Cancer Causes & Control

, Volume 18, Issue 6, pp 595–602 | Cite as

Serum calcium and breast cancer risk: results from a prospective cohort study of 7,847 women

  • Martin Almquist
  • Jonas Manjer
  • Lennart Bondeson
  • Anne-Greth Bondeson


Experimental and epidemiological studies suggest that calcium-regulating hormones—parathyroid hormone (PTH) and vitamin D—may be associated with breast cancer risk. No prospective cohort study has investigated the association between pre-diagnostic calcium levels and subsequent risk of breast cancer. We have examined this in a cohort of 7,847 women where serum calcium levels and established risk factors for breast cancer had been assessed at baseline. During a mean follow-up of 17.8 years, 437 incident breast cancer cases were diagnosed. Incidence of breast cancer was calculated in different quartiles of serum calcium levels and a Cox’s proportional hazards analysis was used to obtain corresponding relative risks (RR), with a 95% confidence interval (CI), adjusted for potential confounders. In premenopausal women, serum calcium levels were inversely associated with breast cancer risk in a dose-response manner. The adjusted RR (95% CI) of breast cancer was in the 2nd calcium quartile 0.91 (0.65–1.30), in the 3rd quartile 0.89 (0.60–1.31), and in the 4th quartile 0.56 (0.32–0.98), as compared to the 1st calcium quartile. In postmenopausal overweight women (BMI > 25), breast cancer risk was higher in calcium quartiles 2–4 as compared to the 1st quartile. Our findings may have implications for primary prevention of breast cancer and for the management of asymptomatic primary hyperparathyroidism.


Breast cancer Calcium Obesity Vitamin-D Parathyroid hormone 



Parathyroid hormone


Primary hyperparathyroidism


Body mass index


Malmö Preventive Project


Hormone replacement therapy


Standard deviation


Relative risk


Confidence interval



Financial support was received from The Ernhold Lundström Foundation, The Einar and Inga Nilsson Foundation, The Malmö University Hospital Cancer Research Fund, The Malmö University Hospital Funds and Donations, The Crafoord Foundation, and The Foundation for Surgical Research at Malmö University Hospital. We are grateful to secretary Christina Bengtsson for generous assistance in collecting data. We state no conflicts of interest.


  1. 1.
    McGrath CM, Soule HD (1984) Calcium regulation of normal human mammary epithelial cell growth in culture. In Vitro 208:652–662Google Scholar
  2. 2.
    Russo J, Mills MJ, Moussalli MJ, Russo IH (1989) Influence of human breast development on the growth properties of primary cultures. In Vitro Cell Dev Biol 257:643–649CrossRefGoogle Scholar
  3. 3.
    VanHouten JN (2005) Calcium sensing by the mammary gland. J Mammary Gland Biol Neoplasia 102:129–139CrossRefGoogle Scholar
  4. 4.
    Moorman PG, Terry PD (2004) Consumption of dairy products and the risk of breast cancer: a review of the literature. Am J Clin Nutr 801:5–14Google Scholar
  5. 5.
    McCarty MF (2000) Parathyroid hormone may be a cancer promoter - an explanation for the decrease in cancer risk associated with ultraviolet light, calcium, and vitamin D. Med Hypotheses 543:475–482CrossRefGoogle Scholar
  6. 6.
    Giovannucci E (2005) The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control 162:83–95CrossRefGoogle Scholar
  7. 7.
    Carmeliet G, Van Cromphaut S, Daci E, Maes C, Bouillon R (2003) Disorders of calcium homeostasis. Best Pract Res Clin Endocrinol Metab 174:529–546CrossRefGoogle Scholar
  8. 8.
    Birch MA, Carron JA, Scott M, Fraser WD, Gallagher JA (1995) Parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptor expression and mitogenic responses in human breast cancer cell lines. Br J Cancer 721:90–95Google Scholar
  9. 9.
    Linforth R, Anderson N, Hoey R et al (2002) Coexpression of parathyroid hormone related protein and its receptor in early breast cancer predicts poor patient survival. Clin Cancer Res 810:3172–3177Google Scholar
  10. 10.
    Hoey RP, Sanderson C, Iddon J et al (2003) The parathyroid hormone-related protein receptor is expressed in breast cancer bone metastases and promotes autocrine proliferation in breast carcinoma cells. Br J Cancer 884:567–573CrossRefGoogle Scholar
  11. 11.
    Palmer M, Adami HO, Krusemo UB, Ljunghall S (1988) Increased risk of malignant diseases after surgery for primary hyperparathyroidism. A nationwide cohort study. Am J Epidemiol 1275:1031–1040Google Scholar
  12. 12.
    Pickard AL, Gridley G, Mellemkjae L et al (2002) Hyperparathyroidism and subsequent cancer risk in Denmark. Cancer 958:1611–1617CrossRefGoogle Scholar
  13. 13.
    Michels KB, Xue F, Brandt L, Ekbom A (2004) Hyperparathyroidism and subsequent incidence of breast cancer. Int J Cancer 1103:449–451CrossRefGoogle Scholar
  14. 14.
    Lowe L, Hansen CM, Senaratne S, Colston KW (2003) Mechanisms implicated in the growth regulatory effects of vitamin D compounds in breast cancer cells. Recent Results Cancer Res 164:99–110PubMedGoogle Scholar
  15. 15.
    Wermers RA, Khosla S, Atkinson EJ et al (2006) Incidence of primary hyperparathyroidism in Rochester, Minnesota, 1993–2001: an update on the changing epidemiology of the disease. J Bone Miner Res 211:171–177CrossRefGoogle Scholar
  16. 16.
    Bolland MJ, Grey AB, Gamble GD, Reid IR (2005) Association between primary hyperparathyroidism and increased body weight: a meta-analysis. J Clin Endocrinol Metab 903:1525–1530Google Scholar
  17. 17.
    Gaugris S, Heaney RP, Boonen S et al (2005) Vitamin D inadequacy among post-menopausal women: a systematic review. Qjm 989:667–676CrossRefGoogle Scholar
  18. 18.
    Manjer J, Janzon L (1999) Covariance of breast cancer incidence with smoking-, oestrogen- and diet-related cancers in pre- and postmenopausal women in Sweden. Med Hypotheses 526:561–568CrossRefGoogle Scholar
  19. 19.
    Lahmann PH, Hoffmann K, Allen N et al (2004) Body size and breast cancer risk: findings from the European Prospective Investigation into Cancer And Nutrition (EPIC). Int J Cancer 1115:762–771CrossRefGoogle Scholar
  20. 20.
    Berglund G, Eriksson KF, Israelsson B et al (1996) Cardiovascular risk groups and mortality in an urban swedish male population: the Malmo Preventive Project. J Intern Med 2396:489–497CrossRefGoogle Scholar
  21. 21.
    Manjer J, Berglund G, Bondesson L et al (2000) Breast cancer incidence in relation to smoking cessation. Breast Cancer Res Treat 612:121–129CrossRefGoogle Scholar
  22. 22.
    Solberg HE (1984) Monitoring long-term analytical quality by computerized combined Shewart-cusum method. Scand J Clin Lab Invest Suppl 172:43–49PubMedGoogle Scholar
  23. 23.
    Nilsson-Ehle P (2003) Laurells klinisk kemi i praktisk medicin, 8th edn. Studentlitteratur AB, Sweden, p 723Google Scholar
  24. 24.
    Sobin LH, Wittekind C (2002) TNM Classification of Malignant Tumours. 6th edn. John Wiley & Sons, Hoboken, New JerseyGoogle Scholar
  25. 25.
    Nordin BE, Jm WI, Clifton PM et al (2004) A longitudinal study of bone-related biochemical changes at the menopause. Clin Endocrinol (Oxf) 611:123–130CrossRefGoogle Scholar
  26. 26.
    Young MM, Nordin BE (1967) Calcium metabolism and the menopause. Proc R Soc Med 6011 Part 1:1137–1138Google Scholar
  27. 27.
    Ricos C, Alvarez V, Cava F et al (1999) Current databases on biological variation: pros, cons and progress. Scand J Clin Lab Invest 597:491–500Google Scholar
  28. 28.
    Gallagher SK, Johnson LK, Milne DB (1989) Short-term and long-term variability of indices related to nutritional status. I: Ca, Cu, Fe, Mg, and Zn. Clin Chem 353:369–373Google Scholar
  29. 29.
    Prince RL, Dick I, Devine A et al (1995) The effects of menopause and age on calcitropic hormones: a cross-sectional study of 655 healthy women aged 35 to 90. J Bone Miner Res 106:835–842CrossRefGoogle Scholar
  30. 30.
    Leifsson BG, Ahren B (1996) Serum calcium and survival in a large health screening program. J Clin Endocrinol Metab 816:2149–2153CrossRefGoogle Scholar
  31. 31.
    Joborn C, Ljunghall S, Larsson K et al (1991) Skeletal responsiveness to parathyroid hormone in healthy females: relationship to menopause and oestrogen replacement. Clin Endocrinol (Oxf) 345:335–339Google Scholar
  32. 32.
    Cosman F, Shen V, Xie F et al (1993) Estrogen protection against bone resorbing effects of parathyroid hormone infusion. Assessment by use of biochemical markers. Ann Intern Med 1185:337–343Google Scholar
  33. 33.
    Clavel-Chapelon F (2002) Differential effects of reproductive factors on the risk of pre- and postmenopausal breast cancer. Results from a large cohort of French women. Br J Cancer 865:723–727CrossRefGoogle Scholar
  34. 34.
    Lundgren E, Hagstrom EG, Lundin J et al (2002) Primary hyperparathyroidism revisited in menopausal women with serum calcium in the upper normal range at population-based screening 8 years ago. World J Surg 268:931–936CrossRefGoogle Scholar
  35. 35.
    Stewart AF (2005) Clinical practice. Hypercalcemia associated with cancer. N Engl J Med 3524:373–379CrossRefGoogle Scholar
  36. 36.
    Garne JP (1996) Invasive breast cancer in Malmö 1961–1992 - an epidemiological study. Dissertation, Lund University, MalmöGoogle Scholar
  37. 37.
    Nystrom L, Rutqvist LE, Wall S et al (1993) Breast cancer screening with mammography: overview of Swedish randomised trials. Lancet 3418851:973–978CrossRefGoogle Scholar
  38. 38.
    Welsh J (2004) Vitamin D and breast cancer: insights from animal models. Am J Clin Nutr 806(Suppl):1721S–1724SGoogle Scholar
  39. 39.
    Boyapati SM, Shu XO, Jin F et al (2003) Dietary calcium intake and breast cancer risk among Chinese women in Shanghai. Nutr Cancer 461:38–43CrossRefGoogle Scholar
  40. 40.
    McCullough ML, Rodriguez C, Diver WR et al (2005) Dairy, calcium, and vitamin D intake and postmenopausal breast cancer risk in the Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev 1412:2898–2904CrossRefGoogle Scholar
  41. 41.
    Hiatt RA, Krieger N, Lobaugh B et al (1998) Prediagnostic serum vitamin D and breast cancer. J Natl Cancer Inst 906:461–463CrossRefGoogle Scholar
  42. 42.
    Bertone-Johnson ER, Chen WY, Holick MF et al (2005) Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 148:1991–1997CrossRefGoogle Scholar
  43. 43.
    Parodi PW (2005) Dairy product consumption and the risk of breast cancer. J Am Coll Nutr 246(Suppl):556S–568SGoogle Scholar
  44. 44.
    Dizdar O, Alyamac E (2004) Obesity: an endocrine tumor? Med Hypotheses 635:790–792CrossRefGoogle Scholar
  45. 45.
    Kaaks R, Lundin E, Rinaldi S et al (2002) Prospective study of IGF-I, IGF-binding proteins, and breast cancer risk, in northern and southern Sweden. Cancer Causes Control 134:307–316CrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media B.V. 2007

Authors and Affiliations

  • Martin Almquist
    • 1
  • Jonas Manjer
    • 1
  • Lennart Bondeson
    • 2
  • Anne-Greth Bondeson
    • 1
  1. 1.Department of SurgeryMalmö University HospitalMalmoSweden
  2. 2.Department of PathologyMalmö University HospitalMalmoSweden

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