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Background: Bone mineral density (BMD) is determined by bone remodeling processes regulated by endocrine, autocrine and genetic mechanisms. Thus, some studies have reported that BMD is associated with single nucleotide polymorphisms (SNPs) associated with vitamin D receptor (VDR), serum 25(OH)D levels and estrogen receptor 1 (ESR1), but without consensus. Therefore, we aimed to map and compare the risk genotypes for forearm and total hip low BMD., Methods and Findings: Data were derived from a population-based study in northern Norway; the Tromsø Study. Distal forearm BMD was measured with a single x-ray absorptiometric device, while total hip BMD was measured with a dual-energy x-ray absorptiometric device. There were 7,317 and 4,082 successful analyses of distal forearm and total hip BMD, respectively, and at least one SNP of interest. We evaluated plausible BMD modulating factors and associations of BMD and SNPs related to vitamin D metabolism (FokI, Cdx2, BsmI, rs2298850, rs10741657, rs3794060, rs6013897), ApaI-BsmI-TaqI haplotypes and ESR1 SNP rs4870044., Results: Age, BMI, physical activity and smoking were significantly associated with BMD. In a linear regression model with adjustment for age and gender and with the major homozygote as reference, rs6013897 had a standardized beta coefficient (β) of -0.031 (P = 0.024) for total hip BMD. β for ESR1 SNP rs4870044 was -0.016 (P = 0.036) for forearm BMD and -0.034 (P = 0.015) for total hip BMD. The other SNPs nor serum 25(OH)D were significantly associated with BMD., Conclusions: Both forearm and total hip BMD were associated with ESR1 SNP rs4870044. Of the vitamin D-related genes, only CYP24A1 gene rs6013897 was associated with total hip BMD, but the association was weak and needs confirmation in other studies. Serum 25(OH)D was not associated with BMD in our population, probably due to the generally sufficient vitamin D levels in the population.

Background: Though the associations between low serum 25-hydroxyvitamin D (25(OH)D) levels and health outcomes such as type 2 diabetes (T2D), myocardial infarction (MI), cancer, and mortality are well-studied, the effect of supplementation with vitamin D is uncertain. This may be related to genetic differences. Thus, rs7968585, a single nucleotide polymorphism (SNP) of the vitamin D receptor (VDR), has recently been reported as a predictor of composite health outcome. We therefore aimed to evaluate whether rs7968585 predicts separate clinical outcomes such as T2D, MI, cancer, and mortality in a community-based Norwegian population., Methods and Findings: Measurements and DNA were obtained from the participants in the Tromsø Study in 1994-1995, registered with the outcomes of interest and a randomly selected control group. The impact of the rs7968585 genotypes was evaluated with Cox proportional hazards. A total of 8,461 subjects were included among whom 1,054 subjects were registered with T2D, 2,287 with MI, 3,166 with cancer, and 4,336 with death. Mean follow-up time from birth was 60.8 years for T2D and MI, 61.2 years for cancer, while mean follow-up time from examination date was 16.5 years for survival. Mean serum 25(OH)D levels did not differ across the rs7968585 genotypes. With the major homozygote genotype as reference, the minor homozygote subjects had hazard ratios of 1.25 (95% CI 1.05-1.49) for T2D and 1.14 (1.02-1.28) for MI (P = 0.011 and 0.023, respectively, without the Bonferroni correction). No significant interaction between serum 25(OH)D status and the rs7968585 genotype was found for any of the endpoints., Conclusions: The VDR-related SNP rs7968585 minor allele is a significant and positive predictor for T2D and possibly for MI. Since the functional mechanism of this SNP is not yet understood, and the association with T2D is reported for the first time, confirmatory studies are needed.

Low-grade inflammation is associated with fractures, while the relationship between inflammation and bone mineral density (BMD) is less clear. Moreover, any gender differences in the sensitivity to inflammation are still poorly elucidated. We therefore tested the hypothesis that high-sensitivity C-reactive protein (CRP) is an independent risk factor for low BMD and non-vertebral fractures, in both genders, and whether there are gender differences in these associations. CRP levels and BMD at the total hip and femoral neck were measured in 1902 women and 1648 men between 55 and 74 years of age, at baseline in the Tromsø Study, Norway, in 2001-2002. Non-vertebral fractures were registered from hospital X-ray archives during an average of 7.2 years follow-up. Linear regression analyses were used for CRP association with BMD and Cox proportional hazards model for fracture prediction by CRP. During 25 595 person-years follow-up, 366 (19%) women and 126 (8%) men suffered a non-vertebral fracture. There was no association between CRP and BMD in women, but an inverse association in men (p=0.001) after adjustment for age and body mass index. Each standard deviation (SD) increase in log-CRP was associated with an increased risk for non-vertebral fracture by 13% in women and 22% in men (hazard ratios (HRs) 1.13, 95% confidence interval (CI) 1.02-1.26, p=0.026 and 1.22, 95% CI=1.00-1.48, p=0.046, respectively). After adjustment for BMD and other risk factors, women with CRP in the upper tertile exhibited 39% higher risk for fracture than those in the lowest tertile of CRP (HR = 1.39, 95% CI = 1.06-1.83, p = 0.017), while men in the upper tertile exhibited 80% higher risk (HR=1.80, 95% CI=1.10-2.94, p=0.019). In summary, CRP was not associated with BMD in women but inversely associated in men, and predicted fractures in both genders. We infer that inflammation influence fracture risk in both women and men, although the biological mechanisms may differ between the genders., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: The efficacy of curative irradiation in the treatment of non-small-cell lung cancer patients is considered limited. The purpose of this study was to evaluate long-term survival in a population-based approach., Methods and Materials: Cases of non-small-cell lung cancer diagnosed from 1993 to 2001 were identified in the Cancer Registry of Norway. Electronic linkage with national data from the hospitals' radiotherapy verification systems identified those who received potentially curative doses (≥ 50 Gy). Hospital records were reviewed for all patients., Results: A total of 497 patients (336 men) were identified with a radiation dose of ≥ 50 Gy delivered to the lung region. Of these, 41% received 60 Gy or more. The majority (70%) of patients included had advanced stage disease: 24% Stage IIIA and 46% Stage IIIB. The overall 1-, 3-, and 5-year observed survival rates were 53%, 16%, and 9%, respectively. Multivariable analyses identified stage and chemotherapy, but not radiation dose, as significant independent prognostic variables for survival. However, 68% of patients treated with chemotherapy participated in prospective studies with inclusion criteria that excluded patients with less favorable prognostic factors, leading to a selection bias. The number of fractions and the radiation doses varied widely among different hospitals., Conclusion: The long-term prognosis after radiation therapy is poor. More sophisticated, targeted, and uniform delivery of radiation therapy is needed. The apparent benefit of chemotherapy may in part be due to selection of patients with more favorable prognostic factors for this therapy., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Some studies suggest that raised blood pressure may increase prostate cancer risk. We investigated associations of blood pressure with prostate cancer within the CONOR collaborative cohorts of Norway., Methods: Between 1994 and 2003, 82,098 men from ten population-based cohorts in Norway completed standardised questionnaires and physical examinations, including resting blood pressure. The unique 11-digit identification number of Norwegian citizens allowed linkage with the Cancer Registry of Norway., Results: A total of 78,768 (96%) men who were cancer-free at baseline and average age of 50.3 years (standard deviation, SD: 15.2) were followed up for a mean of 9.15 years. 11.4% of these men used antihypertensive drugs at baseline. During follow-up (1994-2006), 1,974 incident prostate cancers were diagnosed. We found a 4% (95% confidence interval, CI = 0-9%) increased risk of prostate cancer per one SD (18.3 mmHg) increase in systolic blood pressure and similar findings for diastolic blood pressure (hazard ratio, HR: 1.05 per SD; 95% CI = 1.01-1.10). The association was stronger for advanced (HR: 1.16 per SD increase in systolic blood pressure; 95% CI = 1.05-1.27) compared with localised (1.01; 0.95-1.08) prostate cancer (p for heterogeneity in hazard ratios = 0.02)., Conclusions: Raised blood pressure was associated with an increased risk of prostate cancer, particularly advanced cancers at diagnosis. Understanding the mechanisms underlying these findings may provide biological insights into prostate carcinogenesis. Even if the association was causal, our data suggest that raised blood pressure would account for only 3% of prostate cancers, so the public health impact of this association may be limited.

Background: Hyperthyroidism is associated with osteoporosis, and it has recently been suggested that thyroid-stimulating hormone (TSH) has bone protective properties. We wanted to explore the relationship between serum TSH and bone mineral density (BMD) in a healthy population., Methods: This study included 993 postmenopausal females and 968 males with valid measurements of BMD at the hip and forearm in the fifth Tromsø study conducted in 2001. Participants with major diseases or medication affecting BMD or thyroid function were excluded. The subjects were divided into six different groups based on the 2.5 and 97.5 percentiles of serum TSH and the quartiles in between. Multiple linear regression adjusting for age; weight; height; smoking status; physical activity level; and for women, use of hormonal replacement therapy was used in the analyses., Results: After multivariate adjustment, the 28 men and 18 women with serum TSH below the 2.5 percentile had significantly lower BMD at the ultradistal (women) and distal (both sexes) forearm than the 921 men and 950 women with serum TSH in the normal range. Also, the 25 postmenopausal women with serum TSH above the 97.5 percentile had significantly higher BMD at the femoral neck than women with serum TSH in the normal range. Across the normal range of serum TSH, there was no association between TSH and BMD, and serum TSH as a continuous variable had no effect on BMD in the multiple linear regression model., Conclusions: Within the normal range of serum TSH, serum TSH was not associated with BMD. The small groups of men and women with serum TSH consistent with hyperthyroidism had lower BMD at the forearm than those with serum TSH in the normal range.

Screening for early prostate cancer is frequently employed in the routine management of men with lower urinary tract symptoms (LUTS), but the evidence-base linking LUTS with prostate cancer is limited. We assessed the association of LUTS with a subsequent prostate cancer diagnosis in a prospective cohort study based on 21,159 Norwegian men who completed baseline questionnaires, including the International Prostate Symptom Score (IPSS) questionnaire, between 1995 and 2007 as part of the second Nord-Trøndelag Health Study (HUNT 2). Men were followed-up for prostate cancer incidence and mortality from the date of clinical examination to end 2005. During a mean of 9 years follow-up, 518 incident prostate cancers were diagnosed and 74 men died from prostate cancer. Men with severe LUTS (IPSS 20-35) had a 2.26-fold (95% CI: 1.49-3.42) increased risk of prostate cancer compared to men reporting no symptoms. A positive association was observed for localized (hazard ratio, HR: 4.61; 2.23-9.54), but not advanced (HR: 0.51; 0.15-1.75), cancers (p for heterogeneity <0.001). There was no evidence that moderate/severe symptoms (IPSS 8-35) were associated with prostate cancer mortality (HR: 0.83; 0.42-1.64) vs. no symptoms. Amongst 518 men with prostate cancer, there was a 46% lower (10-68%) risk of death with moderate/severe symptoms vs. no symptoms. We conclude that LUTS are positively associated with localized, but not advanced or fatal, prostate cancer, suggesting that urinary symptoms are not caused by prostate cancer. Thus, screening for early cancers on the basis of LUTS may not be justified.

Objective: To explore the relation between serum parathyroid hormone (PTH) and bone mineral density (BMD), adjusted for lifestyle factors including smoking., Design: Cross-sectional study., Methods: The Tromsø Study is a population-based study performed for the fifth time in 2001. Serum PTH was measured and the subjects filled in a questionnaire covering lifestyle factors. BMD at the hip, distal and ultradistal forearm was measured., Results: Complete datasets were available in 1442 men and 1368 women. Age, body mass index and serum PTH were strong predictors of BMD level at the hip in both genders. No significant relation was seen between serum PTH and BMD at the distal or ultradistal forearm. When smokers and non-smokers were analysed separately, the relation between PTH and BMD at the hip was significant in current non-smokers only. In males, current non-smokers had significantly higher BMD at all three measurement sites compared with current smokers. Male former smokers had values in between current and never smokers. There was a significant and negative relation between number of years smoked and BMD at the hip. In male former smokers, there was an increase in BMD with increasing years since smoking cessation., Conclusion: Serum PTH is negatively associated with BMD at the hip, and the relation seems to be masked, or diminished, by smoking. Smoking reduces BMD at the hip, distal and ultradistal forearm in males, and the effect appears to be mainly time and not dose dependent.