| 1. |
- Johansson, Sara, et al.
(author)
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Subclinical hypervitaminosis A causes fragile bones in rats
- 2002
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In: Bone. - 8756-3282 .- 1873-2763. ; 31:6, s. 685-689
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Journal article (peer-reviewed)abstract
- Excessive intake of vitamin A has been associated with an increased risk of hip fracture in humans. This finding has raised the question of whether long-term intake of relatively moderate doses ("subclinical" hypervitaminosis A) contributes to fracture risk. Although it has been known for more than half a century that toxic doses of vitamin A lead to spontaneous fractures in rats, the lowest intake that induces adverse effects is not known, and the result of exposure to excessive doses that do not cause general toxicity has been rarely investigated. In this study, mature female rats were fed a standard diet with 12 IU vitamin A/g pellet (control, C), or standard diet supplemented with either 120 IU ("10 x C") or 600 IU ("50 x C") vitamin A/g pellet for 12 weeks. Fifteen animals were included in each group. The supplemented diets correspond to a vitamin A intake of approximately 1800 IU/day and 9000 IU/day, respectively. The latter dose is about one third of that previously reported to cause skeletal lesions. At the end of the study, serum retinyl esters were elevated 4- (p < 0.01) and 20-fold (p < 0.001) and the total amount of liver retinoid had increased 3- (p < 0.001) and 7-fold (p < 0.001) in the 10 x C and 50 x C group, respectively. The animals showed no clinical signs of general toxicity, and there were no significant bone changes in the 10 x C group. However, in the 50 x C group, a characteristic thinning of the cortex (cortical area -6.5% [p < 0.001]) and reduction of the diameter of the long bones were evident (bone cross-sectional area -7.2% [p < 0.01] at the midshaft and -11.0% [p < 0.01] at the metaphysis), as measured by peripheral quantitative computed tomography. In agreement with these data and a decreased polar strength strain index (-14.0%, p < 0.01), the three-point bending breaking force of the femur was reduced by 10.3% (p < 0.01) in the 50 x C group. These data indicate that the negative skeletal effects appear at a subchronic vitamin A intake of somewhere between 10 and 50 times the standard diet. This level is considerably lower than previously reported. Our results suggest that long-term ingestion of modest excesses of vitamin A may contribute to fracture risk.
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| 2. |
- Michaëlsson, Karl, 1959-, et al.
(author)
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Dietary calcium and vitamin D intake in relation to osteoporotic fracture risk
- 2003
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In: Bone. - 8756-3282 .- 1873-2763. ; 32:6, s. 694-703
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Journal article (peer-reviewed)abstract
- The etiologic role of dietary calcium and vitamin D intake in primary prevention of osteoporotic fractures is uncertain, despite considerable research efforts. With the aim to examine these associations with an improved precision, we used data from a large population-based prospective cohort study in central Sweden. We estimated nutrient intake from a self-administered food-frequency questionnaire filled in by 60,689 women, aged 40-74 years at baseline during 1987-1990. During follow-up, we observed 3986 women with a fracture at any site and 1535 with a hip fracture. Rate ratio of fractures (RR) and 95% CI were estimated using Cox proportional hazards models. We found no dose-response association between dietary calcium intake and fracture risk. The age-adjusted RR of hip fracture was 1.01 (95% CI 0.96-1.06) per 300 mg calcium/day and the corresponding risk of any osteoporotic fracture was 0.99 (95% CI 0.96-1.03). Furthermore, women with an estimated calcium intake below 400 mg/day and those with a calcium intake higher than 1200 mg/day both had a similar age-adjusted hip fracture risk as those with intermediate calcium intakes: RR 1.07 (95% CI 0.92-1.24) and RR 1.00 (95% CI 0.79-1.27), respectively. Vitamin D intake was not associated with fracture risk. Furthermore, women in the highest quintiles compared to the lowest quintiles of both calcium and vitamin D intake had an age-adjusted RR of 1.02 for all fractures (95% CI 0.88-1.17). Dietary calcium or vitamin D intakes estimated at middle and older age do not seem to be of major importance for the primary prevention of osteoporotic fractures in women.
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| 3. |
- Lind, Thomas, et al.
(author)
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High dietary intake of retinol leads to bone marrow hypoxia and diaphyseal endosteal mineralization in rats
- 2011
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In: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 48:3, s. 496-506
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Journal article (peer-reviewed)abstract
- Vitamin A (retinol) is the only molecule known to induce spontaneous fractures in laboratory animals and we have identified retinol as a risk factor for fracture in humans. Since subsequent observational studies in humans and old animal data both show that high retinol intake appears to only have small effects on bone mineral density (BMD) we undertook a mechanistic study of how excess retinol reduces bone diameter while leaving BMD essentially unaffected. We fed growing rats high doses of retinol for only 1week. Bone analysis involved antibody-based methods, histology, pQCT, biomechanics and bone compartment-specific PCR together with Fourier Transform Infrared Spectroscopy of bone mineral. Excess dietary retinol induced weakening of bones with little apparent effect on BMD. Periosteal osteoclasts increased but unexpectedly endosteal osteoclasts disappeared and there was a reduction of osteoclastic serum markers. There was also a lack of capillary erythrocytes, endothelial cells and serum retinol transport protein in the endosteal/marrow compartment. A further indication of reduced endosteal/marrow blood flow was the increased expression of hypoxia-associated genes. Also, in contrast to the inhibitory effects in vitro, the marrow of retinol-treated rats showed increased expression of osteogenic genes. Finally, we show that hypervitaminotic bones have a higher degree of mineralization, which is in line with biomechanical data of preserved stiffness in spite of thinner bones. Together these novel findings suggest that a rapid primary effect of excess retinol on bone tissue is the impairment of endosteal/marrow blood flow leading to hypoxia and pathological endosteal mineralization.
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| 4. |
- Michaëlsson, Karl, et al.
(author)
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The positive effect of dietary vitamin D intake on bone mineral density in men is modulated by the polyadenosine repeat polymorphism of the vitamin D receptor
- 2006
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In: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 39:6, s. 1343-1351
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Journal article (peer-reviewed)abstract
- INTRODUCTION: Few studies have considered the dietary influence of vitamin D intake on bone mineral density (BMD). Numerous studies have examined the association between VDR polymorphism and BMD, but no previous study has examined the joint influence of dietary vitamin D intake and VDR polymorphism on BMD. METHODS: We therefore conducted a study in 230 men aged 41-76 years of age. BMD was measured with DXA. A second bone scan was performed on average 2.7 years after the first investigation. Dietary habits were assessed by 14 dietary 24-h recall interviews. The polyadenosine (A) VDR genotypes were determined. RESULTS: Dietary vitamin D intake was associated with BMD at all sites, also after multivariate adjustment. Those in the highest quintile of intake had 9% higher femoral neck BMD (p = 0.004), 6% higher BMD at the lumbar spine (p = 0.06) and 5% higher total body BMD (p = 0.003) compared to men in the lowest quintile of dietary vitamin D intake. However, the positive association between vitamin D intake and BMD was especially apparent among those with the L/L polyadenosine (A) VDR genotype explaining between 10 and 15% of the variability in BMD depending on site (p < 0.004). There was furthermore a trend, in the lumbar spine, of less reduction in BMD with increasing vitamin D intake (p = 0.07) but not at the other sites. Calcium intake conferred no association with BMD. CONCLUSIONS: Our results indicate that the extent of positive association between dietary vitamin D intake and BMD in men is dependent on VDR polymorphism, a novel conceivable important gene-environmental interaction.
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| 5. |
- Snellman, Greta, 1978-, et al.
(author)
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Long-term dietary vitamin D intake and risk of fracture and osteoporosis : a longitudinal cohort study of Swedish middle-aged and elderly women
- 2012
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In: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 50:Suppl 1, s. S65-S65
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Journal article (other academic/artistic)abstract
- Context: Vitamin D deficiency may lead to osteoporosis and fracture but the importance of dietary vitamin D intake for skeletal health in adults is uncertain.Objective: To investigate associations between long-term dietary intake of vitamin D with risk of fractures and osteoporosis.Design: A prospective longitudinal cohort study.Setting: The population-based Swedish Mammography Cohort and the subcohort SMC Clinical.Participants: 61,433 women (age range 38 to 76 years) were followed for 19 years. Of these, 5,022 participated in the subcohort. Diet was assessed by repeated food frequency questionnaires. Main outcome measures: Incident fractures of any type and hip fractures, which were identified from registry data. Secondary outcome was osteoporosis diagnosed by dual energy x ray absorptiometry in the subcohort.Results: 14,738 women experienced any type of first fracture during follow-up, with 3,871 of these being hip fractures. Twenty percent of the women in the subcohort were classified as osteoporotic. A multivariable-adjusted hazard ratio (HR) and 95% confidence interval (CI) for any first fracture was 0.96 (95% CI 0.92-1.01) for the lowest and 1.02 (95% CI 0.96-1.07) for the highest quintile when compared with the third quintile of vitamin D intake. The corresponding HR for a first hip fracture was 1.02 (95% CI, 0.96-1.08) for the lowest and 1.14 (95% CI, 1.03-1.26) for the highest quintile. The odds ratio of osteoporosis by quintiles of vitamin D intake was 1.20 (95% CI, 0.85-1.71) for the lowest and 0.99 (95% CI, 0.78-1.25) for the highest quintile. Bone mineral density, however, were 2% higher at the lumbar spine and 0.3% higher at the total hip in women with highest vs. women with lowest intake of vitamin D (p<0.0001). Conclusions: Dietary intake of vitamin D seems to be of minor importance for the occurrence of fractures and osteoporosis in community-dwelling Swedish middle-aged and elderly women.
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