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Supplement Material:

Title: C-reactive protein and fracture risk: European Prospective Investigation into Cancer Norfolk Study

Table of contents:

Supplement Table 1: Baseline characteristics of EPIC-Norfolk study participants comparing those with and without data on C-reactive protein

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Supplement Figure 1: Hazard ratio of incident fractures of all types by log-C-reactive protein in fractional polynomial regression model.

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Supplement Table 2: Hazard ratio of fracture in men and women across serum C-reactive protein categories and after additional adjustment for serum creatinine, or after excluding participants with low body mass index or women taking hormone replacement therapy, and analysis stratified by age and sex

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Supplement Table 1: Baseline characteristics of EPIC-Norfolk study participants comparing those with and without data on C-reactive protein

|  |  |CRP available |  |CRP missing |

|N | |18586 | |7053 |

|Age | |58.7 (9.2) | |58.8 (9.7) |

|Body mass index |26.3 (3.8) | |26.7 (4.2) |

|Height |166.8 (9.1) | |166.9 (9.2) |

|Alcohol (units/week) |7.0 (9.3) | |7.2 (9.9) |

|Smoking | | | |

| |Current (%) |2,089 (11.3 %) | |895 (12.8 %) |

| |Never (%) |8,605 (46.7 %) | |3,069 (43.9 %) |

|Physical activity (% active) |7,657 (41.2 %) | |2,767 (39.2 %) |

|History of fracture (%) |1,306 (7.0 %) | |456 (6.5 %) |

|History of osteoporosis (%) |316 (1.7 %) | |114 (1.6 %) |

|Hormone replacement therapy (current %) |2,138 (20.1 %) |  |710 (18.8 %) |

Supplement Figure 1: Hazard ratio of incident fractures of all types by log-C-reactive protein in fractional polynomial regression model.

Hazard ratio of fracture is adjusted for age, sex, body mass index, smoking, alcohol intake, physical activity, past history of fractures, history of osteoporosis, use of NSAIDs and corticosteroid medication, medical history of arthritis, cancer, myocardial infarction, stroke, and diabetes, and in women only menopausal status and Hormone Replacement Therapy.

Supplement Table 2: Hazard ratio of fracture in men and women across serum C-reactive protein categories and after additional adjustment for serum creatinine, or after excluding participants with low body mass index or women taking hormone replacement therapy, and analysis stratified by age and sex *

| | | | | | |C-Reactive Protein |

| | |Participants |Person |Fractures |0 - 0.5 | |0.6 - 1 | |1.1 - 2 | |2.1 - 3 | |3.1 - 10 | |10 - 188 | | |(N) | |-Years |(N) | |HR (95% CI) | |HR (95% CI) | |HR (95% CI) | |HR (95% CI) | |HR (95% CI) | |HR (95% CI) | |All Fractures | | | | | | | | | | | | | | | | | | | | |All Participants | | | | | | | | | | | | | | | | | | | | |18,559 | |261,563 | |792 | |1.31 (1.03, 1.66) | |1.21 (0.98, 1.51) | |1.00 (Referent) | |1.06 (0.82, 1.35) | |1.22 (1.00, 1.51) | |1.29 (0.91, 1.81) | | | |Additionally adjusted for serum creatinine | | | | | | | | | | | | | | | | |18,298 | |257,907 | |780 | |1.32 (1.04, 1.69) | |1.22 (0.97, 1.52) | |1.00 (Referent) | |1.06 (0.82, 1.36) | |1.23 (1.00, 1.52) | |1.31 (0.93, 1.84) | | | |Excluding HRT users | | | | | | | | | | | | | | | | | | | | |16,425 | |229,832 | |731 | |1.25 (0.98, 1.61) | |1.19 (0.95, 1.49) | |1.00 (Referent) | |1.04 (0.80, 1.35) | |1.21 (0.97, 1.50) | |1.29 (0.90, 1.85) | | | |Excluding BMI 60 |7,993 | |103,855 | |535 | |1.10 (0.80, 1.52) | |1.15 (0.88, 1.49) | |1.00 (Referent) | |0.93 (0.69, 1.26) | |1.25 (0.99, 1.59) | |1.22 (0.82, 1.83) | | | | | | | | | | | | | | | | | | | | | | |Hip Fractures | | | | | | | | | | | | | | | | | | | | |All Participants | | | | | | | | | | | | | | | | | | | | |18,559 | |264,903 | |291 | |1.10 (0.74, 1.63) | |0.87 (0.60, 1.25) | |1.00 (Referent) | |0.87 (0.58, 1.30) | |1.10 (0.79, 1.53) | |1.34 (0.79, 2.26) | | | |Additionally adjusted for serum creatinine | | | | | | | | | | | | | | | | |18,298 | |261,190 | |288 | |1.12 (0.75, 1.67) | |0.86 (0.59, 1.24) | |1.00 (Referent) | |0.84 (0.56, 1.26) | |1.11 (0.80, 1.53) | |1.35 (0.80, 2.27) | | | |Excluding HRT users | | | | | | | | | | | | | | | | | | | | |16,425 | |232,843 | |277 | |1.13 (0.76, 1.68) | |0.83 (0.57, 1.21) | |1.00 (Referent) | |0.81 (0.54, 1.24) | |1.06 (0.75, 1.48) | |1.41 (0.84, 2.38) | | | |Excluding BMI 60 |7,993 | |105,549 | |254 | |1.10 (0.72, 1.69) | |0.77 (0.52, 1.15) | |1.00 (Referent) | |0.71 (0.46, 1.10) | |.98 (0.70, 1.39) | |1.17 (0.67, 2.04) | |HRT: Hormone replacement therapy. BMI: body mass index. * Hazard ratios are adjusted for age, sex (where appropriate), body mass index, smoking, alcohol intake, physical activity, past history of fractures, history of osteoporosis, use of NSAIDs and corticosteroid medication, medical history of arthritis, cancer, myocardial infarction, stroke, and diabetes, and in women only menopausal status and Hormone Replacement Therapy.

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