Prediagnostic serum calcium concentrations and risk of colorectal cancer development in 2 large European prospective cohorts

Nena Karavasiloglou, David J Hughes, Neil Murphy, Lutz Schomburg, Qian Sun, Vartiter Seher, Sabine Rohrmann, Elisabete Weiderpass, Anne Tjønneland, Anja Olsen, Kim Overvad, Marie-Christine Boutron-Ruault, Francesca Romana Mancini, Yahya Mahamat-Saleh, Rudolf Kaaks, Tilman Kuhn, Matthias B Schulze, Rosario Tumino, Salvatore Panico, Giovanna MasalaValeria Pala, Carlotta Sacerdote, Jeroen W G Derksen, Guri Skeie, Anette Hjartåker, Cristina Lasheras, Antonio Agudo, Maria-José Sánchez, Maria-Dolores Chirlaque, Eva Ardanaz, Pilar Amiano, Bethany Van Guelpen, Björn Gylling, Kathryn E Bradbury, Keren Papier, Heinz Freisling, Elom K Aglago, Amanda J Cross, Elio Riboli, Dagfinn Aune, Marc J Gunter, Mazda Jenab*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Background: Higher dietary calcium consumption is associated with lower colorectal cancer (CRC) risk. However, little data are available on the association between circulating calcium concentrations and CRC risk. Objectives: To explore the association between circulating calcium concentrations and CRC risk using data from 2 large European prospective cohort studies. Methods: Conditional logistic regression models were used to calculate multivariable-adjusted ORs and 95% CIs in case-control studies nested within the European Prospective Investigation into Cancer and Nutrition (EPIC; n-cases = 947, n-controls = 947) and the UK Biobank (UK-BB; n-cases = 2759, n-controls = 12,021) cohorts. Results: In EPIC, nonalbumin-adjusted total serum calcium (a proxy of free calcium) was not associated with CRC (OR: 0.94; 95% CI: 0.85, 1.03; modeled as continuous variable, per 1 mg/dL increase), colon cancer (OR: 0.93; 95% CI: 0.82, 1.05) or rectal cancer (OR: 1.01; 95% CI: 0.84, 1.20) risk in the multivariable adjusted model. In the UK-BB, serum ionized calcium (free calcium, most active form) was inversely associated with the risk of CRC (OR: 0.85; 95% CI: 0.76, 0.95; per 1 mg/dL) and colon cancer (OR: 0.78; 95% CI: 0.68, 0.90), but not rectal cancer (OR: 1.02; 95% CI: 0.83, 1.24) in multivariable adjusted models. Meta-analysis of EPIC and UK-BB CRC risk estimates showed an inverse risk association for CRC in the multivariable adjusted model (OR: 0.90; 95%CI: 0.84, 0.97). In analyses by quintiles, in both cohorts, higher levels of serum calcium were associated with reduced CRC risk (EPIC: ORQ5vs.Q1: 0.69; 95% CI: 0.47, 1.00; P-trend = 0.03; UK-BB: ORQ5vs.Q1: 0.82; 95% CI: 0.72, 0.94; P-trend < 0.01). Analyses by anatomical subsite showed an inverse cancer risk association in the colon (EPIC: ORQ5vs.Q1: 0.63, 95% CI: 0.39, 1.02; P-trend = 0.05; UK-BB: ORQ5vs.Q1: 0.75; 95% CI: 0.64, 0.88; P-trend < 0.01) but not the rectum. Conclusions: In UK-BB, higher serum ionized calcium levels were inversely associated with CRC, but the risk was restricted to the colon. Total serum calcium showed a null association in EPIC. Additional prospective studies in other populations are needed to better investigate these associations.

Original languageEnglish
Pages (from-to)33-45
Number of pages13
JournalAmerican Journal of Clinical Nutrition
Issue number1
Publication statusPublished - Jan 2023


  • cancer
  • cohort
  • colorectal
  • risk
  • serum calcium


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