0.79 $4 cups 2,041 202,877 10.1 0.87 0.91 447 211,106 2.1 0.85 0.89 CI: self-confidence interval, HR: hazard ratio. a Covariates integrated were: 1485-00-3 web intake of total energy, calcium, retinol, vitamin D, potassium, phosphorus, protein, alcohol, physique mass index, height, physical activity , intake of any vitamins, cortisone use, educational level, smoking status, prior fractures and Charlson’s 374913-63-0 chemical information comorbidity index. doi:10.1371/journal.pone.0097770.t002 of few fractures, that the only exposure viewed as was caffeine as a pooled estimate, i.e. the exposure calculation integrated not simply coffee, or that coffee consumption was considered as any vs. no consumption. The present study exceeds by far the total number of hip fractures in preceding cohort studies as well as had the possibility to study a large quantity of fractures of any kind. Strengths and Limitations One of the most critical strengths of our study is that we had the chance to collect information from a big population-based cohort of middle-aged and elderly guys during a mean follow-up of 11.3 years. Such a follow-up is sufficiently extended to observe an sufficient number of fractures. Simply because all fractures were identified by the usage of registers, we think that the danger of not possessing detected men using a fracture for the duration of follow-up is tiny. There was considerable variation in consumption of coffee within this cohort having a massive quantity of participants consuming high amounts of coffee, which improves the chances of detecting associations. In this context it should really be noted that the consumption of decaffeinated coffee is very low in Sweden . Moreover, we did not concentrate on intake of caffeine, but on consumption of coffee, which may be yet another benefit in that a number of studies have indicated that tea could possess a good influence on BMD and fracture danger, likely since of the fluoride, phytoestrogen or antioxidant content material of tea. Ultimately, it should really be achievable to generalise our final results to all males in Sweden because the participants effectively represent the Tunicamycin web source population. We also acknowledge a number of possible limitations. Simply because this investigation is primarily based on data from 1 single FFQ, some degree of error inside the exposure measurement cannot be excluded. Attenuation of a accurate KDM5A-IN-1 site association is most likely in that the potentially resulting misclassification likely will be non-differential. Fractures associated with higher trauma were not excluded for the reason that a comparable enhanced risk of both low- and high-trauma fracture with decreasing bone density inside the elderly has been indicated. However, there has been discourse as to irrespective of whether inclusion of both higher and low influence fractures will result in a lower danger estimate compared with low trauma fractures only. Despite controlling for known significant risk components for fractures, like comorbidity, it is actually nevertheless probable that residual confounding could have influenced the results of this study. As an example, we couldn’t adjust for vitamin D status or sunlight exposure in the present study. Even so, we’ve got previously shown that the impact of coffee intake on BMD was not stronger amongst girls with low vitamin D status. The importance on the dietary source of protein on the association amongst coffee consumption and fracture couldn’t be assessed in the present study. There is certainly to date no consensus around the relation between dietary protein and fracture risk but current systematic testimonials and meta-analyses suggest that the postulated dietary acidic load exaggerated by protein intak.0.79 $4 cups 2,041 202,877 ten.1 0.87 0.91 447 211,106 2.1 0.85 0.89 CI: self-confidence interval, HR: hazard ratio. a Covariates included have been: intake of total energy, calcium, retinol, vitamin D, potassium, phosphorus, protein, alcohol, body mass index, height, physical activity , intake of any vitamins, cortisone use, educational level, smoking status, previous fractures and Charlson’s comorbidity index. doi:ten.1371/journal.pone.0097770.t002 of handful of fractures, that the only exposure regarded as was caffeine as a pooled estimate, i.e. the exposure calculation included not merely coffee, or that coffee consumption was regarded as as any vs. no consumption. The present study exceeds by far the total quantity of hip fractures in earlier cohort research as well as had the possibility to study a large number of fractures of any sort. Strengths and Limitations Certainly one of one of the most essential strengths of our study is the fact that we had the opportunity to gather data from a sizable population-based cohort of middle-aged and elderly guys through a imply follow-up of 11.3 years. Such a follow-up is sufficiently long to observe an adequate number of fractures. Since all fractures were identified by the usage of registers, we believe that the danger of not having detected guys with a fracture throughout follow-up is little. There was considerable variation in consumption of coffee in this cohort having a big variety of participants consuming high amounts of coffee, which improves the probabilities of detecting associations. In this context it need to be noted that the consumption of decaffeinated coffee is extremely low in Sweden . Moreover, we did not concentrate on intake of caffeine, but on consumption of coffee, which might be an additional advantage in that various studies have indicated that tea could possess a positive influence on BMD and fracture risk, likely simply because of the fluoride, phytoestrogen or antioxidant content material of tea. Finally, it need to be achievable to generalise our outcomes to all men in Sweden due to the fact the participants nicely represent the supply population. We also acknowledge numerous prospective limitations. For the reason that this investigation is primarily based on data from one single FFQ, some degree of error within the exposure measurement can’t be excluded. Attenuation of a correct association is likely in that the potentially resulting misclassification most likely would be non-differential. Fractures connected with higher trauma were not excluded mainly because a comparable increased threat of each low- and high-trauma fracture with decreasing bone density within the elderly has been indicated. Even so, there has been discourse as to no matter whether inclusion of each higher and low influence fractures will result in a reduce threat estimate compared with low trauma fractures only. Despite controlling for known main danger variables for fractures, such as comorbidity, it is actually still possible that residual confounding could have influenced the outcomes of this study. For example, we could not adjust for vitamin D status or sunlight exposure inside the present study. Even so, we’ve got previously shown that the impact of coffee intake on BMD was not stronger among females with low vitamin D status. The significance of the dietary supply of protein on the association between coffee consumption and fracture couldn’t be assessed in the present study. There’s to date no consensus on the relation in between dietary protein and fracture threat but recent systematic evaluations and meta-analyses suggest that the postulated dietary acidic load exaggerated by protein intak.