Bone and Phosphate in Relation to Health, Survival and Genetic Factors

In this thesis, we found that a) low bone mineral density was related to increased mortality from chronic obstructive pulmonary disease and b) increased serum phosphate, even at normal levels, was related to fracture risk, low BMD at the lumbar spine and coronary artery calcification. For the latter association, we found evidence of causality, due to the implementation of Mendelian Randomization technique. All our results were more consistent or even unique in men. The genetic analyses on phosphate levels identified 264 loci in the human genome and highlighted the importance of the Major Histocompatibility Complex (6p21.3) also on phosphate levels, as the top hit mapped to the flanking region of the MHC. Interestingly, the same finding has been described in White British and East Asian Japanese populations. Our next step will be the replication in BioBank Japan followed by trans-ethnic meta-analysis and Bayesian fine-mapping

Bone health and coronary artery calcification: The Rotterdam Study

Objectives: Vascular calcification has been associated inconsistently to low bone mineral density and fractures. The aims of the present study were to investigate the associations between coronary artery calcification (CAC) and BMD change, BMD and fracture risk in elderly subjects of the population-based Rotterdam Study. Methods: BMD was assessed through dual-energy X-ray absorptiometry and CAC through Electron-Beam Computed Tomography in 582 men and 694 women. We investigated the associations between BMD change (6.4 years follow-up) and CAC at follow-up and between BMD and CAC (measured simultaneously). In sensitivity analyses we stratified analyses for estradiol levels in women. The association between CAC and fracture risk (9 years follow-up) was tested through competing-risks models. Models were sex-stratified and adjusted for age, body mass index, smoking, bisphosphonate use and age at menopause. Results: There was no association between BMD change and CAC in men. In women, each 1% increase in annual BMD loss was significantly associated with higher follow-up CAC [β = 0.22 (0.06-0.38), p. =. 0.006; prevalence ratio: 4%]. Stratified analyses showed significant associations between BMD loss and follow-up CAC only in women with lower estradiol levels. We found no association between CAC and fracture risk and no association between BMD and CAC cross-sectionally. Conclusions: BMD loss was associated with higher follow-up CAC in women, which might be related to low estrogen levels. No association between CAC and BMD or fracture risk was found. Further studies are required to elucidate the mechanisms that might underlie the association between BMD change and coronary calcification in women

Serum 25-hydroxyvitamin D3 is associated with advanced glycation end products (AGEs) measured as skin autofluorescence: The Rotterdam Study

Advanced glycation end products (AGEs) accumulate in tissues with aging and may influence age-related diseases. They can be estimated non-invasively by skin autofluorescence (SAF) using the AGE Reader™. Serum 25-hydroxyvitamin D3 (25(OH)D3) may inhibit AGEs accumulation through anti-oxidative and anti-inflammatory properties but evidence in humans is scarce. The objective was to investigate the association between serum 25(OH)D3 and SAF in the population-based cohort study. Serum 25(OH)D3 and other covariates were measured at baseline. SAF was measured on average 11.5 years later. Known risk factors for AGE accumulation such as higher age, BMI, and coffee intake, male sex, smoking, diabetes, and decreased renal function were measured at baseline. Linear regression models were adopted to explore the association between 25(OH)D3 and SAF with adjustment for confounders. Interaction terms were tested to identify effect modification. The study was conducted in the general community. 2746 community-dwelling participants (age ≥ 45 years) from the Rotterdam Study were included. Serum 25(OH)D3 inversely associated with SAF and explained 1.5% of the variance (unstandardized B = − 0.002 (95% CI[− 0.003, − 0.002]), standardized β = − 0.125), independently of known risk fa

Serum phosphate levels are related to all-cause, cardiovascular and COPD mortality in men

Hyperphosphatemia has been associated with increased mortality in chronic kidney disease but the nature of such a relation in the general population is unclear. To investigate the association between phosphate (P) levels and all-cause and cause-specific mortality, we assessed two cohorts from the Rotterdam Study, with follow-up of 14.5 (RS-I) and 10.9 (RS-II) years until January 2012 with availability of fasting phosphate levels. Deaths were classified according to International Classification of Diseases into 7 groups: cardiovascular, cancer, infections, external, dementia, chronic lung diseases and other causes. Sex-stratified Weibull and competing-risks models were adjusted for age, BMI and smoking. Hazard ratios are expressed per 1 mg/dL increase in phosphate levels. The total number of participants included 3731 (RS-I, 2154 women) and 2494 (RS-II, 1361 women) subjects. The main outcome measures were all-cause and cause-specific mortality. A significant positive association was found between phosphate and all-cause mortality in men (pooled HR (95% CI): 1.46 (1.26–1.69)) but not in women (0.90 (0.77–1.05)). In men, higher phosphate increased the risk for cardiovascular mortality (1.66 (1.29–2.14)), other causes (1.67 (1.16–2.40)) and chronic lung disease mortality (1.94 (1.02–3.72)), the latter driven by mortality due to chronic obstructive pulmonary disease (COPD) (4.44 (2.08–9.49)). No relations were found for mortality due to infections, cancer, dementia or external causes. In conclusion, serum P is associated with increased all-cause, cardiovascular and COPD mortality in men but not women. The association with COPD mortality is novel and needs further research on underlying mechanisms

Dietary vitamin A intake and bone health in the elderly: the Rotterdam Study

BACKGROUND/OBJECTIVES: High vitamin A intake may be associated with a decreased bone mineral density (BMD) and increased risk of fractures. Our objectives were to study whether dietary intake of vitamin A (total, retinol or beta-carotene) is associated with BMD and fracture risk and if associations are modified by body mass index (BMI) and vitamin D. SUBJECTS/METHODS: Participants were aged 55 years and older (n = 5288) from the Rotterdam Study, a population-based prospective cohort. Baseline vitamin A and D intake was measured by a food frequency questionnaire. BMD was measured by dual-energy X-ray absorptiometry at four visits between baseline (1989-1993) and 2004. Serum vitamin D was assessed in a subgroup (n = 3161). Fracture incidence data were derived from medical records with a mean follow-up time of 13.9 years. RESULTS: Median intake of vitamin A ranged from 684 retinol equivalents (REs)/day (quintile 1) to 2000 REs/day (quintile 5). After adjustment for confounders related to lifestyle and socioeconomic status, BMD was significantly higher in subjects in the highest quintile of total vitamin A (mean difference in BMD (95% confidence interval (CI)) = 11.53 (0.37-22.7) mg/cm(2)) and retinol intake (mean difference in BMD (95% CI) = 12.57 (1.10-24.05) mg/cm(2)) than in the middle quintile. Additional adjustment for BMI diluted these associations. Fracture risk was reduced in these subjects. Significant interaction was present between intake of retinol and overweight (BMI >25 kg/m(2)) in relation to fractures (P for interaction = 0.05), but not BMD. Stratified analysis showed that these favourable associations with fracture risk were only present in overweight subjects (BMI >25 kg/m(2)). No effect modification by vitamin D intake or serum levels was observed. CONCLUSIONS: Our results suggest a plausible favourable relation between high vitamin A intake from the diet and fracture risk in overweight subjects, whereas the association between vitamin A and BMD is mainly explained by BMI

Bone health and coronary artery calcification: The Rotterdam Study

Objectives: Vascular calcification has been associated inconsistently to low bone mineral density and fractures. The aims of the present study were to investigate the associations between coronary artery calcification (CAC) and BMD change, BMD and fracture risk in elderly subjects of the population-based Rotterdam Study. Methods: BMD was assessed through dual-energy X-ray absorptiometry and CAC through Electron-Beam Computed Tomography in 582 men and 694 women. We investigated the associations between BMD change (6.4 years follow-up) and CAC at follow-up and between BMD and CAC (measured simultaneously). In sensitivity analyses we stratified analyses for estradiol levels in women. The association between CAC and fracture risk (9 years follow-up) was tested through competing-risks models. Models were sex-stratified and adjusted for age, body mass index, smoking, bisphosphonate use and age at menopause. Results: There was no association between BMD change and CAC in men. In women, each 1% increase in annual BMD loss was significantly associated with higher follow-up CAC [beta = 0.22 (0.06-0.38), p = 0.006; prevalence ratio: 4%]. Stratified analyses showed significant associations between BMD loss and follow-up CAC only in women with lower estradiol levels. We found no association between CAC and fracture risk and no association between BMD and CAC cross-sectionally. Conclusions: BMD loss was associated with higher follow-up CAC in women, which might be related to low estrogen levels. No association between CAC and BMD or fracture risk was found. Further studies are required to elucidate the mechanisms that might underlie the association between BMD change and coronary calcification in women. (C) 2015 Elsevier Ireland Ltd. All rights reserved