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Controversies in vitamin D: Deficiency and supplementation after Roux-en-Y gastric bypass surgery
Abstract
Current vitamin D recommendations are insufficient and a higher intake is necessary in the general population. The requirements of bariatric surgery patients can be augmented by longstanding obesity coupled with, gastro-intestinal malabsorption. Vitamin D deficiency promotes metabolic bone disease and may increase risks for a multitude of other medical conditions. This article reviews some controversies surrounding vitamin D and proposes a management strategy for bariatric surgery patients.
... This is considered to be the consequence of surgically induced weight loss. In that regard, postoperative bone loss seems to be a dynamic process and the role of vitamin D deficiency is not fully elucidated nor has the use of supplements been proven to reverse this process [20]. Vitamin D status might be a modifying factor in bone loss but the requirements of vitamin D supplementation or a 25(OH)D concentration which is adequate after OAGB remains elusive and to our knowledge has not been studied in those patients. ...
... In addition to that, the patients were advised to perform physical activity. Up to now, the role of vitamin D inadequacy in postoperative bone loss is not fully understood and the use of supplements has not been proven to reverse this process [20]. In that regard, we found that a lower bone loss, in left hip BMD, was associated with a higher 25(OH)D concentrations during the first postoperative year. ...
Background:
Little is known about changes in bone mineral density (BMD) following weight loss after one-anastomosis gastric bypass (OAGB) and the role of serum vitamin D and its supplementation on bone metabolism. We evaluated BMD after OAGB as a function of vitamin D supplementation with respect to a minimum threshold of 25-hydroxy-vitamin-D [25(OH)D] concentration, which could prevent or decelerate an eventual bone loss.
Methods:
Fifty bariatric patients who participated in the randomized controlled trial were included in this analysis. BMD and anthropometric measurements by DXA and laboratory parameters were assessed before (T0), at 6 (T6), and 12 months (T12) after surgery.
Results:
OAGB resulted in a 36% total body weight loss with a decrease in body fat and an increase in lean body mass. A significant decrease in BMD was seen in lumbar spine by 7%, left hip 13%, and total body 1%, but not in forearm. Bone turnover markers increased significantly but with normal parathyroid hormone concentrations. Weight loss was not associated with changes in BMD. A serum 25(OH)D concentration > 50 nmol/l at T6 and T12 (adequate-vitamin-D-group; AVD) showed a significant lower bone loss, compared to the inadequate-vitamin-D-group (IVD; < 50 nmol/l). Lower bone loss in the left hip showed a strong correlation with higher 25(OH)D concentrations (r = 0.635, p = 0.003).
Conclusion:
These findings support a dose effect of vitamin D supplementation on bone health and suggest that 25(OH)D concentrations need to be above 50 nmol/l at least during the first postoperative year to decelerate bone loss in patients undergoing OAGB.
Clinical trial registry number and website:
Clinicaltrials.gov (NCT02092376) at https://clinicaltrials.gov /. EudraCT (2013-003546-16) at https://eudract.ema.europa.eu /.
... Data from the bariatric surgery literature have shown that morbidly obese individuals prior to bariatric surgery can manifest 2HPT, possibly due to vitamin D deficiency [36] . Furthermore, after surgery with repleted levels of 25-and 1,25-dihydroxyvitamin D, a form of hyperparathyroidism due to vitamin D resistance can be observed, reinforcing the complicated relationship between PTH, vitamin D, and obesity [37] . ...
Aims:
The relationship between parathyroid hormone (PTH) and the cardiorenal metabolic syndrome was examined among non-diabetic persons with chronic kidney disease (CKD).
Methods:
In a cross-sectional analysis, the relationship between PTH levels and the cardiorenal metabolic syndrome was investigated in 3,215 non-diabetic participants in the National Kidney Foundation-Kidney Early Evaluation Program (KEEP 2.0) found to have CKD (eGFR <60 ml/min/1.73 m2).
Results:
In unadjusted analyses, the prevalence of the cardiorenal metabolic syndrome increased along increasing PTH quartiles (31.7, 33.8, 37.3, and 48.7%, respectively, p for trend <0.0001). After multivariate adjustment, as compared to the first PTH quartile, odds of the cardiorenal metabolic syndrome were 16% (p = 0.18), 35% (p = 0.006), and 80% (p < 0.0001) higher for the second, third, and fourth quartiles, respectively. When taken as a continuous predictor, each standard deviation increase of natural log transformed PTH was associated with 26% (p < 0.0001) higher odds of the cardiorenal metabolic syndrome. The association of PTH with the cardiorenal metabolic syndrome was not modified by age or gender (p for interaction was not significant for both modifiers).
Conclusions:
Among an outpatient non-diabetic population with CKD, higher PTH levels were associated with a higher prevalence of the cardiorenal metabolic syndrome.
Obesity as well as bariatric surgery may increase the risk for vitamin D deficiency. We retrospectively compared vitamin D levels in obese patients (n = 123) prior to bariatric surgery and 1 year postoperatively. We also evaluated parathyroid hormone levels (PTH) 1 year after surgery. A higher percentage of patients had baseline vitamin D deficiency (86%), defined as 25-hydroxy vitamin D <32 ng/mL, compared with the 1-year (post-surgical) levels, (70%; p < 0.001). Body mass index (BMI) inversely correlated with vitamin D deficiency at baseline (r = -0.3, p = 0.06) and at the postoperative follow-up (r = -0.2, p = 0.013). One third of the postoperative population had secondary hyperparathyroidism, defined by a serum PTH level >62 pg/mL; however, postoperative PTH and vitamin D levels were unrelated (r = -0.001, p = 0.994). Pre- and postoperative vitamin D levels were inversely correlated with BMI. Secondary hyperparathyroidism was observed in 33% of patients postoperatively; however, this did not correlate with vitamin D.
The objective of the study was to examine the relationship of obesity and parathyroid hormone (PTH) levels among persons with chronic kidney disease (CKD). This was a cross-sectional analysis of 4551 participants in the National Kidney Foundation-Kidney Early Evaluation Program found to have CKD (estimated glomerular filtration rate <60 mL/[min 1.73 m(2)]) examining the relationship of body mass index (BMI) and PTH levels. In unadjusted analysis, PTH levels increased with increasing BMI quartiles. After adjustment for age, race, sex, diabetes, calcium, phosphorus, estimated glomerular filtration rate, and presence of microalbuminuria, PTH levels were 7.3% (P = .008), 11.9% (P < .0001), and 18.1% (P < .0001) higher in the second, third, and fourth BMI quartiles, respectively, as compared with the first quartile. In a companion analysis, higher BMI was associated with increased odds of having an elevated PTH measurement (>70 pg/mL). Compared with the first quartile, odds ratios for elevated PTH were 1.26 (95% confidence interval, 1.06-1.50; P = .01), 1.38 (1.15-1.65, P = .0005), and 1.66 (1.37-2.00, P < .0001) for the second, third, and fourth quartiles, respectively. We found no effect modification by race, diabetes, or presence of microalbuminuria. Therefore, in a large community-dwelling population with CKD, the presence of obesity and of increasing BMI is associated with higher PTH levels independent of measured confounders and may be an additional target in the management of secondary hyperparathyroidism in CKD.
Serum immunoreactive parathyroid hormone (PTH) is increased in obese as compared with nonobese subjects and declines with weight loss. To determine whether alteration of the vitamin D-endocrine system occurs in obesity and whether ensuing secondary hyperparathyroidism is associated with a reduction in urinary calcium, a study was performed in 12 obese white individuals, five men and seven women, and 14 nonobese white subjects, eight men and six women, ranging in age from 20 to 35 yr. Body weight averaged 106 +/- 6 kg in the obese and 68 +/- 2 kg in the nonobese subjects (P less than 0.01). Each of them were hospitalized on a metabolic ward and were given a constant daily diet containing 400 mg of calcium and 900 mg of phosphorus. Whereas mean serum calcium, serum ionized calcium, and serum phosphorus were the same in the two groups, mean serum immunoreactive PTH (518 +/- 48 vs. 243 +/- 33 pg/ml, P less than 0.001), mean serum 1,25-dihydroxyvitamin D [1,25(OH)2D] (37 +/- 2 vs. 29 +/- 2, P less than 0.01), and mean serum Gla protein (33 +/- 2 vs. 24 +/- 2 ng/ml, P less than 0.02) were significantly higher, and mean serum 25-hydroxyvitamin D (25-OHD) (8 +/- 1 vs. 20 +/- 2 ng/ml, P less than 0.001) was significantly lower in the obese than in the nonobese men and women. Mean urinary phosphorus was the same in the two groups, whereas mean urinary calcium (115 +/- 10 vs. 166 +/- 13 mg/d, P less than 0.01) was significantly lower, and mean urinary cyclic AMP (3.18 +/- 0.43 vs. 1.84 +/- 0.25 nM/dl GF, P less than 0.01) and creatinine clearance (216 +/- 13 vs. 173 +/- 6 liter/d, P less than 0.01) were significantly higher in the obese than in the nonobese individuals. There was a significant positive correlation between percentage of ideal body weight and urinary cyclic AMP (r = 0.524, P less than 0.01) and between percentage of ideal body weight and serum immunoreactive PTH (r = 0.717, P less than 0.01) in the two groups. The results provide evidence that alteration of the vitamin D-endocrine system in obese subjects is characterized by secondary hyperparathyroidism which is associated with enhanced renal tubular reabsorption of calcium and increased circulating 1,25(OH)2D. The reduction of serum 25-OHD in them is attributed to feedback inhibition of hepatic synthesis of the precursor by the increased serum 1,25(OH)2D.
The purpose of the study was to determine the effect of vitamin D supplementation on bone turnover and bone loss in elderly women. Three hundred forty-eight women, ages 70 yr and older, were randomized to receive 400 IU vitamin D3 per day (n = 177) or placebo (n = 171), double-blind, for a period of 2 yr. Main outcome measures were bone mineral density of both hips (femoral neck and trochanter) and the distal radius, as well as biochemical markers of bone turnover. The effect of vitamin D supplementation was expressed as the difference in mean (percentage) change between the placebo group and the vitamin D group. The measurements were repeated in 283 women after 1 yr and in 248 women after 2 yr. Vitamin D supplementation significantly increased serum 25-hydroxyvitamin D (250HD) (+35 nmol/L) and 1,25-dehydroxyvitamin D [1,25-(OH)2D] (+7.0 pmol/L) levels and urinary calcium/creatinine ratios (+0.5%) and significantly decreased PTH(1-84) secretion (-0.74 pmol/L) after 1 yr. No effect was found for the parameters of bone turnover. The effect on the bone mineral density of the left femoral neck was +1.8% in the first yr, +0.2% in the second yr, and +1.9% during the whole period (95% confidence interval 0.4, 3.4%). At the right femoral neck the effects were +1.5%, +1.1%, and +2.6% (confidence interval 1.1, 4.0%), respectively. No effect was found at the femoral trochanter and the distal radius. Supplementation with 400 IU vitamin D3 daily in elderly women slightly decreases PTH secretion and increases bone mineral density at the femoral neck.
To investigate whether greater intakes of calcium, vitamin D, or milk products may protect against ischemic heart disease mortality, the authors analyzed data from a prospective cohort study of 34,486 postmenopausal Iowa women 55-69 years old and without a history of ischemic heart disease who completed a dietary questionnaire in 1986. Through 1994, 387 deaths due to ischemic heart disease were documented (International Classification of Diseases, Ninth Revision, codes 410-414, 429.2). The multivariate-adjusted relative risks for the highest versus the lowest quartiles of total calcium, vitamin D, and milk product intakes were as follows: 0.67 (95% confidence interval (CI) 0.47-0.94; p for trend = 0.09) for calcium, 1.41 (95% CI 0.93-2.15; p for trend = 0.12) for vitamin D, and 0.94 (95% CI 0.66-1.35; p for trend = 0.68) for milk products. The relative risk was 0.63 (95% CI 0.40-0.98) for high dietary calcium but no supplemental calcium intake and 0.66 (95% CI 0.36-1.23) for high supplemental calcium but low dietary calcium intake. These results suggest that a higher intake of calcium, but not of vitamin D or milk products, is associated with reduced ischemic heart disease mortality in postmenopausal women, and reduced risk may be achievable whether the higher intake of calcium is attained by diet, supplements, or both.
Low vitamin D levels may contribute to hip fractures in women, although limited data are available on vitamin D levels in US women admitted with acute hip fractures.
To determine whether postmenopausal women with hip fractures have low vitamin D and high parathyroid hormone levels compared with nonosteoporotic and osteoporotic women admitted for elective joint replacement.
Comparative case series conducted between January 1995 and June 1998.
Ninety-eight postmenopausal community-dwelling women with no secondary causes of bone loss admitted for hip replacement, of whom 30 women had acute hip fractures and 68 women were admitted for elective joint replacement. Of the women admitted for elective joint replacement, 17 had osteoporosis and 51 did not. Women with comorbid conditions or who were taking medications that affect bone density and turnover were excluded.
Primary measures were levels of vitamin D and parathyroid hormone; secondary measures were body composition and markers of bone turnover.
Women with hip fractures had lower levels of 25-hydroxyvitamin D than women without osteoporosis admitted for elective joint replacement (P = .02) and than women with osteoporosis admitted for elective joint replacement (P = .01) (medians, 32.4, 49.9, and 55.0 nmol/L, respectively; comparisons adjusted for age and estrogen intake). Parathyroid hormone levels were higher in women with fractures than women in the nonosteoporotic control group (P<.001) or than elective osteoporotic women (P = .001) (medians, 5.58, 3.26, and 3.79 pmol/L, respectively; comparisons adjusted for age and estrogen intake). Fifteen patients (50.0%) with hip fractures had deficient vitamin D levels (< or =30.0 nmol/L) and 11 (36.7%) had a parathyroid hormone level greater than 6.84 pmol/L. Levels of N-telopeptide, a marker of bone resorption, were greater in the women with hip fractures than in the elective nonosteoporotic controls (P = .004).
Postmenopausal community-living women who presented with hip fracture showed occult vitamin D deficiency. Repletion of vitamin D and suppression of parathyroid hormone at the time of fracture may reduce future fracture risk and facilitate hip fracture repair. Because vitamin D deficiency is preventable, heightened awareness is necessary to ensure adequate vitamin D nutrition, particularly in northern latitudes.
To estimate the incidence of MS and its relation to latitude in two ongoing prospective studies of US women.
A higher incidence of MS has been found in northern areas compared with southern areas of the United States and other countries, but the attenuation of this gradient in Europe in the last few decades and the consideration of ethnic factors have led some authors to question the existence of a strong association between MS and latitude.
The authors identified new cases of MS among participants in the Nurses' Health Study (NHS), which took place between 1976 and 1994, and in the Nurses' Health Study II (NHS II), which took place between 1989 and 1995. The NHS included women born between 1920 and 1946, and the NHS II included women born between 1947 and 1964.
The incidence of MS among NHS participants (181 definite/probable patients) increased significantly with latitude (p = 0.03, trend). Adjusted rate ratios were 3.5 (95% CI, 1.1, 11.3) for the north and 2.7 (95% CI, 0.8, 8.9) for the middle tiers relative to the southern tier. Among NHS II women (131 definite/probable patients), no association between latitude and MS was found (p = 0.89, trend). Adjusted rate ratios were 0.8 (95% CI, 0.4, 1.6) for the northern areas and 0.9 (95%, 0.4, 1.8) for the middle areas, relative to the southern areas.
The association between latitude and risk of MS in the United States was corroborated, but there was an attenuation of the north-south gradient over time. If confirmed, this finding could provide new clues to identifying environmental causes of the disease.
The Food and Nutrition Board of the National Academy of Sciences states that 95 microg vitamin D/d is the lowest observed adverse effect level (LOAEL).
Our objective was to assess the efficacy and safety of prolonged vitamin D3 intakes of 25 and 100 microg (1000 and 4000 IU)/d. Efficacy was based on the lowest serum 25-hydroxyvitamin D [25(OH)D] concentration achieved by subjects taking vitamin D3; potential toxicity was monitored by measuring serum calcium concentrations and by calculating urinary calcium-creatinine ratios.
Healthy men and women (n = 61) aged 41 +/- 9 y (mean +/- SD) were randomly assigned to receive either 25 or 100 microg vitamin D3/d for 2-5 mo, starting between January and February. Serum 25(OH)D was measured by radioimmunoassay.
Baseline serum 25(OH)D was 40.7 +/- 15.4 nmol/L (mean +/- SD). From 3 mo on, serum 25(OH)D plateaued at 68.7 +/- 16.9 nmol/L in the 25-microg/d group and at 96.4 +/- 14.6 nmol/L in the 100-microg/d group. Summertime serum 25(OH)D concentrations in 25 comparable subjects not taking vitamin D3 were 46.7 +/- 17.8 nmol/L. The minimum and maximum plateau serum 25(OH)D concentrations in subjects taking 25 and 100 microg vitamin D3/d were 40 and 100 nmol/L and 69 and 125 nmol/L, respectively. Serum calcium and urinary calcium excretion did not change significantly at either dosage during the study.
The 100-microg/d dosage of vitamin D3 effectively increased 25(OH)D to high-normal concentrations in practically all adults and serum 25(OH)D remained within the physiologic range; therefore, we consider 100 microg vitamin D3/d to be a safe intake.
Vitamin D affects calcium metabolism and prevents proliferation of colon cells in vitro. In human beings the main circulating form of vitamin D is 25-hydroxyvitamin D; to regulate calcium homoeostasis, this form must be converted to 1alpha, 25-dihydroxyvitamin D by 1alpha-hydroxylation in the kidney with 25-hydroxyvitamin D-1alpha-hydroxylase. Cultured transformed colon cancer cells can convert 25-hydroxyvitamin D(3) to 1alpha,25-dihydroxyvitamin D(3). We identified messenger RNA (mRNA) for 25-hydroxyvitamin D-1alpha-hydroxylase in normal colon tissue and in malignant and adjacent normal colon tissue. These findings support the notion that vitamin D might have a role in cell growth regulation and cancer protection, and might be the explanation for why the risk of dying from colorectal cancer is highest in areas with the least amount of sunlight.
Obesity is associated with alterations in the vitamin D endocrine system. Lower levels of serum 25-hydroxyvitamin D (25-OHD) in morbidly obese individuals may be secondary to an alteration in tissue distribution resulting from an increase in adipose mass. Therefore, morbidly obese individuals are expected to need higher doses of vitamin D supplementation than the general population. However, it is still unknown whether adiposity (or percentage body fat) should be taken into consideration while assessing vitamin D requirements in the general population. To study the relationship between 25-OHD levels and percentage body fat content in healthy women, we studied 410 healthy women between 20 and 80 yr of age with body mass index ranging from 17 to 30 kg/m2. We analyzed the correlation between serum 25-OHD level and percentage body fat measured by dual energy x-ray absorptiometry. We also analyzed the influence of season, dietary vitamin D intake, age, and race on this relationship. The levels of serum 25-OHD inversely correlated with percentage body fat. The correlation was -0.13 (P = 0.013) after adjusting for race, age, season, and dietary vitamin D intake. In a multiple stepwise regression, race and season were found to have a major influence on serum 25-OHD (cumulative R2 = 0.34), and percentage body fat, although modest (additional R2 = 0.02), also had an independent statistically significant influence on serum 25-OHD levels. We conclude, percentage body fat content is inversely related to the serum 25-OHD levels in healthy women.
Vitamin D is metabolised by a hepatic 25-hydroxylase into 25-hydroxyvitamin D (25(OH)D) and by a renal 1alpha-hydroxylase into the vitamin D hormone calcitriol. Calcitriol receptors are present in more than thirty different tissues. Apart from the kidney, several tissues also possess the enzyme 1alpha-hydroxylase, which is able to use circulating 25(OH)D as a substrate. Serum levels of 25(OH)D are the best indicator to assess vitamin D deficiency, insufficiency, hypovitaminosis, adequacy, and toxicity. European children and young adults often have circulating 25(OH)D levels in the insufficiency range during wintertime. Elderly subjects have mean 25(OH)D levels in the insufficiency range throughout the year. In institutionalized subjects 25(OH)D levels are often in the deficiency range. There is now general agreement that a low vitamin D status is involved in the pathogenesis of osteoporosis. Moreover, vitamin D insufficiency can lead to a disturbed muscle function. Epidemiological data also indicate a low vitamin D status in tuberculosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, hypertension, and specific types of cancer. Some intervention trials have demonstrated that supplementation with vitamin D or its metabolites is able: (i) to reduce blood pressure in hypertensive patients; (ii) to improve blood glucose levels in diabetics; (iii) to improve symptoms of rheumatoid arthritis and multiple sclerosis. The oral dose necessary to achieve adequate serum 25(OH)D levels is probably much higher than the current recommendations of 5-15 microg/d.
A protective effect of vitamin D on risk of multiple sclerosis (MS) has been proposed, but no prospective studies have addressed this hypothesis.
Dietary vitamin D intake was examined directly in relation to risk of MS in two large cohorts of women: the Nurses' Health Study (NHS; 92,253 women followed from 1980 to 2000) and Nurses' Health Study II (NHS II; 95,310 women followed from 1991 to 2001). Diet was assessed at baseline and updated every 4 years thereafter. During the follow-up, 173 cases of MS with onset of symptoms after baseline were confirmed.
The pooled age-adjusted relative risk (RR) comparing women in the highest quintile of total vitamin D intake at baseline with those in the lowest was 0.67 (95% CI = 0.40 to 1.12; p for trend = 0.03). Intake of vitamin D from supplements was also inversely associated with risk of MS; the RR comparing women with intake of >or=400 IU/day with women with no supplemental vitamin D intake was 0.59 (95% CI = 0.38 to 0.91; p for trend = 0.006). No association was found between vitamin D from food and MS incidence.
These results support a protective effect of vitamin D intake on risk of developing MS.
Background: Obesity is associated with vitamin D insufficiency and secondary hyperparathyroidism.
Objective: This study assessed whether obesity alters the cutaneous production of vitamin D3 (cholecalciferol) or the intestinal absorption of vitamin D2 (ergocalciferol).
Design: Healthy, white, obese [body mass index (BMI; in kg/m²) ≥ 30] and matched lean control subjects (BMI ≤ 25) received either whole-body ultraviolet radiation or a pharmacologic dose of vitamin D2 orally.
Results: Obese subjects had significantly lower basal 25-hydroxyvitamin D concentrations and higher parathyroid hormone concentrations than did age-matched control subjects. Evaluation of blood vitamin D3 concentrations 24 h after whole-body irradiation showed that the incremental increase in vitamin D3 was 57% lower in obese than in nonobese subjects. The content of the vitamin D3 precursor 7-dehydrocholesterol in the skin of obese and nonobese subjects did not differ significantly between groups nor did its conversion to previtamin D3 after irradiation in vitro. The obese and nonobese subjects received an oral dose of 50000 IU (1.25 mg) vitamin D2. BMI was inversely correlated with serum vitamin D3 concentrations after irradiation (r = −0.55, P = 0.003) and with peak serum vitamin D2 concentrations after vitamin D2 intake (r = −0.56, P = 0.007).
Conclusions: Obesity-associated vitamin D insufficiency is likely due to the decreased bioavailability of vitamin D3 from cutaneous and dietary sources because of its deposition in body fat compartments.
The ecologic approach is applied to determining for which cancers solar UV-B radiation reduces the risk. Cancer mortality rates from 16 western European countries for 1989–91 are used along with dietary supply factors for 1979–81, and latitude is used as an index of solar UV-B radiation. This study is a follow on to a recent study using cancer mortality rates in 500 state economic areas in the U.S.A. along with DNA-weighted UV-B radiation for July 1992 from the Total Ozone Mapping Spectrometer (TOMS) in which a protective role for UV-B was found for 12 types of cancer (Grant, submitted). Increasing latitude is found to be a risk factor for 7 types of cancer identified in Grant (submitted), cancers of the breast, colon, esophagus, kidney, ovary and prostate, and non-Hodgkin’s lymphoma (NHL), as well as 2 additional cancers, cancer of the pancreas and multiple myeloma. Those cancers for which the U.S.A. results could not be confirmed tend to be the minor cancers. These results should form the basis for further studies on the protective role of solar UV-B radiation and/or vitamin D against cancer.
Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor–null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis are still intact in the mutant mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] synthesis also led to an increase in renin expression, whereas 1,25(OH)2D3 injection led to renin suppression. We found that vitamin D regulation of renin expression was independent of calcium metabolism and that 1,25(OH)2D3 markedly suppressed renin transcription by a VDR-mediated mechanism in cell cultures. Hence, 1,25(OH)2D3 is a novel negative endocrine regulator of the renin-angiotensin system. Its apparent critical role in electrolytes, volume, and blood pressure homeostasis suggests that vitamin D analogues could help prevent or ameliorate hypertension.
Objective:
To investigate the cause of osteomalacia following biliopancreatic diversion (BPD) surgery for obesity.
Design:
A retrospective, case-comparison study.
Setting:
A tertiary care center.
Patients:
A case group of 12 subjects (including 9 women; mean age±SEM, 48.5±3.0 years; mean preoperative body mass index ±SEM, 43.7 ± 2.3 kg/m2; and mean weight loss±SEM, 75± 14 kg) who have undergone BPD (referred to as BPD group hereafter) and a comparison group of 10 subjects (including 9 women; mean age±SEM,49.6±3.3 years; mean preoperative body mass index ±SEM, 44.0 ± 2.5 kg/m2; and mean weight loss±SEM, 55±15 kg) following vertical banded gastroplasty (VBG) (referred to as VBG group hereafter).
Main Outcome Measures:
Serum and urine markers for bone metabolism.
Results:
Compared with the VBG group, the BPD group had significantly lower concentrations of the following components: serum calcium (2.14±0.05 mmol/L vs 2.37±0.05 mmol/L [8.6±0.2 mg/dL vs 9.5±0.2 mg/ dL]), serum 25-hydroxyvitamin D (24±6 nmol/L vs 64±6 nmol/L), urine calcium excretion (1.7±0.7 mmol/d vs 4.5±0.7 mmol/d [68±28 mg/d vs 180±28 mg/d]), and serum carotene (0.40±0.15 mmol/L vs 1.29±0.16 mmol/ L). The BPD group had significantly higher concentrations of the following components: serum parathyroid hormone (13.6±2.1 pmol/L vs 5.2±2.3 pmol/L), serum alkaline phosphatase (139±8 U/L vs 86 ± 9 U/L), and urinary hydroxyproline/creatinine (52±5 μmol/mmol vs 19±5 μmol/mmol).
Conclusion:
These data suggest that following BPD, secondary hyperparathyroidism attributed to hypocalcemia results from malabsorption of vitamin D. However, we cannot exclude the possibility of concurrent calcium malabsorption with vitamin D malabsorption.Arch Surg. 1996;113:1048-1052
Background:
Prostate cancer is the most prevalent nonskin cancer among men in the United States and is the second leading cause of cancer deaths in men. The cause of prostate cancer remains obscure. Recently it was hypothesized that low levels of vitamin D, a hormone with potent antitumor properties, may increase the risk for clinical prostate cancer.
Methods:
Because the major source of vitamin D is casual exposure to ultraviolet (UV) radiation, the authors examined the geographic distributions of UV radiation and prostate cancer mortality in 3073 counties of the contiguous United States using linear regression and trend surface analyses.
Results:
The geographic distributions of UV radiation and prostate cancer mortality are correlated inversely (P < 0.0001). Prostate cancer mortality exhibits a significant north-south trend, with lower rates in the South. These geographic patterns are not readily explicable by other known risk factors for prostate cancer.
Conclusions:
These data lend support to the hypothesis that UV radiation may protect against clinical prostate cancer. Viewed in conjunction with other recent data, including those demonstrating a differentiating effect of vitamin D on human prostate cancer cells, these findings suggest that vitamin D may have an important role in the natural history of prostate cancer.
Bone mobilization, lowering of bone mineral density (BMD), and osteoporotic fractures are recognized in postmenopausal women with weight loss. Because a high-calcium intake suppresses bone loss in peri- and postmenopausal women, the present randomized, double-blind, placebo-controlled study was designed to test the hypothesis that calcium supplementation prevents net bone mobilization and consequent bone mineral loss during voluntary weight reduction in obese postmenopausal women. Subjects were placed on a moderate energy-restricted diet and either calcium supplementation (1 g/day) or placebo for 6 months. Body weight, bone turnover markers (pyridinium cross-links), osteocalcin, and parathyroid hormone (PTH) were measured at treatment weeks 1–5, 7, 10, 13, 16, 20, and 25. Total body BMD, insulin-like growth factor, 25-hydroxyvitamin D, and sex hormone binding globulin (SHBG) were measured at baseline and week 25. The calcium supplemented (n = 15; age 60.9 ± 9.4 years, body mass index [BMI] 33.2 ± 4.6 kg/m2) and placebo (n = 16; age 55.8 ± 8.3 years, BMI 32.9 ± 4.5 kg/m2) groups lost similar amounts of weight over the study interval (10.2 ± 5.3% vs. 10.0 ± 5.2%) and both groups increased SHBG (p < 0.001). There was a statistical effect of calcium supplementation during weight loss to suppress pyridinium cross-links, osteocalcin, and PTH (p < 0.05, < 0.01, and < 0.05, respectively). Loss of BMD tended to be greater in the placebo group by 1.4% (p < 0.08) after weight loss. One gram per day calcium supplementation normalizes the increased calcium–PTH axis activity and the elevated bone turnover rate observed during moderate voluntary energy restriction in postmenopausal women.
Twenty-six female patients were recalled for examination 10 years after a Roux-Y gastric bypass (RGB) procedure for morbid
obesity, to determine whether there was biochemical and/or bone densitometry evidence of metabolic bone disease. These patients
were compared with seven control patients who had achieved weight loss by dietary restriction. The serum calcium (4.3 ± 0.03
vs 4.6 ± 0.06 mEq/l; p = 0.002) was decreased in the RGB group. Both the serum alkaline phosphatase level (121.0 ± 7.6 vs 87.3 ± 8.3 U/l; p = 0.018) and the serum osteocalcin (12.6 ± 1.2 vs 9.5 ± 1.9 mug/ml; p = 0.078) level increased in the RGB group. The 1,25(OH) vitamin D level (50.5 ± 2.5 vs 40.5 ± 4.9 pg/ml; p = 0.152) was similar for both groups; the 25(OH) vitamin D level (24.3 ± 1.6 vs 35.9 ± 3.4 ng/ml; p = 0.008) was decreased in the RGB group as compared with the control group. Bone mineral density was elevated in three of
the lumbar measurement sites, and marginally decreased (0.90 ± 0.02 g/cm2 vs 1.03 ± 0.06 g/cm2; p = 0.067) in the femoral neck of the RGB group compared with the controls. This biochemical pattern suggests the development
of metabolic bone disease following the RGB.
Previous studies demonstrated decreases in serum 25-hydroxyvitamin D in obese subjects. Studies were carried out to determine
whether serum vitamin D is low in obesity. The results indicate that serum vitamin D is significantly lower in obese than
in nonobese individuals and may contribute to lower serum 25-hydroxyvitamin D in obesity.
Epidemiologic and laboratory evidence suggests that vitamin D may play a role in reducing breast cancer risk. Lack of exposure to ultraviolet sunlight can increase the prevalence of vitamin D deficiency. This deficiency may place some populations at higher risk for breast cancer. The association between total average annual sunlight energy striking the ground and age-adjusted breast cancer mortality rates in 87 regions of the United States was evaluated. Annual age-adjusted mortality rates for breast cancer varied over a 1.8-fold range, from 17-19 per 100,000 in the South and Southwest United States to 33 per 100,000 in the Northeast; the overall U.S. rate was 27.3 per 100,000. Risk of fatal breast cancer in the major urban areas of the United States was inversely proportional to intensity of local sunlight (r = -0.80, P = 0.0001); multiple regression with stratospheric ozone measurements, r = -0.82, P = 0.0001). Vitamin D from sunlight exposure may be associated with low risk for fatal breast cancer, and differences in ultraviolet light reaching the United States population may account for the striking regional differences in breast cancer mortality. The ecological nature of this study is emphasized, and the possibility that an indirect association with dietary and socioeconomic factors could explain these findings is discussed.
Blood samples taken in 1974 in Washington County, Maryland, from 25 620 volunteers were used to investigate the relation of serum 25-hydroxyvitamin D (25-OHD) with subsequent risk of getting colon cancer. 34 cases of colon cancer diagnosed between August, 1975, and January, 1983, were matched to 67 controls by age, race, sex, and month blood was taken. Risk of colon cancer was reduced by 75% in the third quintile (27-32 ng/ml) and by 80% in the fourth quintile (33-41 ng/ml) of serum 25-OHD. Risk of getting colon cancer decreased three-fold in people with a serum 25-OHD concentration of 20 ng/ml or more. The results are consistent with a protective effect of serum 25-OHD on colon cancer.
A competitive protein binding assay for 25-hydroxycholecalciferol (25-H.c.c.) has been used to study rickets and osteomalacia in Asian immigrants to Britain. Compared with levels in a Caucasian control group, serum-25-H.C.C. concentrations were significantly lower in a group of Asians with no clinical or biochemical evidence of rickets or osteomalacia, and were still lower in another group without clinical disease but with raised serum-alkaline-phosphatase concentrations. In a group with overt rickets or osteomalacia 25-H.C.C. was undetectable in all cases. It seems that vitamin-D deficiency is the major factor leading to rickets and osteomalacia in Indian and Pakistani immigrants to Britain.
Vitamin D in all body tissues was radio-labeled by supplementing completely vitamin D-deficient weanling rats with oral vitamin D(3)-4-(14)C for 2 wk. All vitamin D was then withheld, and radioactivity and vitamin D content in a variety of organs and tissues were measured. Adipose tissue was found to contain by far the greatest quantity of radioactivity throughout the 3 month experimental period. Immediately after supplementation, half of the total radioactivity in adipose tissue corresponded to unaltered vitamin D(3), and the other half to polar metabolites and esters of vitamin D(3) and unidentified peak II. 1 month later there was approximately the same proportion but a decrease in the total quantity of each form. We conclude that adipose tissue is the major storage site for vitamin D(3) in its several forms. Unaltered vitamin D(3) was the principal storage form observed and presumably a source available for conversion to other metabolites during deprivation.
Ergocalciferol and cholecalciferol powders were studied at 25 and 40 degrees and at different humidities. Ergocalciferol decomposed rapidly at 25 and 40 degrees when stored in dry air. Decomposition of ergocalciferol led to the formation of products of higher polarity. Cholecalciferol was not as labile under dry conditions, but decomposed rapidly at high temperature.
Fifty patients who had undergone partial gastrectomy for benign ulcer disease 3-4 years previously were examined. Blood haemoglobin, serum iron, calcium, and phosphorus, alkaline phosphatase, urine excretion of calcium and phosphorus, faecal fat, body weight, and bone mineral density by 241Am gamma ray attenuation were determined preoperatively and at the follow-up investigation. Radiocalcium (47Ca) absorption was measured at the follow-up and compared with that of controls. An increase was found in serum alkaline phosphatase and a decrease in serum inorganic phosphorus and urinary calcium excretion. The other biochemical data did not change significantly. The bone mineral density of the gastrectomized patients did not differ from that of the controls in either sex. The intestinal 47Ca absorption showed no significant difference between the patients and controls.
Plasma 25-hydroxyvitamin D concentrations and bone histomorphometry were investigated in 24 grossly obese subjects. The mean plasma 25OHD concentration was significantly lower in the obese group than in age-matched, healthy controls. Subnormal values were found in four obese subjects and in a further two subjects, who were investigated at the end of the summer, plasma 25-hydroxyvitamin D levels were at the lower end of the normal winter range. Bone histology was abnormal in two patients. In one, mild osteomalacia and secondary hyperparathyroidism were present while in the other patient the appearance suggested increased bone turnover, possibly as a result of healing osteomalacia. We conclude that gross obesity is associated with an increased risk of vitamin D deficiency, probably because of reduced exposure to uv radiation. Histological evidence of metabolic bone disease may also occur. Preoperative vitamin D deficiency may contribute in some patients to the development of metabolic bone disease after intestinal bypass.
The effects of oral 1 alpha-hydroxyvitamin D3 have been investigated in 12 patients with bone disease after jejunoileal bypass for obesity. Bone histology became normal or improved greatly after four to 12 months' treatment in eight patients but showed little change or worsened in four. There was a significant rise in plasma calcium and fall in plasma alkaline phosphatase concentration with 1 alpha-hydroxyvitamin D3 therapy in the patients with a good histological response. Administration of metronidazole and cotrimoxazole to two patients who had failed to respond to 1 alpha-hydroxyvitamin D3 resulted in clinical and biochemical improvement; in one of these patients histological improvement was also documented. It is concluded that oral 1 alpha-hydroxyvitamin D3 can be effective in healing post-bypass bone disease; the failure of some patients to respond may be related to bacterial contamination of the small intestine and in those patients antibiotics may also be indicated.
A non-invasive evaluation of bone metabolism was performed in 44 morbidly obese patients before and after a mean weight loss of 22.4 kg (range 7.9-43.4 kg) after 2 months and a further weight loss of 7.3 kg after 8 months (0.8-20.0 kg). This weight reduction was obtained by a nutritionally adequate very-low-calorie diet. Before treatment the bone mineral content of the distal forearm was increased compared to normals (51.9 U vs. 43.7 U, p < 0.001). Bone formation was evaluated by serum alkaline phosphatase and serum osteocalcin. Serum alkaline phosphatase was increased (187.8 U/l vs 147.4 U/l, p < 0.001) while serum osteocalcin was lower than in the controls (0.67 nmol/l vs 0.98 nmol/l, p < 0.01). Bone resorption, as measured by the urinary hydroxyproline/creatinine ratio, was not increased in the obese patients (19.2 molar ratio x 10(-3) vs 16.7 molar ratio x 10(-3), NS). After 2 months, the bone mineral content had declined by 3.3%. Serum alkaline phosphatase remained unchanged (187.8 U/l vs 186.9 U/l, NS) but serum osteocalcin demonstrated a significant rise (3.94 nmol/l vs 10.53 nmol/l, p < 0.001), parallel to changes in the hydroxyproline/creatinine ratio (19.2 molar ratio x 10(-3) vs 25.2 molar ratio x 10(-3), p < 0.001). At 8 months, no further change in the bone mineral content was seen. The hydroxyproline/creatinine ratio did still increase (from 25.8 molar ratio x 10(-3) to 30.1 molar ratio x 10(-3), p < 0.05), while serum alkaline phosphatase and serum osteocalcin remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
For an eating disorder study over a period of 1 year, we measured total-body bone mineral using a Hologic QDR 1000 W in a total of 157 subjects and observed anomalies that questioned the accuracy of such measurements. Using the recommended Enhanced software, a change in total bone mineral content (delta BMC) correlated positively with a change in weight (delta W; r = 0.66), but a loss of weight was associated with an increase in bone mineral areal density (BMD; r = 0.58), arising from a reduction in bone area (AREA). Both regressions were highly significant. The dominant factor in this relationship was a strong correlation between delta AREA and delta BMC, for all parts of the skeleton, r > 0.9, with a slope close to 1. This is implausible because bone area would not be expected to change. When Standard software was used, the slope of the delta BMC/delta W correlation was steeper, but the delta BMD/delta W regression became positive. An artefact of dual-energy X-ray absorptiometry processing was suspected, and phantom measurements were made. The phantom consisted of tissue-equivalent hardboard cut and stacked to form cylinders corresponding to the head, trunk, arms, and legs of a standard man. The skeleton was constructed from layers of aluminium sheet as an approximation of the average shape, BMD, BMC, and AREA in each region. When aluminium thickness was varied, BMD thresholds were found, approximately 0.4 g/cm2 for the legs and 0.2 g/cm2 for the arms. Above these, bone area rose fairly rapidly toward a plateau. At higher skeletal densities, the relationships between measured and true BMDs were close to linear, but slopes were less than unity, so that changes would be underestimated by 10-30%. Increases of thickness of the soft tissue of the phantom lowered AREA slightly. Uniform fat proportion increases led to decreases in BMC and AREA, but lard wrapped in an annulus around the limbs led to spurious increases in BMC and AREA of a similar magnitude to those observed in vivo, while BMD fell slightly, although there had been no true change of bone variables. Similar results were obtained with lard around the limbs of a volunteer. Reanalysis of phantom scans using Standard software confirmed the software differences noted in vivo. The phantom measurements offer an explanation of the anomaly in vivo and demonstrate that, under different circumstances, change in both BMC and BMD can be wrongly recorded. We believe that no valid conclusions can be drawn from measurements by the Holgic QDR 1000 W of bone changes during weight change.
The activated form of vitamin D, 1,25(OH)2D3, and its analogues can prevent type I diabetes in NOD mice. Protection is achieved without signs of systemic immunosuppression and is associated with a restoration of the defective immune regulator system of the NOD mice. The aim of the present study was to investigate whether this restoration of regulator cell function is the only mechanism in the prevention of diabetes by 1,25(OH)2D3. We tested therefore if 1,25(OH)2D3 could prevent cyclophosphamide-induced diabetes, since diabetes occurring after cyclophosphamide injection is believed to be due to an elimination of suppresser cells. NOD mice treated with 1,25(OH)2D3 (5 microg/kg every 2 days) from the time of weaning were clearly protected against diabetes induced by cyclophosphamide (200 mg/kg body wt at 70 days old) (2/12 (17%) versus 36/53 (68%) in control mice, P < 0.005). By co-transfer experiments it was demonstrated that cyclophosphamide had indeed eliminated the suppresser cells present in 1,25(OH)2D3-treated mice. Since cyclophosphamide injection did not break the protection offered by 1,25(OH)2D3, it was clear that diabetogenic effector cells were affected by 1,25(OH)2D3 treatment as well. This was confirmed by the finding that splenocytes from 1,25(OH)2D3-treated mice were less capable of transferring diabetes in young, irradiated NOD mice, and by the demonstration of lower Th1 cytokine levels in the pancreases of 1,25(OH)2D3-treated, cyclophosphamide-injected mice. This better elimination of effector cells in 1,25(OH)2D3-treated mice could be explained by a restoration of the sensitivity to cyclophosphamide-induced apoptosis in both thymocytes and splenocytes, in normally apoptosis-resistant NOD mice. Altogether, these data indicate that the protection against diabetes offered by 1,25(OH)2D3 may be independent of the presence of suppresser cells, and may involve increased apoptosis of Th1 autoimmune effector cells.
This study was undertaken to describe the musculoskeletal manifestations in a selected population of 26 patients with biopsy-proven osteomalacia (OM) and provide a literature update.
The 26 patients with biopsy-proven OM were selected from a total number of 79 patients who underwent anterior iliac crest biopsy. The diagnosis of OM was confirmed by the presence of an osteoid volume greater than 10%, osteoid width greater than 15 microm, and delayed mineralization assessed by double-tetracycline labeling.
OM was caused by intestinal malabsorption in 13 patients, whereas six other patients presented with hypophosphatemia of different causes. Five elderly patients presented with hypovitaminosis D, and in two patients the OM was part of renal osteodystrophy. Twenty-three patients presented with bone pain and diffuse demineralization, whereas three other patients had normal or increased bone density. Characteristic pseudofractures were seen in only seven patients. Six of the 23 patients with diffuse demineralization had an "osteoporotic-like pattern" without pseudofractures. Prominent articular manifestations were seen in seven patients, including a rheumatoid arthritis-like picture in three, osteogenic synovitis in three, and ankylosing spondylitis-like in one. Two other patients were referred to us with the diagnosis of possible metastatic bone disease attributable to polyostotic areas of increased radio nuclide uptake caused by pseudofractures. Six patients also had proximal myopathy, two elderly patients were diagnosed as having polymalgia rheumatica, and two young patients were diagnosed as having fibromyalgia. One of the patients who presented with increased bone density was misdiagnosed as possible fluorosis.
OM is usually neglected when compared with other metabolic bone diseases and may present with a variety of clinical and radiographic manifestations mimicking other musculoskeletal disorders.
The National Institutes of Health Consensus Development Conference on Gastrointestinal Surgery for Severe Obesity brought together surgeons, gastroenterologists, endocrinologists, psychiatrists, nutritionists, and other health care professionals as well as the public to address the nonsurgical treatment options for severe obesity, the surgical treatments for severe obesity and the criteria for selection, the efficacy and risks of surgical treatments for severe obesity, and the need for future research on and epidemiological evaluation of these therapies. Following 2 days of presentations by experts and discussion by the audience, a consensus panel weighed the evidence and prepared their consensus statement. Among their findings, the panel recommended that 1) patients seeking therapy for severe obesity for the first time should be considered for treatment in a nonsurgical program with integrated components of a dietary regimen, appropriate exercise, and behavioral modification and support, 2) gastric restrictive or bypass procedures could be considered for well-informed and motivated patients with acceptable operative risks, 3) patients who are candidates for surgical procedures should be selected carefully after evaluation by a multidisciplinary team with medical, surgical, psychiatric, and nutritional expertise, 4) the operation be performed by a surgeon substantially experienced with the appropriate procedures and working in a clinical setting with adequate support for all aspects of management and assessment, and 5) lifelong medical surveillance after surgical therapy is a necessity. The full text of the consensus panel's statement follows.
Modulation of angiogenesis is now a recognized strategy for the prevention and treatment of pathologies categorized by their reliance on a vascular supply. The purpose of this study was to evaluate the effect of 1 alpha,25-dihydroxyvitamin D(3) [1, 25(OH)(2)D(3)], the active metabolite of vitamin D(3), on angiogenesis by using well-characterized in vitro and in vivo model systems. 1,25(OH)(2)D(3) (1 x 10(-9) to 1 x 10(-7) mol/L) significantly inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell sprouting and elongation in vitro in a dose-dependent manner and had a small, but significant, inhibitory effect on VEGF-induced endothelial cell proliferation. 1, 25(OH)(2)D(3) also inhibited the formation of networks of elongated endothelial cells within 3D collagen gels. The addition of 1, 25(OH)(2)D(3) to endothelial cell cultures containing sprouting elongated cells induced the regression of these cells, in the absence of any effect on cells present in the cobblestone monolayer. Analysis of nuclear morphology, DNA integrity, and enzymatic in situ labeling of apoptosis-induced strand breaks demonstrated that this regression was due to the induction of apoptosis specifically within the sprouting cell population. The effect of 1,25(OH)(2)D(3) on angiogenesis in vivo was investigated by using a model in which MCF-7 breast carcinoma cells, which had been induced to overexpress VEGF, were xenografted subcutaneously together with MDA-435S breast carcinoma cells into nude mice. Treatment with 1,25(OH)(2)D(3) (12.5 pmol/d for 8 weeks) produced tumors that were less well vascularized than tumors formed in mice treated with vehicle alone. These results highlight the potential use of 1,25(OH)(2)D(3) in both the prevention and regression of conditions characterized by pathological angiogenesis.
Osteomalacia due to vitamin D depletion is believed to be rare in the United States because of the routine fortification of milk and other dairy products with vitamin D. We present a series of patients with histologically verified osteomalacia due to vitamin D depletion to emphasize the need for more careful and systematic surveillance of patients at risk of this metabolic bone disease.
Between 1989 and 1994, 17 patients with osteomalacia due to vitamin D depletion were seen in the Bone and Mineral Division of Henry Ford Health System, Detroit. All patients had a transiliac bone biopsy after in vivo double tetracycline labeling. Biochemical indexes of vitamin D nutritional status, parathyroid function, markers of bone turnover, and bone mineral density were assessed at the time of bone biopsy. The duration of symptoms, the lag between the cause of vitamin D depletion and the development of symptoms, and the radiologic findings were recorded.
Osteomalacia was suspected by the referring physician in only 4 of the 17 patients, although a gastrointestinal disorder that can lead to vitamin D depletion was present in every patient. Thirteen of the patients had sustained at least one osteoporotic fracture (wrist, spine, or hip), and most had low appendicular and axial bone mineral density. All patients had one or more biochemical abnormalities consistent with vitamin D depletion. In 4 patients, a progressive rise in the serum alkaline phosphatase level was recorded but was not investigated until the patient presented with bone pain, muscle weakness, or fracture.
Osteomalacia due to vitamin D depletion appears not to be suspected or diagnosed promptly in susceptible patients, perhaps because their physicians were not sufficiently aware of this condition.
The aim was to evaluate the association between serum vitamin D (25-hydroxyvitamin D) level and risk of prostate cancer.
The nested case-control study was based on a 13-year follow-up of about 19,000 middle-aged men who attended the first screening visit within the Helsinki Heart Study and were free of clinically verified prostate cancer at baseline. Through record linkage with the files of the Finnish Cancer Registry, 149 prostate cancer cases were identified in the cohort. They were matched (1:4) to probability density sampled controls for age, time of sample retrieval, and residence. Serum levels of 25-hydroxyvitamin D (25-VD) at entry were measured for cases and controls. The relative risks of prostate cancer were derived using conditional logistic regression analysis.
Prostate cancer risk, analyzed by quartiles of the 25-VD levels, was inversely related to 25-VD. Men with 25-VD concentration below the median had an adjusted relative risk (OR) of 1.7 compared to men with 25-VD level above the median. The prostate cancer risk was highest among younger men (< 52 years) at entry and low serum 25-VD (OR 3.1 nonadjusted and 3.5 adjusted). Among those younger men (< 52 years), low 25-VD entailed a higher risk of non-localized cancers (OR 6.3). The mean age at diagnosis of the patients with 25-VD concentration above the median was 1.8 years higher than that of patients with vitamin D below the median (63.1 vs 61.3 years).
We conclude that low levels of 25-VD associated with an increased risk for subsequent earlier exposure and more aggressive development of prostate cancer, especially before the andropause.
Dietary vitamin D supplementation is associated with reduced risk of type 1 diabetes in animals. Our aim was to ascertain whether or not vitamin D supplementation or deficiency in infancy could affect development of type 1 diabetes.
A birth-cohort study was done, in which all pregnant women (n=12055) in Oulu and Lapland, northern Finland, who were due to give birth in 1966 were enrolled. Data was collected in the first year of life about frequency and dose of vitamin D supplementation and presence of suspected rickets. Our primary outcome measure was diagnosis of type 1 diabetes by end of December, 1997.
12058 of 12231 represented live births, and 10821 (91% of those alive) children were followed-up at age 1 year. Of the 10366 children included in analyses, 81 were diagnosed with diabetes during the study. Vitamin D supplementation was associated with a decreased frequency of type 1 diabetes when adjusted for neonatal, anthropometric, and social characteristics (rate ratio [RR] for regular vs no supplementation 0.12, 95% CI 0.03-0.51, and irregular vs no supplementation 0.16, 0.04-0.74. Children who regularly took the recommended dose of vitamin D (2000 IU daily) had a RR of 0.22 (0.05-0.89) compared with those who regularly received less than the recommended amount. Children suspected of having rickets during the first year of life had a RR of 3.0 (1.0-9.0) compared with those without such a suspicion.
Dietary vitamin D supplementation is associated with reduced risk of type 1 diabetes. Ensuring adequate vitamin D supplementation for infants could help to reverse the increasing trend in the incidence of type 1 diabetes.
Randomized controlled trials have shown that a combination of vitamin D and calcium can prevent fragility fractures in the elderly. Whether this effect is attributed to the combination of vitamin D and calcium or to one of these nutrients alone is not known. We studied if an intervention with 10 microg of vitamin D3 per day could prevent hip fracture and other osteoporotic fractures in a double-blinded randomized controlled trial. Residents from 51 nursing homes were allocated randomly to receive 5 ml of ordinary cod liver oil (n = 569) or 5 ml of cod liver oil where vitamin D was removed (n = 575). During the study period of 2 years, fractures and deaths were registered, and the principal analysis was performed on the intention-to-treat basis. Biochemical markers were measured at baseline and after 1 year in a subsample. Forty-seven persons in the control group and 50 persons in the vitamin D group suffered a hip fracture. The corresponding figures for all nonvertebral fractures were 76 persons (control group) and 69 persons (vitamin D group). There was no difference in the incidence of hip fracture (p = 0.66, log-rank test), or in the incidence of all nonvertebral fractures (p = 0.60, log-rank test) in the vitamin D group compared with the control group. Compared with the control group, persons in the vitamin D group increased their serum 25-hydroxyvitamin D concentration with 22 nmol/liter (p = 0.001). In conclusion, we found that an intervention with 10 microg of vitamin D3 alone produced no fracture-preventing effect in a nursing home population of frail elderly people.
There are large geographic gradients in mortality rates for a number of cancers in the U.S. (e.g., rates are approximately twice as high in the northeast compared with the southwest). Risk factors such as diet fail to explain this variation. Previous studies have demonstrated that the geographic distributions for five types of cancer are related inversely to solar radiation. The purpose of the current study was to determine how many types of cancer are affected by solar radiation and how many premature deaths from cancer occur due to insufficient ultraviolet (UV)-B radiation.
UV-B data for July 1992 and cancer mortality rates in the U.S. for between 1970-1994 were analyzed in an ecologic study.
The findings of the current study confirm previous results that solar UV-B radiation is associated with reduced risk of cancer of the breast, colon, ovary, and prostate as well as non-Hodgkin lymphoma. Eight additional malignancies were found to exhibit an inverse correlation between mortality rates and UV-B radiation: bladder, esophageal, kidney, lung, pancreatic, rectal, stomach, and corpus uteri. The annual number of premature deaths from cancer due to lower UV-B exposures was 21,700 (95% confidence interval [95% CI], 20,400-23,400) for white Americans, 1400 (95% CI, 1100-1600) for black Americans, and 500 (95% CI, 400-600) for Asian Americans and other minorities.
The results of the current study demonstrate that much of the geographic variation in cancer mortality rates in the U.S. can be attributed to variations in solar UV-B radiation exposure. Thus, many lives could be extended through increased careful exposure to solar UV-B radiation and more safely, vitamin D3 supplementation, especially in nonsummer months.
TNFalpha and IL-1alpha are potent stimulators of bone resorption in vivo and in vitro. Recently, it has been demonstrated that these two cytokines directly induce osteoclastogenesis in mouse marrow cultures. This study determined whether TNFalpha (+/- IL-1alpha) is also capable of inducing human osteoclastogenesis. The CD14(+) monocyte fraction of human peripheral mononuclear cells was cultured with TNFalpha +/- IL-1alpha in the presence of M-CSF. TNFalpha induced the formation of multinucleated cells (MNCs) which were positive for TRAP, VNR and cathepsin K and showed evidence of resorption pit formation. IL-1alpha stimulated TNFalpha-induced lacunar resorption two- to four-fold. Osteoprotegerin, the decoy receptor for RANKL, did not inhibit this process. Anti-human IL-1alpha neutralizing antibodies significantly inhibited resorption without inhibiting the formation of TRAP(+)/VNR(+) MNCs. These results suggest that, in the presence of M-CSF, TNFalpha is sufficient for inducing human osteoclast differentiation from circulating precursors by a process which is distinct from the RANK/RANKL signalling pathway.
Metabolic bone disease is a well-documented long-term complication of obesity surgery. It is often undiagnosed, or misdiagnosed, because of lack of physician and patient awareness. Abnormalities in calcium and vitamin D metabolism begin shortly after gastrointestinal bypass operations; however, clinical and biochemical evidence of metabolic bone disease may not be detected until many years later.
A 57-year-old woman presented with severe hypocalcemia, vitamin D deficiency, and radiographic evidence of osteomalacia, 17 years after vertical banded gastroplasty and Roux-en-Y gastric bypass. Following these operations, she was diagnosed with a variety of medical disorders based on symptoms that, in retrospect, could have been attributed to metabolic bone disease. Additionally, she had serum metabolic abnormalities that were consistent with metabolic bone disease years before this presentation. Radiographic evidence of osteomalacia at the time of presentation suggests that her condition was advanced, and went undiagnosed for many years. These symptoms and laboratory and radiographic abnormalities most likely were a result of the long-term malabsorptive effects of gastric bypass, food intake restriction, or a combination of the two.
This case illustrates not only the importance of informed consent in patients undergoing obesity operations, but also the importance of adequate follow-up for patients who have undergone these procedures. A thorough history and physical examination, a high index of clinical suspicion, and careful long-term follow-up, with specific laboratory testing, are needed to detect early metabolic bone disease in these patients.
Multiple sclerosis (MS) patients were randomized, in a double blind design, and placed into either a vitamin D supplemented group or a placebo control group. As expected, serum 25-hydroxyvitamin D levels increased significantly following 6 month vitamin D supplementation (17+/-6 ng/ml at baseline to 28+/-8 ng/ml at 6 months). Vitamin D supplementation also significantly increased serum transforming growth factor (TGF)-beta 1 levels from 230+/-21 pg/ml at baseline to 295+/-40 pg/ml 6 months later. Placebo treatment had no effect on serum TGF-beta 1 levels. Tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-13 were not different following vitamin D supplementation. IL-2 mRNA levels decreased following vitamin D supplementation but the differences did not reach significance. Vitamin D supplementation of MS patients for 6 months was associated with increased vitamin D status and serum TGF-beta 1.
This study was designed to evaluate the association between vitamin D status and congestive heart failure (CHF).
Impaired intracellular calcium metabolism is an important factor in the pathogenesis of CHF. The etiology of CHF, however, is not well understood.
Twenty patients age <50 years and 34 patients age >/=50 years with New York Heart Association classes >/=2 and 34 control subjects age >/=50 years were recruited. N-terminal pro-atrial natriuretic peptide (NT-proANP), a predictor of CHF severity; vitamin D metabolites; and parameters of calcium metabolism were measured in fasting blood samples collected between November 2000 and March 2001.
Both groups of CHF patients had markedly increased serum levels of NT-proANP (p < 0.001), increased serum phosphorus levels (p < 0.001), and reduced circulating levels of both 25-hydroxyvitamin D (p < 0.001) and calcitriol (p < 0.001). Albumin-corrected calcium levels were reduced and parathyroid hormone levels were increased in the younger CHF patients compared with the controls (both p values <0.001). Moreover, parathyroid hormone levels tended to be higher in the elderly CHF patients than in the controls (p = 0.074). In a nonlinear regression analysis 25-hydroxyvitamin D and calcitriol were inversely correlated with NT-proANP (r(2) = 0.16; p < 0.001 and r(2) = 0.12; p < 0.01, respectively). The vitamin D genotype at the BmsI restriction site did not differ between the study groups.
The low vitamin D status can explain alterations in mineral metabolism as well as myocardial dysfunction in the CHF patients, and it may therefore be a contributing factor in the pathogenesis of CHF.
The risk of hyperparathyroidism after the duodenal switch operation is related to the length of the common channel.
A retrospective analysis of patients following the duodenal switch operation from October 2, 2000, through February 1, 2002.
Academic tertiary referral hospital.
One hundred sixty-five consecutive patients underwent the duodenal switch operation, performed for morbid obesity, with common channel lengths of 75 cm (n = 103 [group A]) and 100 cm (n = 62 [group B]).
Weight loss and parathyroid hormone, corrected calcium, and 25-hydroxyvitamin D (25-OH D) levels were compared between groups A and B. Values were determined preoperatively, early postoperatively (3-6 months), and late postoperatively (9-18 months).
Both groups exhibited a slight reduction in serum calcium concentration, with one quarter decreasing below the normal range. Hyperparathyroidism was more common in group A than group B preoperatively (38.9% vs 14.9%), reflecting the higher body mass index of patients in group A. Hyperparathyroidism was also more frequent in the early (54.9% vs 30.9%) and late (49.4% vs 20.5%) postoperative periods in group A vs group B. New-onset hyperparathyroidism was also more common in group A than group B (42.0% vs 13.3%). After 1 year, subnormal 25-OH D levels were found in 17.0% of the patients in group A and in 10.0% of the patients in group B. Median 25-OH D levels increased in both groups, but tended to be higher in group B.
Patients with shorter common channels had a higher risk of developing hyperparathyroidism. This may be related to limited 25-OH D absorption.
Vitamin D is a potent regulator of calcium homeostasis and may have immunomodulatory effects. The influence of vitamin D on human autoimmune disease has not been well defined. The purpose of this study was to evaluate the association of dietary and supplemental vitamin D intake with rheumatoid arthritis (RA) incidence.
We analyzed data from a prospective cohort study of 29,368 women of ages 55-69 years without a history of RA at study baseline in 1986. Diet was ascertained using a self-administered, 127-item validated food frequency questionnaire that included supplemental vitamin D use. Risk ratios (RRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards regression, adjusting for potential confounders.
Through 11 years of followup, 152 cases of RA were validated against medical records. Greater intake (highest versus lowest tertile) of vitamin D was inversely associated with risk of RA (RR 0.67, 95% CI 0.44-1.00, P for trend = 0.05). Inverse associations were apparent for both dietary (RR 0.72, 95% CI 0.46-1.14, P for trend = 0.16) and supplemental (RR 0.66, 95% CI 0.43-1.00, P for trend = 0.03) vitamin D. No individual food item high in vitamin D content and/or calcium was strongly associated with RA risk, but a composite measure of milk products was suggestive of an inverse association with risk of RA (RR 0.66, 95% CI 0.42-1.01, P for trend = 0.06).
Greater intake of vitamin D may be associated with a lower risk of RA in older women, although this finding is hypothesis generating.
To examine bone mass and metabolism in women who had previously undergone Roux-en-Y gastric bypass (RYGB) and determine the effect of supplementation with calcium (Ca) and vitamin D.
Bone mineral density and bone mineral content (BMC) were examined in 44 RYGB women (> or = 3 years post-surgery; 31% weight loss; BMI, 34 kg/m(2)) and compared with age- and weight-matched control (CNT) women (n = 65). In a separate analysis, RYGB women who presented with low bone mass (n = 13) were supplemented to a total 1.2 g Ca/d and 8 microg vitamin D/d over 6 months and compared with an unsupplemented CNT group (n = 13). Bone mass and turnover and serum parathyroid hormone (PTH) and 25-hydroxyvitamin D were measured.
Bone mass did not differ between premenopausal RYGB and CNT women (42 +/- 5 years), whereas postmenopausal RYGB women (55 +/- 7 years) had higher bone mineral density and BMC at the lumbar spine and lower BMC at the femoral neck. Before and after dietary supplementation, bone mass was similar, and serum PTH and markers of bone resorption were higher (p < 0.001) in RYGB compared with CNT women and did not change significantly after supplementation.
Postmenopausal RYGB women show evidence of secondary hyperparathyroidism, elevated bone resorption, and patterns of bone loss (reduced femoral neck and higher lumbar spine) similar to other subjects with hyperparathyroidism. Although a modest increase in Ca or vitamin D does not suppress PTH or bone resorption, it is possible that greater dietary supplementation may be beneficial.