(n=6279). Continuous variables are reported as mean with 95% confidence interval and T1 T2 T3. Number of subjects
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1 Table 1. Distribution of baseline characteristics across tertiles of OPG adjusted for age and sex (n=6279). Continuous variables are reported as mean with 95% confidence interval and categorical values as percentage. The Tromsø Study ( ) OPG tertiles T1 T2 T ng/ml ng/ml ng/ml p (trend) Number of subjects Age (years)* 53.6 ( ) 61.5 ( ) 66.7 ( ) <0.001 Sex (% men) <0.001 Never smoking (%) Former smoker (%) Current smoker (%) Body mass index (kg/m 2 ) 26.4 ( ) 26.1 ( ) 25.6 ( ) <0.001 Systolic BP (mm Hg) 142 ( ) 144 ( ) 149 ( ) <0.001 Diastolic BP (mm Hg) 82 (82-83) 83 (83-84) 84 (84-85) <0.001 Total cholesterol (mmol/l) 6.63 ( ) 6.81 ( ) 6.73 ( ) HDL cholesterol (mmol/l) 1.48 ( ) 1.53 ( ) 1.57 ( ) <0.001 Triglycerides (mmol/l) 1.67 ( ) 1.62 ( ) 1.59 ( ) HbA1c (%) 5.40 ( ) 5.45 ( ) 5.56 ( ) <0.001 C-reactive protein (mg/l) 2.26 ( ) 2.52 ( ) 3.13 ( ) <0.001 Creatinine (µmol/l) 78.7 ( ) 77.7 ( ) 79.6 ( ) DM or HbA1c>6.1 (%) <0.001 DM (selfreported) (%) <
2 *Adjusted for sex adjusted for age. BP = Blood pressure; DM = Diabetes Mellitus 8 % missing, all other variables complete or <1% missing. 2
3 Table 2. Organ distribution (numbers with percentages in brackets) of incident cancer (n=948) in the total population (n=6279). The Tromsø Study ( ) N % OPG tertiles T1 T2 T3 Gastrointestinal system 276 (29.1) Respiratory system 167 (17.6) Breast 76 (8.0) Female genital organs 43 (4.5) Prostate gland 178 (18.8) Urinary system 83 (8.8) Miscellaneous* 125 (13.2) *(peritoneum, connective tissue, thyroid, hematopoietic, unknown primary site) 3
4 Table 3. Hazard ratios (HR) with 95% confidence intervals (CI) for incident cancer across tertiles of osteoprotegerin (OPG) and per 1 standard deviation (SD) increase in OPG levels. The Tromsø Study ( ) (n) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) (n=6279) (n=6279) (n=5717) (n=5717) T T ( ) 1.14 ( ) 1.08 ( ) 1.08 ( ) T ( ) 1.13 ( ) 1.04 ( ) 1.05 ( ) P (trend) < Per 1 SD ( ) 1.06 ( ) 1.02 ( ) 1.03 ( ) Women n=3174 n=3174 n=2899 n=2899 T T ( ) 0.78 ( ) 0.72 ( ) 0.72 ( ) T ( ) 0.90 ( ) 0.85 ( ) 0.85 ( ) P (trend) Per 1 SD ( ) 1.01 ( ) 0.98 ( ) 0.98 ( ) Men n=3105 n=3105 n=2818 n=2818 T T ( ) 1.20 ( ) 1.17 ( ) 1.17 ( ) T ( ) 1.25 ( ) 1.18 ( ) 1.19 ( ) P (trend) < Per 1 SD ( ) 1.10 ( ) 1.06 ( ) 1.07 ( ) 1 SD OPG: total population 1.12 mg/ml, women 1.06 mg/ml, men 1.17 mg/ml Model 1: Adjusted for age (and sex) Model 2; Adjusted for age, (sex), smoking, systolic blood pressure, BMI, HDL cholesterol, CRP and diabetes mellitus or HbA1c >6.1 % Model 3; As model 1 + ischemic stroke and/or myocardial infarction before baseline Number of events in model 2 and 3: total population n=869, women n=343, men n=526 4
5 Table 4. Hazard ratios (HR) with 95% confidence intervals (CI) for incident cancer across tertiles of osteoprotegerin (OPG) and per 1 standard deviation (SD) increase in OPG levels. The Tromsø Study ( ). HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Gastrointestinal * n=6279 n=6279 n=5717 n=5717 T T ( ) 1.29 ( ) 1.36 ( ) 1.36 ( ) T ( ) 1.75 ( ) 1.77 ( ) 1.79 ( ) P (trend) < Per 1 SD ( ) 1.15 ( ) 1.14 ( ) 1.15 ( ) Respiratory n=6279 n=6279 n=5717 n=5717 T T ( ) 1.13 ( ) 0.99 ( ) 0.99 ( ) T ( ) 0.98 ( ) 0.89 ( ) 0.89 ( ) P (trend) Per 1 SD ( ) 1.09 ( ) 1.09 ( ) 1.09 ( ) Breast (women) n=3174 n=3174 n=2899 n=2899 T T ( ) 0.70 ( ) 0.68 ( ) 0.68 ( ) T ( ) 0.52 ( ) 0.54 ( ) 0.55 ( ) P (trend) Per 1 SD ( ) 0.72 ( ) 0.73 ( ) 0.74 ( ) Prostatic n=3105 n=3105 n=2818 n=2818 T T ( ) 1.32 ( ) 1.23 ( ) 1.23 ( ) T ( ) 0.97 ( ) 0.85 ( ) 0.86 ( ) P (trend) Per 1 SD ( ) 0.85 ( ) 0.82 ( ) 0.82 ( ) Genital (women) n=3174 n=3174 n=2899 n=2899 T T ( ) 0.33 ( ) 0.19 ( ) 0.19 ( ) T ( ) 0.64 ( ) 0.46 ( ) 0.47 ( ) P (trend) Per 1 SD ( ) 0.94 ( ) 0.85 ( ) 0.86 ( ) Urinary tract n=6279 n=6279 n=5717 n=5717 T T ( ) 1.34 ( ) 1.20 ( ) 1.20 ( ) T ( ) 1.16 ( ) 0.91 ( ) 0.91 ( ) P (trend) Per 1 SD ( ) 1.17 ( ) 1.10 ( ) 1.10 ( ) 5
6 1 SD OPG; total population 1.12 ng/ml, women 1.06 ng/ml, men 1.17 ng/ml Model 1: adjusted for age (and sex) Model 2: Adjusted for age, (sex), smoking, BMI, systolic blood pressure, HDL cholesterol, CRP diabetes mellitus or HbA1c >6.1 % Model 3: As model 1 + ischemic stroke and/or myocardial infarction before baseline Number of events model 2 and 3: * n=252, n= 158, n=72, n=165, n=37, n=74 6
7 Table 5. Hazard ratios with 95% confidence intervals (HR, 95% CI) of death of cancer calculated for OPG tertile groups and per SD (1.12 ng/ml) increase in OPG levels (n=6279). The Tromsø Study ( ). (n) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) All cancers * n=6279 n=6279 n=5717 n=5717 T T ( ) 1.40 ( ) 1.33 ( ) 1.33 ( ) T ( ) 1.77 ( ) 1.61 ( ) 1.63 ( ) P (trend) <0.001 < Per 1 SD ( ) 1.24 ( ) 1.24 ( ) 1.25 ( ) Gastrointestinal n=6279 n=6279 n=5717 n=5717 T T ( ) 1.70 ( ) 1.77 ( ) 1.77 ( ) T ( ) 2.21 ( ) 2.23 ( ) 2.28 ( ) P (trend) < Per 1 SD ( ) 1.22 ( ) 1.24 ( ) 1.26 ( ) Respiratory n=6279 n=6279 n=5717 n=5717 T T ( ) 1.10 ( ) 1.03 ( ) 1.03 ( ) T ( ) 1.14 ( ) 1.09 ( ) 1.09 ( ) P (trend) Per 1 SD ( ) 1.18 ( ) 1.21 ( ) 1.21 ( ) Model 1: adjusted for age (and sex) Model 2: Adjusted for age, sex, smoking, BMI, systolic blood pressure, HDL cholesterol, CRP, diabetes mellitus or HbA1c >6.1 % Model 3: As model 1 + ischemic stroke and/or myocardial infarction before baseline Number of events model 2 and 3: * n=352, n= 118, n=103 7
8 Appendix table 1. Age- and sex-stratified hazard ratios (HR) with 95% confidence intervals (CI) for incident cancer across OPG tertile groups and per SD increase in OPG levels. The Tromsø Study ( ). HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Women < 60 yrs n=1264 n= 1264 n=1146 n=1146 T T ( ) 0.60 ( ) 0.53 ( ) 0.53 ( ) T ( ) 0.59 ( ) 0.45 ( ) 0.44 ( ) P (trend) Per 1SD ( ) 0.86 ( ) 0.75 ( ) 0.73 ( ) Women 60 yrs n=1910 n=1910 n=1753 n=1753 T T ( ) 1.05 ( ) 1.03 ( ) 1.03 ( ) T ( ) 1.21 ( ) 1.26 ( ) 1.27 ( ) P (trend) Per 1 SD ( ) 1.08 ( ) 1.06 ( ) 1.07 ( ) Men < 60 yrs n=1390 n=1390 n=1246 n=1246 T T ( ) 1.02 ( ) 1.03 ( ) 1.03 ( ) T ( ) 1.64 ( ) 1.48 ( ) 1.48 ( ) P (trend) < Per 1 SD ( ) 1.18 ( ) 1.10 ( ) 1.10 ( ) Men 60yrs n=1715 n=1715 n=1572 n=1572 1: : ( ) 1.14 ( ) 1.11 ( ) 1.11 ( ) 3: ( ) 1.25 ( ) 1.24 ( ) 1.25 ( ) P (trend) Per 1 SD ( ) 1.11 ( ) 1.09 ( ) 1.09 ( ) 1 SD OPG: Men; < 60 years; 0.99 ng/ml, 60 years 1.14 ng/ml, women; < 60 years 0.81 ng/ml, 60 years 1.03 ng/ml Model 1: Adjusted for age 8
9 Model 2: Adjusted for age, smoking, systolic blood pressure, BMI, HDL cholesterol, CRP diabetes mellitus or HbA1c >6.1 % Model 3: As model 1 + ischemic stroke and/or myocardial infarction before baseline Number of events in model 2 and 3: women: < 60 yrs n=94, 60 yrs n=249, men < 60 yrs n=153, 60 yrs n=373 9
10 Appendix table 2. Age stratified hazard ratios (HR) with 95% confidence intervals (CI) for incident breast cancer and gastrointestinal cancer across tertiles of osteoprotegerin (OPG) and per 1 standard deviation (SD)* increase in OPG levels. The Tromsø Study ( ). (n) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Breast (women) < 60 years n=1264 n=1264 n=1146 T T ( ) 0.28 ( ) 0.23 ( ) T ( ) 0.29 ( ) 0.24 ( ) P (trend) Per 1 SD ( ) 0.55 ( ) 0.51 ( ) Breast (women) 60 years n=1910 n=1910 n=1753 n=1753 T T ( ) 0.88 ( ) 0.90 ( ) 0.91 ( ) T ( ) 0.98 ( ) 1.10 ( ) 1.10 ( ) P (trend) Per 1 SD ( ) 0.93 ( ) 0.96 ( ) 0.96 ( ) Gastrointestinal < 60 years n=2654 n=2654 n=2392 n=2392 T T ( ) 0.64 ( ) 0.74 ( ) 0.74 ( ) T ( ) 1.39 ( ) 1.44 ( ) 1.44 ( ) P (trend) Per 1 SD ( ) 1.15 ( ) 1.08 ( ) 1.09 ( ) P value Gastrointestinal 60 years n=3625 n=3625 n=3325 n=3325 T T ( ) 1.20 ( ) 1.20 ( ) 1.20 ( ) T ( ) 1.63 ( ) 1.67 ( ) 1.68 ( ) P (trend) < Per 1 SD ( ) 1.16 ( ) 1.16 ( ) 1.17 ( ) *1 SD OPG; total population; < 60 years 0.91 ng/ml, 60 years 1.09 ng/ml, women < 60 years 0.81 ng/ml, women, 60 years 1.03 ng/ml Model 1: adjusted for age (and sex) Model 2: Adjusted for age, (sex), smoking, BMI, systolic blood pressure, HDL cholesterol, CRP, diabetes mellitus or HbA1c >6.1 % Model 3: As model 1 + ischemic stroke and/or myocardial infarction before baseline Number of events model 2 and 3: n=30, n= 42, n=57, n=195 10
11 Appendix table 3. Hazard ratios with 95% confidence intervals (HR, 95% CI) of death of cancer calculated for OPG tertile groups and per SD (women; 1.06 ng/ml, men; 1.17 ng/ml) increase in OPG levels in women (n=3174) and men (n=3105). The Tromsø Study ( ). (n) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) Women All cancers * n=3174 n=3174 n=2899 n=2899 T T ( ) 0.70 ( ) 0.67 ( ) 0.67 ( ) T ( ) 1.11 ( ) 1.07 ( ) 1.07 ( ) P (trend) < Per 1 SD ( ) 1.21 ( ) 1.18 ( ) 1.19 ( ) Gastrointestinal n=3174 n=3174 n=2899 n=2899 T T ( ) 0.93 ( ) 0.93 ( ) 0.94 ( ) T ( ) 1.72 ( ) 1.96 ( ) 1.97 ( ) P (trend) < Per 1 SD ( ) 1.30 ( ) 1.37 ( ) 1.39 ( ) Men All cancers * n=3105 n=3105 n=2818 n=2818 T T ( ) 1.34 ( ) 1.35 ( ) 1.35 ( ) T ( ) 1.66 ( ) 1.55 ( ) 1.57 ( ) P (trend) < Per 1 SD ( ) 1.26 ( ) 1.28 ( ) 1.28 ( ) Gastrointestinal n=3105 n=3105 n=2818 n=2818 T T ( ) 1.39 ( ) 1.45 ( ) 1.47 ( ) T ( ) 1.23 ( ) 1.15 ( ) 1.19 ( ) P (trend) < Per 1 SD ( ) 1.16 ( ) 1.13 ( ) 1.13 ( ) Model 1: adjusted for age Model 2: Adjusted for age, smoking, BMI, systolic blood pressure, total cholesterol, CRP diabetes mellitus or HbA1c >6.1 % Model 3: As model 1 + ischemic stroke and/or myocardial infarction before baseline Number of events model 2 and 3: Women: all cancers n=128, GI n=51. Men: All cancers 224, GI cancer n=57. 11
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