6, 12 and 24 h and ammonia nitrogen levels at 6, 12 and 24 h and total rumen protozoa counts at 6, 12 and 24 h were significantly higher in the second group as compared with control. In contrary, butyrate levels at 6, 12 and 24 h, lactate levels at 6, 12 and 24 h were lower in second group than in control. There was no statistically significant difference among the groups in the pH values. In conclusion, the addition of vitamin E to in vitro ruminal fluid was found to increase the concentrations of acetate and propionate, total counts of protozoa, levels of ammonia nitrogen, but to decrease the butyrate and lactate levels of the ruminal aliquots in in vitro ruminal fermentation.     

Dietary Fructose Inhibits Intestinal Calcium Absorption and Induces Vitamin D Insufficiency in CKD

Renal disease leads to perturbations in calcium and phosphate homeostasis and vitamin D metabolism. Dietary fructose aggravates chronic kidney disease (CKD), but whether it also worsens CKD-induced derangements in calcium and phosphate homeostasis is unknown. Here, we fed rats diets containing 60% glucose or fructose for 1 mo beginning 6 wk after 5/6 nephrectomy or sham operation. Nephrectomized rats had markedly greater kidney weight, blood urea nitrogen, and serum levels of creatinine, phosphate, and calcium-phosphate product; dietary fructose significantly exacerbated all of these outcomes. Expression and activity of intestinal phosphate transporter, which did not change after nephrectomy or dietary fructose, did not correlate with hyperphosphatemia in 5/6-nephrectomized rats. Intestinal transport of calcium, however, decreased with dietary fructose, probably because of fructose-mediated downregulation of calbindin 9k. Serum calcium levels, however, were unaffected by nephrectomy and diet. Finally, only 5/6-nephrectomized rats that received dietary fructose demonstrated marked reductions in 25-hydroxyvitamin D₃ and 1,25-dihydroxyvitamin D₃ levels, despite upregulation of 1α-hydroxylase. In summary, excess dietary fructose inhibits intestinal calcium absorption, induces marked vitamin D insufficiency in CKD, and exacerbates other classical symptoms of the disease. Future studies should evaluate the relevance of monitoring fructose consumption in patients with CKD.In the past 20 yr, the cases of end stage renal disease (ESRD) in the United States quadrupled to 382,000 in 2000, and its prevalence is expected to increase by 85% to 713,000 patients in 2015, so reducing the incidence of ESRD is widely recognized as a major public health goal.¹ When patients have been identified as having the major risk factors (diabetes, hypertension, and uricemia) for rapid progression from chronic kidney disease (CKD) to ESRD,^2,3 efforts are made to slow the rate of progression, and these efforts involve tight management of these risk factors. Dietary fructose may be a major contributor to the rapid development of all of these chronic diseases considered risk factors for ESRD. For example, diabetes via hyperinsulinemia, hypertriglyceridemia via hepatic lipogenesis,^4,5 and hypertension via uricemia^6,7 each are exacerbated by excessive fructose consumption. Despite these documented linkages to symptoms of metabolic syndrome, fructose consumption instead has increased in the overall population and is not restricted or even monitored in patients with CKD. The average rate of fructose consumption is now approximately 80 g/d in the United States.^4,8,9 In addition, more recent work indicated a strong correlation between excessive fructose consumption and renal disease. Chronic fructose but not glucose or starch consumption in 5/6-nephrectomized (5/6Nx) rats leads to a marked decrease in creatinine clearance as well as to sharp increases in blood urea nitrogen (BUN), renal mass index, and histologic biomarkers of renal pathology.¹⁰ Fructose-induced pathology seems to be caused by increases in levels of oxidative stress and inflammation, as demonstrated in immortalized proximal tubular cells (HK-2) incubated in fructose.¹¹Other complications of CKD, such as osteodystrophy, hyperphosphatemia, hyperparathyroidism, and deficiency in 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃] levels,^12–14 may also be affected by dietary fructose. For example, dietary fructose perturbs intestinal phosphate (Pi)¹⁵ and calcium (Ca) absorption¹⁶ as well as Ca and Pi balance.^17,18 Excessive consumption of carbonated beverages known to contain high-fructose corn syrups have been strongly associated with increased incidence of bone fractures in the adolescent population.¹⁹ It seems clear from these studies that fructose could exacerbate the mineral imbalance usually associated with CKD; however, the studies investigating fructose effects on mineral metabolism have focused on young, actively growing individuals whereas ESRD and CKD are diseases that generally affect the aged population.We first tested the hypothesis that dietary fructose consumption exacerbates the classical symptoms of CKD that can lead to ESRD. Using sham-operated rats as controls, we allowed 5/6Nx rats to develop clear symptoms of CKD for 6 wk, then subsequently fed either a high-fructose or -glucose diet for an additional 4 wk and determined the classical blood and bone markers of renal disease. No study has related fructose consumption to vitamin D metabolism, yet the liver and the kidney, the main sites of vitamin D synthesis, are organs adversely affected by both chronic fructose consumption^20,21 and renal failure^10,11; therefore, we next tested the hypothesis that fructose consumption aggravates the already adverse effects of ESRD on the synthesis of the major active form of vitamin D, 1,25-(OH)₂D₃. Because 1,25-(OH)₂D₃ regulates intestinal Ca and Pi absorption,^22,23 we also examined rates of transepithelial transport of these minerals as well as determined expression levels of transporters and proteins involved in their uptake. Expression and activity levels of sugar transporters were also monitored as positive control because these transporters are affected by dietary sugars and as negative control because they are not affected by nephrectomy.     

Sodium Transport Across the Isolated Epithelium of Sheep Omasum is Influenced by Luminal Ammonia

Ammonia is a physiological fermentation product in the forestomachs and is absorbed from the rumen and omasum. Cellular uptake of ammonia affects the intracellular pH of polar and non‐polar cells. The effect of the uptake on the pH of the cytosol depends on the predominant form of ammonia. NH₃ uptake and its intracellular protonation tend to alkalinize the cytoplasm, whereas the uptake of NH acidifies the cytoplasm by reversing this reaction. Consequently, the absorption of ammonia across the omasal epithelium could cause a change of the intracellular pH and pH‐dependent transport mechanisms like Na/H exchange. Because no information is available about the form of ammonia absorbed in the omasum and, hence, possible modulation of Na transport by ammonia, the effect of increasing luminal ammonia concentrations (0, 5, 15 and 30 mmol/l) on Na transport were studied. In epithelia of hay‐fed animals, ammonia linearly inhibited Na transport in a dose‐dependent manner, at a luminal pH of 7.40, but not at a pH of 6.40. Ammonia did not influence Na transport in epithelia of concentrate‐fed animals. Because luminal ammonia did not consistently change the short circuit current or tissue conductance absorption of ammonia as NH appears to be unlikely. The predominant form of ammonia absorbed in the omasum is probably NH₃, which is protonated in the cytosol. The reduced availability of protons may be the cause of inhibition of Na transport via Na/H exchange.     

Osteoporosis Treatment by a New Active Vitamin D3 Compound, Eldecalcitol, in Japan

Although vitamin D is used mainly as a nutritional supplement in osteoporosis treatment, its active form, 1,25-dihydroxyvitamin D [1,25(OH)₂D], has an effect to maintain bone remodeling balance as well. Eldecalcitol is an analog of 1,25(OH) ₂D₃ with stronger effects than its native form in improving bone remodeling balance and increasing bone mineral density in osteoporotic patients. Daily 0.75???g eldecalcitol is superior to 1.0???g alfacalcidol in preventing new vertebral fractures under vitamin D supplementation, and is approved for osteoporosis treatment in Japan. Eldecalcitol also decreases wrist fractures. Further studies are warranted to examine the effect of eldecalcitol on other nonvertebral fractures, extraskeletal systems including falls, and combined treatment with other drugs in osteoporotic patients, as well as the mechanism of action of eldecalcitol.     

Intestinal Calcium Absorption Decreases Dramatically After Gastric Bypass Surgery Despite Optimization of Vitamin D Status

Roux‐en‐Y gastric bypass (RYGB) surgery has negative effects on bone, mediated in part by effects on nutrient absorption. Not only can RYGB result in vitamin D malabsorption, but the bypassed duodenum and proximal jejunum are also the predominant sites of active, transcellular, 1,25(OH)₂D‐mediated calcium (Ca) uptake. However, Ca absorption occurs throughout the intestine, and those who undergo RYGB might maintain sufficient Ca absorption, particularly if vitamin D status and Ca intake are robust. We determined the effects of RYGB on intestinal fractional Ca absorption (FCA) while maintaining ample 25OHD levels (goal ≥30 ng/mL) and Ca intake (1200 mg daily) in a prospective cohort of 33 obese adults (BMI 44.7 ± 7.4 kg/m²). FCA was measured preoperatively and 6 months postoperatively with a dual stable isotope method. Other measures included calciotropic hormones, bone turnover markers, and BMD by DXA and QCT. Mean 6‐month weight loss was 32.5 ± 8.4 kg (25.8% ± 5.2% of preoperative weight). FCA decreased from 32.7% ± 14.0% preoperatively to 6.9% ± 3.8% postoperatively (p < 0.0001), despite median (interquartile range) 25OHD levels of 41.0 (33.1 to 48.5) and 36.5 (28.8 to 40.4) ng/mL, respectively. Consistent with the FCA decline, 24‐hour urinary Ca decreased, PTH increased, and 1,25(OH)₂D increased (p ≤ 0.02). Bone turnover markers increased markedly, areal BMD decreased at the proximal femur, and volumetric BMD decreased at the spine (p < 0.001). Those with lower postoperative FCA had greater increases in serum CTx (ρ = ?0.43, p = 0.01). Declines in FCA and BMD were not correlated over the 6 months. In conclusion, FCA decreased dramatically after RYGB, even with most 25OHD levels ≥30 ng/mL and with recommended Ca intake. RYGB patients may need high Ca intake to prevent perturbations in Ca homeostasis, although the approach to Ca supplementation needs further study. Decline in FCA could contribute to the decline in BMD after RYGB, and strategies to avoid long‐term skeletal consequences should be investigated. © 2015 American Society for Bone and Mineral Research.     

Relationships Between Intestinal Calcium Absorption,Serum Vitamin D Metabolites and Smoking in Postmenopausal Women

Smoking has been associated with low bone density, fractures and poor intestinal calcium absorption. Calcium absorption is a critical factor in calcium balance in postmenopausal women but the mechanisms causing decreased absorption efficiency in postmenopausal smokers are controversial and poorly defined. We performed a cross-sectional study of 405 postmenopausal women attending a clinic for the management of osteoporosis to compare intestinal calcium absorption efficiency, serum vitamin D metabolites and parathyroid hormone levels in postmenopausal women who had never smoked, who were smokers previously or who were current smokers, to examine the relationships between these variables in smokers. Two hundred and fifty-two of the women had never smoked, 79 had smoked previously and 74 were current smokers. The hourly fractional rate of calcium absorption was similar in non-smokers and those who had previously smoked. Radiocalcium absorption was less in the 74 smokers compared with the 331 non-smokers [0.60 (0.29 SD) vs 0.71 (0.27); p= 0.004], as were serum calcitriol (p<0.001) and parathyroid hormone (PTH) (p<0.01). There was no difference in the relationship between calcium absorption and serum calcitriol between smokers (r= 0.38) and non-smokers (r= 0.28); hence the impaired calcium absorption in the smokers was almost entirely attributable to suppression of the PTH–calcitriol endocrine axis. In postmenopausal women smoking is associated with a reduction in calcium absorption efficiency due to suppression of the PTH–calcitriol axis. This impairment of calcium absorption could lead to accelerated bone loss and limit the usefulness of dietary calcium supplementation. Received: 21 May 2001 / Accepted: 4 September 2001     

Vitamin D Does Not Increase Calcium Absorption in Young Women: A Randomized Clinical Trial

It is commonly said that vitamin D should be used to increase calcium absorption. We tested this statement in a dose‐response study of vitamin D on calcium absorption. A total of 198 white and African American women, aged 25 to 45 years, with vitamin D insufficiency, serum 25‐hydroxyvitamin D (25OHD) <20 ng/mL, were randomized in a double‐blind study to vitamin D3 400, 800, 1600, 2400 IU, or placebo. A calcium supplement was given to increase mean calcium intake at baseline from 706 mg/d to 1031 mg/d. Calcium absorption was measured at baseline and after 12 months using a single isotope method with radiocalcium45 and 100 mg of calcium. Mean baseline serum 25OHD was 13.4 ng/mL (33.5 nmol/L) and increased to 40 ng/mL (100 nmol/L) on the highest dose of 2400 IU. Using a multivariate regression analysis with significant predictors, baseline absorption, calcium intake, and weight, there was no increase in 12‐month calcium absorption compared with baseline on any dose of vitamin D in either whites or African Americans. There was no significant relationship between 12‐month calcium absorption and final serum 25OHD. In an analysis of calcium absorption and serum 25OHD at baseline, serum 25OHD levels were divided into groups: 0 to 5, 6 to 10, 11 to 15, or 16 to 20 ng/mL. There was no evidence of a threshold decrease in calcium absorption or serum 1,25 dihydroxyvitamin D (1,25(OH)₂D) amongst the lowest groups. Vitamin D doses up to 2400 IU daily did not increase calcium absorption. No threshold level of serum 25OHD for calcium absorption was found at baseline or in the longitudinal study, suggesting that active transport of calcium is saturated at very low serum 25OHD levels <5 ng/mL. There is no need to recommend vitamin D for increasing calcium absorption in normal subjects. Very efficient calcium absorption at very low levels of serum 25OHD explains why people do not develop osteomalacia provided that dietary intakes of calcium and phosphorus are adequate. © 2014 American Society for Bone and Mineral Research.     

Polyamines in the Gastro‐intestinal Tract of Goat Kids and in the Regenerating Ruminal Epithelium of Sheep

The aim of the present study was to investigate whether temporal changes in polyamine concentration and synthesis could be found in the luminal content and wall tissue of the rumen and abomasum, two organs which have entirely different growth patterns during the first month of life. In the abomasal mucosa there was a marked gradual decrease in the ornithine decarboxylase (ODC) activity during the first month of life, while the ODC activity in the ruminal mucosa was low during the whole experimental period. However, injury of the rumen wall was followed by increased ODC activity. The ODC activity in duodenal mucosa was about 10 times higher than in the ileal mucosa and the ruminal epithelium. In ruminal liquid a clear peak in ODC activity was observed during the period 51–70 days after birth. The polyamine concentration did not parallel the ODC activity, in either the ruminal epithelium or the ruminal liquid. Of the polyamines, the spermine concentration was always highest, and with the exception of duodenal mucosa, the putrescine concentration was lowest. In liver a clear decrease in spermidine concentration from day 1 to about day 60 after birth was observed. Otherwise no marked temporal changes in tissue polyamine concentrations were observed. Two and a half hours after oral administration of ¹⁴C‐labelled spermine, nearly all of the radioactivity was found in the lumen of the gastrointestinal tract. On the other hand, 1 h after intravenous injection of polyamines the walls of the gastrointestinal tract were strongly labelled. In conclusion, the polyamines needed for ruminal epithelial development seem to come from sources other than the ruminal epithelium itself or the ruminal lumen.     

Active Vitamin D Treatment for Reduction of Residual Proteinuria: A Systematic Review

Despite renin-angiotensin-aldosterone system blockade, which retards progression of CKD by reducing proteinuria, many patients with CKD have residual proteinuria, an independent risk factor for disease progression. We aimed to address whether active vitamin D analogs reduce residual proteinuria. We systematically searched for trials published between 1950 and September of 2012 in the Medline, Embase, and Cochrane Library databases. All randomized controlled trials of vitamin D analogs in patients with CKD that reported an effect on proteinuria with sample size≥50 were selected. Mean differences of proteinuria change over time and odds ratios for reaching ≥15% proteinuria decrease from baseline to last measurement were synthesized under a random effects model. From 907 citations retrieved, six studies (four studies with paricalcitol and two studies with calcitriol) providing data for 688 patients were included in the meta-analysis. Most patients (84%) used an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker throughout the study. Active vitamin D analogs reduced proteinuria (weighted mean difference from baseline to last measurement was −16% [95% CI, −13% to −18%]) compared with controls (+6% [95% CI, 0% to +12%]; P<0.001). Proteinuria reduction was achieved more commonly in patients treated with an active vitamin D analog (204/390 patients) than control patients (86/298 patients; OR, 2.72 [95% CI, 1.82 to 4.07]; P<0.001). Thus, active vitamin D analogs may further reduce proteinuria in CKD patients in addition to current regimens. Future studies should address whether vitamin D therapy also retards progressive renal functional decline.CKD is a worldwide health burden, affecting about 15% of the Western adult population.¹ CKD is associated with premature death, cardiovascular disease, infection, and cancer, and it consumes disproportionate health care resources.^2–4 The mainstay of current CKD treatment is pharmacological blockade of the renin-angiotensin-aldosterone system (RAAS) by angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Although these drugs may retard progression of both renal and cardiovascular disease^5–9 partly through their capacity to reduce proteinuria,^10,11 progression to ESRD and cardiovascular complications cannot be prevented in many CKD patients.A recent single-level meta-analysis including over 2 million participants showed that albuminuria is independently associated with mortality and ESRD, regardless of age.¹² The amount of residual albuminuria/proteinuria under RAAS blockade is a strong predictor of both long-term renal disease progression^13,14 and cardiovascular complications,¹⁵ and an absent or blunted proteinuria response to the use of RAAS blockers is an especially strong predictor.¹⁶ The efficacy of RAAS blockade intensification in an attempt to further reduce residual proteinuria is, however, limited by side effects, such as hyperkalemia and hypotension.^17,18 Adjunctive therapies, which can offer the lowering of residual proteinuria but without these drawbacks, may improve renal and cardiovascular protection.Studies in animal models of CKD suggested that proteinuria, renal fibrosis, and renal function loss may be reduced by treatment with an active vitamin D analog not only as monotherapy but also when given as adjunctive therapy to conventional RAAS blockade.^19–21 In CKD patients, lower vitamin D concentrations have been associated with an increased risk of mortality,^22,23 cardiovascular complications,²⁴ and renal disease progression.²⁵ These findings have resulted in a number of small- to medium-sized prospective randomized controlled trials (RCTs) with the use of active vitamin D analogs targeting reduction of (residual) proteinuria in CKD patients. So far, results have been inconclusive, with studies reporting significant,^26–28 borderline significant,^29–31 or nonsignificant^32,33 effects. We performed a systematic review and meta-analysis of all available RCTs to address the effect of active vitamin D analogs on residual proteinuria in patients with CKD.     

Vitamin D Therapy of Osteoporosis: Plain Vitamin D Therapy Versus Active Vitamin D Analog (D-Hormone) Therapy

Normal intestinal calcium (Ca) absorption is an essential feature of bone homeostasis. As with many other organ systems, intestinal Ca absorption declines with aging, and this is one pathological factor that has been identified as a cause of senile osteoporosis in the elderly. This abnormality leads to secondary hyperparathyroidism, which is characterized by high serum parathyroid hormone (PTH) and an increase in bone resorption. Secondary hyperparathyroidism due to poor intestinal Ca absorption has been implicated not only in senile osteoporosis but also in age-related bone loss. Accordingly, in population-based studies, there is a gradual increase in serum PTH from about 20 years of age onward, which constitutes a maximum increase at 80 years of age of 50% of the basal value seen at 30 years of age. The cause of the increase in PTH is thought to be partly due to impaired intestinal Ca absorption that is associated with aging, a cause that is not entirely clear but at least in some instances is related to some form of vitamin D deficiency. There are three types of vitamin D deficiency: (1) primary vitamin D deficiency, which is due to a deficiency of vitamin D, the parent compound; (2) a deficiency of 1,25(OH)₂D₃ resulting from decreased renal production of 1,25(OH)₂D₃; and (3) resistance to 1,25(OH)₂D₃ action owing to decreased responsiveness to 1,25(OH)₂D₃ of target tissues. The cause for the resistance to 1,25(OH)₂D₃ could be related to the finding that the vitamin D receptor level in the intestine tends to decrease with age. All three types of deficiencies can occur with aging, and each has been implicated as a potential cause of intestinal Ca malabsorption, secondary hyperparathyroidism, and senile osteoporosis. There are two forms of vitamin D replacement therapies: plain vitamin D therapy and active vitamin D analog (or D-hormone) therapy. Primary vitamin D deficiency can be corrected by vitamin supplements of 1000 U a day of plain vitamin D whereas 1,25(OH)₂D₃ deficiency/resistance requires active vitamin D analog therapy [1,25(OH)₂D₃ or 1α(OH)D₃] to correct the high serum PTH and the Ca malabsorption. In addition, in the elderly, there are patients with decreased intestinal Ca absorption but with apparently normal vitamin D metabolism. Although the cause of poor intestinal Ca absorption in these patients is unclear, these patients, as well as all other patients with secondary hyperparathyroidism (not due to decreased renal function), show a decrease in serum PTH and an increase in Ca absorption in response to therapy with 1,25(OH)₂D₃ or 1α(OH)D₃. In short, it is clear that some form of vitamin D therapy, either plain vitamin D or 1,25(OH)₂D₃ or 1α(OH)D₃, can be used to correct all types of age-dependent impairments in intestinal Ca absorption and secondary hyperparathyroidism during aging. However, from a clinical standpoint, it is important to recognize the type of vitamin D deficiency in patients with senile osteoporosis so that primary vitamin D deficiency can be appropriately treated with plain vitamin D therapy, whereas 1,25(OH)₂D₃ deficiency/resistance will be properly treated with 1,25(OH)₂D₃ or 1α(OH)D₃ therapy. With respect to postmenopausal osteoporosis, there is strong evidence that active vitamin D analogs (but not plain vitamin D) may have bone-sparing actions. However, these effects appear to be results of their pharmacologic actions on bone formation and resorption rather than through replenishing a deficiency.     

Wintertime Vitamin D Deficiency in Male Adolescents: Effect on Parathyroid Function and Response to Vitamin D3 Supplements

The first part of this study consisted of an 18 month follow-up of the vitamin D status and parathyroid function in a group of 54 French male adolescents, aged from 13 to 16 years old and all pupils of a jockey training school. During the 18 month period four samplings were made, one every 6 months. The first was during September of the first year, the second and third during March and October of the second year, and the last in March of the third year. Therefore we had two main periods: summer and winter. The summer 25-hydroxyvitamin D (25(OH)D) concentrations were higher (71.6 ± 19.9 and 52.4 ± 16.5 nmol/l) than the winter ones (20.4 ± 6.9 and 21.4 ± 6.1 nmol/l). Conversely, the winter intact parathyroid hormone (iPTH) serum levels (4.18 ± 1.18 and 4.11 ± 1.35 pmol/l) were higher than the summer ones (2.44 ± 0.82 and 2.71 ± 0.71 pmol/l). At the two winter time points the 25(OH)D concentrations were lower than 25 nmol/l (10 ng/ml) in 72% (2nd year) and 68% (3rd year) of the adolescents. In the second part of the study we tried a vitamin D₃ supplementation procedure designed to maintain the 25(OH)D and iPTH postsummer serum levels throughout the winter. Pairs of male adolescents matched for height, weight and Tanner pubertal stage were randomly assigned to either vitamin D₃ supplementation (2.5 mg, i.e., 100 000 IU) administered orally at three specific periods (end of September, November and January) or no vitamin D₃ treatment (control subjects). Blood was collected just before the first intake of vitamin D₃ and 2 months after the last intake (March). The control subjects had blood drawn at the same time points. In the vitamin D₃-treated subjects, the concentrations of 25 (OH)D (55.3 ± 11.5 nmol/l) and of iPTH (3.09 ± 1.16 pmol/l) in March and September (53.8 ± 12.3 nmol/l and 2.75 ± 1.26 pmol/l) were not significantly different. In the control subjects, March 25(OH)D levels (21.0 ± nmol/l were low, with values below 25 nmol/l in 78% of subjects, and iPTH concentrations (3.97 ± 1.08 pmol/l) were significantly (p<0.001) higher than in September (2.91 ± 0.81 pmol/l). The constant vitamin D wintertime deficiency and wintertime rise in iPTH in adolescent French males throughout puberty has been demonstrated. In adolescents with low dairy calcium intakes, the vitamin D₃ treatment was sufficient to maintain 25(OH)D concentrations at their summer levels throughout winter and to prevent an excessive wintertime rise in iPTH levels. Received: 6 February 2001 / Accepted: 9 May 2001     

Effect of Supplementation with Vitamin D3 and Calcium on Quantitative Ultrasound of Bone in Elderly Institutionalized Women: A Longitudinal Study

Supplementation of elderly institutionalized women with vitamin D and calcium decreased hip fractures and increased hip bone mineral density. Quantitative ultrasound (QUS) measurements can be performed in nursing homes, and easily repeated for follow-up. However, the effect of the correction of vitamin D deficiency on QUS parameters is not known. Therefore, 248 institutionalized women aged 62–98 years were included in a 2-year open controlled study. They were randomized into a treated group (n = 124), receiving 440 IU of vitamin D₃ combined with 500 mg calcium (1250 mg calcium carbonate, Novartis) twice daily, and a control group (n = 124). One hundred and three women (42%), aged 84.5 ± 7.5 years, completed the study: 50 in the treated group, 53 in the controls. QUS of the calcaneus, which measures BUA (broadband ultrasound attenuation) and SOS (speed of sound), and biochemical analysis were performed before and after 1 and 2 years of treatment. Only the results of the women with a complete follow-up were taken into account. Both groups had low initial mean serum 25-hydroxyvitamin D levels (11.9 ± 1.2 and 11.7 ± 1.2 mg/l; normal range 6.4–40.2 mg/l) and normal mean serum parathyroid hormone (PTH) levels (43.1 ± 3.2 and 44.6 ± 3.5 ng/l; normal range 10–70 ng/l, normal mean 31.8 ± 2.3 ng/l). The treatment led to a correction of the metabolic disturbances, with an increase in 25-hydroxyvitamin D by 123% (p50.01) and a decrease in PTH by 18% (p50.05) and of alkaline phosphatase by 15% (p50.01). In the controls there was a worsening of the hypovitaminosis D, with a decrease of 25-hydroxyvitamin D by 51% (p50.01) and an increase in PTH by 51% (p50.01), while the serum calcium level decreased by only 2% (p5 0.01). After 2 years of treatment BUA increased significantly by 1.6% in the treated group (p50.05), and decreased by 2.3% in the controls (p50.01). Therefore, the difference in BUA between the treated subjects and the controls (3.9%) was significant after 2 years (p50.01). However, SOS decreased by the same amount in both groups (approximately 0.5%). In conclusion, BUA, but not SOS, reflected the positive effect on bone of supplementation with calcium and vitamin D₃ in a population of elderly institutionalized women. Received: 23 February 1998 / Accepted: 19 October 1998     

活性维生素D3对透析前慢性肾脏病患者肾脏保护作用研究

目的：探讨活性维生素D3对透析前慢性肾脏病（CKD）患者的肾保护作用及安全性。方法：选择透析前3～4期慢性肾脏病患者200例,随机分为治疗组和对照组各100例。对照组给予优质低蛋白饮食、α-酮酸、血管紧张素转换酶抑制剂（ACEI）和（或）血管紧张素Ⅱ受体拮抗剂（ARB）和（或）钙通道拮抗剂以及抗血小板集聚等常规治疗,治疗组在常规治疗的基础上加用骨化三醇（0.5μg/d,疗程1年）。分别在治疗前和治疗后3,6,9和12月检测患者肾功能、血清白蛋白、甲状旁腺素、血钙、磷及24h尿蛋白定量等指标,并观察其副作用。结果：两组治疗后3月血肌酐、尿素氮、血尿酸和24h尿蛋白均明显下降（P〈0.05）,估算肾小球滤过率和血清白蛋白显著上升（P〈0.05）。治疗组治疗12月后肾功能进一步改善（P〈0.05）,尿蛋白进一步减少（P〈0.05）,而对照组治疗12月后肾功能和尿蛋白与治疗3月相比无明显改变。对照组患者血钙降低,血磷升高,甲状旁腺素水平明显升高（P〈0.05）。治疗组患者血钙升高,血磷降低,甲状旁腺素水平明显下降（P〈0.05）,但无明显高钙血症等副作用。结论：骨化三醇能显著改善透析前CKD患者的肾功能,减少蛋白尿,抑制继发性甲状旁腺素分泌,具有明显的肾脏保护作用,且无明显副作用。