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Hatlen, P., Langhammer, A., Forsmo, S., Carlsen, S. M., & Amundsen, T. (2013). Bone mass density, fracture history, self-reported osteoporosis as proxy variables for estrogen and the risk of non-small-cell lung cancer--a population based cohort study, the HUNT study: are proxy variables friends or faults? Lung Cancer, 81(1), 39–46.
Abstract: Lung cancer has the highest mortality of all cancers. Patients with early stage disease have the best cure rates and that emphasizes the importance of early detection. About half of all non-small cell lung cancers (NSCLC) are estrogen receptor positive. The impact of estrogen and its receptors for NSCLC carcinogenesis has been studied but is still unclear. Low estrogen levels are associated with osteoporosis. We hypothesize that low bone mineral density (BMD), a positive history of fracture or self-reported osteoporosis, used as a proxy variable for life time estrogen exposure, are associated with a low incidence of NSCLC. We analyzed data from a cohort study, the Nord-Trondelag Health Study 2 (1995-1997) linked to the Norwegian Cancer Registry. Using the logistic regression model we calculated the odds ratio (OR) with a 95% confidence interval (CI) for the risk of NSCLC for the three proxy variables, stratified by sex. Participants older than 50 years of age, having measured bone density (N = 18,156), having answered the questions on self-reported fracture (N = 37,883) and osteoporosis (N = 25,701) and known body mass index (BMI) (N = 29,291), were evaluated for inclusion. In 6996 participants all these information was available in addition to tobacco use, and in women also hormonal replacement therapy (HRT). Lung function (FEV1 percent of predicted) was included in a sensitivity analysis. We identified 132 (1.9%) cases of NSCLC, 59 (1.2%) and 73 (3.3%) cases in women and men, respectively. Low BMD was associated with a higher risk of NSCLC, OR: 2.38, 95% CI: 1.09-5.18 and OR: 2.67, 95% CI: 1.39-5.16 in women and men, respectively. No association was found between the two other proxy variables and the risk of NSCLC. Inclusion of lung function in the model did not change the results. Contrary to our hypothesis, women and men with low BMD had a higher risk for NSCLC. In addition the study demonstrates that the risk depends on which proxy variable was chosen, and we may ask: are proxy variables reliable?