Skip to main content
Top
Published in: Calcified Tissue International 4/2011

01-04-2011 | Original Research

Use of Bisphosphonates and Risk of Breast Cancer

Authors: Peter Vestergaard, Lone Fischer, Marco Mele, Leif Mosekilde, Peer Christiansen

Published in: Calcified Tissue International | Issue 4/2011

Login to get access

Abstract

A decreased risk of breast cancer has been reported among patients given bisphosphonates. The present aims were to study potential associations between different antiosteoporosis drugs, including bisphosphonates, and the risk of breast cancer before and after start of treatment and to appraise possible dose–effect relationships. From national Danish registers, all female users of bisphosphonates aged ≥40 years and other drugs against osteoporosis between 1996 and 2006 were identified (n = 87,104). This cohort was compared with a control group, where each patient was matched on age with three nonexposed women from the general population (n = 261,322). Before start of most drugs against osteoporosis an increased risk of breast cancer was seen compared to controls (e.g., adjusted OR = 1.09, 95% CI 1.04–1.16 for alendronate). This excess risk was higher in younger women (e.g., OR = 4.48, 95% CI 2.98–6.75 for alendronate in women ≤50 years) and disappeared in women older than 70 years (e.g., OR = 0.95, 95% CI 0.88–1.01 for alendronate). In contrast, a decreased risk of breast cancer was seen after start of alendronate (HR = 0.53, 95% CI 0.38–0.73), etidronate (HR = 0.80, 95% CI 0.73–0.89), and raloxifene (HR = 0.53, 95% CI 0.38–0.73). No dose–response relationship was present for alendronate and etidronate, whereas a decreasing risk was seen with increasing daily dose of raloxifene. Bisphosphonate treatment in women was associated with a reduced risk of breast cancer. However, no causal relationship seemed to be present.
Literature
1.
go back to reference Body J, Diel I, Lichinitzer M, Lazarev A, Pecherstorfer M, Bell R et al (2004) Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 90:1133–1137PubMedCrossRef Body J, Diel I, Lichinitzer M, Lazarev A, Pecherstorfer M, Bell R et al (2004) Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 90:1133–1137PubMedCrossRef
2.
go back to reference Cleton F, Holten-Verzantvoort A, Bijvoet O (1989) Effect of long-term bisphosphonate treatment on morbidity due to bone metastases in breast cancer patients. Recent Results Cancer Res 116:73–78PubMed Cleton F, Holten-Verzantvoort A, Bijvoet O (1989) Effect of long-term bisphosphonate treatment on morbidity due to bone metastases in breast cancer patients. Recent Results Cancer Res 116:73–78PubMed
3.
go back to reference Santini D, Vincenzi B, Galluzzo S, Battistoni F, Rocci L, Venditti O et al (2007) Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. Clin Cancer Res 13:4482–4486PubMedCrossRef Santini D, Vincenzi B, Galluzzo S, Battistoni F, Rocci L, Venditti O et al (2007) Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. Clin Cancer Res 13:4482–4486PubMedCrossRef
4.
go back to reference Mystakidou K, Katsouda E, Parpa E, Kelekis A, Galanos A, Vlahos L (2005) Randomized, open label, prospective study on the effect of zoledronic acid on the prevention of bone metastases in patients with recurrent solid tumors that did not present with bone metastases at baseline. Med Oncol 22:195–201PubMedCrossRef Mystakidou K, Katsouda E, Parpa E, Kelekis A, Galanos A, Vlahos L (2005) Randomized, open label, prospective study on the effect of zoledronic acid on the prevention of bone metastases in patients with recurrent solid tumors that did not present with bone metastases at baseline. Med Oncol 22:195–201PubMedCrossRef
5.
go back to reference Daubiné F, Le Gall C, Gasser J, Green J, Clézardin P (2007) Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst 99:322–330PubMedCrossRef Daubiné F, Le Gall C, Gasser J, Green J, Clézardin P (2007) Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst 99:322–330PubMedCrossRef
6.
go back to reference Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger S, Menzel C et al (2009) Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360:679–691PubMedCrossRef Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger S, Menzel C et al (2009) Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 360:679–691PubMedCrossRef
7.
go back to reference Rennert G, Pinchev M, Rennert H (2009) Use of bisphosphonates and risk of postmenopausal breast cancer. Presented at the 32nd annual San Antonio Breast Cancer Symposium, San Antonio, December 9–13, 2009. Cancer Res 69 Suppl 1 Rennert G, Pinchev M, Rennert H (2009) Use of bisphosphonates and risk of postmenopausal breast cancer. Presented at the 32nd annual San Antonio Breast Cancer Symposium, San Antonio, December 9–13, 2009. Cancer Res 69 Suppl 1
8.
go back to reference Chlebowski R, Chen Z, Cauley J, Rodabough R, McTiernan A, Lane D, et al. (2009) Oral bisphosphonates and breast cancer: prospective results from the Women’s Health Initiative (WHI). Presented at the 32nd annual San Antonio Breast Cancer Symposium, San Antonio, December 9–13, 2009. Cancer Res 69 Suppl 1 Chlebowski R, Chen Z, Cauley J, Rodabough R, McTiernan A, Lane D, et al. (2009) Oral bisphosphonates and breast cancer: prospective results from the Women’s Health Initiative (WHI). Presented at the 32nd annual San Antonio Breast Cancer Symposium, San Antonio, December 9–13, 2009. Cancer Res 69 Suppl 1
9.
go back to reference Brufsky A, Bundred N, Coleman R, Lambert-Falls R, Mena R, Hadji P et al (2008) Integrated analysis of zoledronic acid for prevention of aromatase inhibitor–associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Oncologist 13:503–514PubMedCrossRef Brufsky A, Bundred N, Coleman R, Lambert-Falls R, Mena R, Hadji P et al (2008) Integrated analysis of zoledronic acid for prevention of aromatase inhibitor–associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Oncologist 13:503–514PubMedCrossRef
10.
go back to reference Writing Group for the Women’s Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288:321–333CrossRef Writing Group for the Women’s Health Initiative Investigators (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288:321–333CrossRef
11.
go back to reference Beral V, Million Women Study Collaborators (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362:419–427PubMedCrossRef Beral V, Million Women Study Collaborators (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362:419–427PubMedCrossRef
12.
go back to reference The Women’s Health Initiative Steering Committee (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291:1701–1712CrossRef The Women’s Health Initiative Steering Committee (2004) Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 291:1701–1712CrossRef
13.
go back to reference Torgerson D, Bell-Syer S (2001) Hormone replacement therapy and prevention of nonvertebral fractures. A meta-analysis of randomized trials. JAMA 285:2891–2897PubMedCrossRef Torgerson D, Bell-Syer S (2001) Hormone replacement therapy and prevention of nonvertebral fractures. A meta-analysis of randomized trials. JAMA 285:2891–2897PubMedCrossRef
14.
go back to reference Torgerson D, Bell-Syer S (2001) Hormone replacement therapy and prevention of vertebral fractures: a meta-analysis of randomised trials. BMC Musculoskelet Disord 2:7–10PubMedCrossRef Torgerson D, Bell-Syer S (2001) Hormone replacement therapy and prevention of vertebral fractures: a meta-analysis of randomised trials. BMC Musculoskelet Disord 2:7–10PubMedCrossRef
15.
go back to reference Vestergaard P, Mosekilde L (2003) Fracture risk associated with smoking—a meta-analysis. J Intern Med 254:572–583PubMedCrossRef Vestergaard P, Mosekilde L (2003) Fracture risk associated with smoking—a meta-analysis. J Intern Med 254:572–583PubMedCrossRef
16.
go back to reference Magnusson C, Wedrén S, Rosenberg LU (2007) Cigarette smoking and breast cancer risk: a population-based study in Sweden. Br J Cancer 97:1287–1290PubMedCrossRef Magnusson C, Wedrén S, Rosenberg LU (2007) Cigarette smoking and breast cancer risk: a population-based study in Sweden. Br J Cancer 97:1287–1290PubMedCrossRef
17.
go back to reference Vestergaard P, Rejnmark L, Mosekilde L (2006) Socioeconomic aspects of fractures within universal public healthcare: a nationwide case-control study from Denmark. Scand J Public Health 34:371–377PubMedCrossRef Vestergaard P, Rejnmark L, Mosekilde L (2006) Socioeconomic aspects of fractures within universal public healthcare: a nationwide case-control study from Denmark. Scand J Public Health 34:371–377PubMedCrossRef
18.
go back to reference Bagnardi V, Blangiardo M, La Vecchia C, Corrao G (2001) Alcohol consumption and the risk of cancer: a meta-analysis. Alcohol Res Health 25:263–270PubMed Bagnardi V, Blangiardo M, La Vecchia C, Corrao G (2001) Alcohol consumption and the risk of cancer: a meta-analysis. Alcohol Res Health 25:263–270PubMed
19.
go back to reference Garland C, Gorham E, Mohr S, Grant W, Giovannucci E, Lipkin M, Newmark H, Holick M, Garland F (2007) Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol 103:708–711PubMedCrossRef Garland C, Gorham E, Mohr S, Grant W, Giovannucci E, Lipkin M, Newmark H, Holick M, Garland F (2007) Vitamin D and prevention of breast cancer: pooled analysis. J Steroid Biochem Mol Biol 103:708–711PubMedCrossRef
20.
go back to reference Gissel T, Rejnmark L, Mosekilde L, Vestergaard P (2008) Intake of vitamin D and risk of breast cancer—a meta-analysis. J Steroid Biochem Mol Biol 111:195–199PubMedCrossRef Gissel T, Rejnmark L, Mosekilde L, Vestergaard P (2008) Intake of vitamin D and risk of breast cancer—a meta-analysis. J Steroid Biochem Mol Biol 111:195–199PubMedCrossRef
21.
go back to reference Boonen S, Vanderschueren D, Cheng X, Verbeke G, Dequeker J, Geusens P, Broos P, Bouillon R (1997) Age-related (type II) femoral neck osteoporosis in men: biochemical evidence for both hypovitaminosis D–and androgen deficiency–induced bone resorption. J Bone Miner Res 12:2119–2126PubMedCrossRef Boonen S, Vanderschueren D, Cheng X, Verbeke G, Dequeker J, Geusens P, Broos P, Bouillon R (1997) Age-related (type II) femoral neck osteoporosis in men: biochemical evidence for both hypovitaminosis D–and androgen deficiency–induced bone resorption. J Bone Miner Res 12:2119–2126PubMedCrossRef
22.
go back to reference Bruce D, St John A, Nicklason F, Goldswain P (1999) Secondary hyperparathyroidism in patients from Western Australia with hip fracture: relationship to type of hip fracture, renal function, and vitamin D deficiency. J Am Geriatr Soc 47:354–359PubMed Bruce D, St John A, Nicklason F, Goldswain P (1999) Secondary hyperparathyroidism in patients from Western Australia with hip fracture: relationship to type of hip fracture, renal function, and vitamin D deficiency. J Am Geriatr Soc 47:354–359PubMed
23.
go back to reference Andersen T, Madsen M, Jørgensen J, Mellemkjær L, Olsen J (1999) The Danish National hospital register. Dan Med Bull 46:263–268PubMed Andersen T, Madsen M, Jørgensen J, Mellemkjær L, Olsen J (1999) The Danish National hospital register. Dan Med Bull 46:263–268PubMed
24.
go back to reference Mosbech J, Jørgensen J, Madsen M, Rostgaard K, Thornberg K, Poulsen T (1995) The Danish National Patient Register: evaluation of data quality [in Danish]. Ugeskr Laeger 157:3741–3745PubMed Mosbech J, Jørgensen J, Madsen M, Rostgaard K, Thornberg K, Poulsen T (1995) The Danish National Patient Register: evaluation of data quality [in Danish]. Ugeskr Laeger 157:3741–3745PubMed
25.
go back to reference Jensen AR, Overgaard J, Storm HH (2002) Validity of breast cancer in the Danish Cancer Registry. A study based on clinical records from one county in Denmark. Eur J Cancer Prev 11:359–364PubMedCrossRef Jensen AR, Overgaard J, Storm HH (2002) Validity of breast cancer in the Danish Cancer Registry. A study based on clinical records from one county in Denmark. Eur J Cancer Prev 11:359–364PubMedCrossRef
26.
go back to reference Lynge E (1994) Danish Cancer Registry as a resource for occupational research. J Occup Med 36:1169–1173PubMedCrossRef Lynge E (1994) Danish Cancer Registry as a resource for occupational research. J Occup Med 36:1169–1173PubMedCrossRef
27.
go back to reference Shapiro CL, Recht A (2001) Side effects of adjuvant treatment of breast cancer. N Engl J Med 344:1997–2008PubMedCrossRef Shapiro CL, Recht A (2001) Side effects of adjuvant treatment of breast cancer. N Engl J Med 344:1997–2008PubMedCrossRef
28.
go back to reference Bruning P, Pit M, de Jong-Bakker M, van den Ende A, Hart A, van Enk A (1990) Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer. Br J Cancer 61:308–310PubMedCrossRef Bruning P, Pit M, de Jong-Bakker M, van den Ende A, Hart A, van Enk A (1990) Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer. Br J Cancer 61:308–310PubMedCrossRef
29.
go back to reference Fogelman I, Blake GM, Blamey R, Palmer M, Sauerbrei W, Schumacher M et al (2003) Bone mineral density in premenopausal women treated for node-positive early breast cancer with 2 years of goserelin or 6 months of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Osteoporos Int 14:1001–1006PubMedCrossRef Fogelman I, Blake GM, Blamey R, Palmer M, Sauerbrei W, Schumacher M et al (2003) Bone mineral density in premenopausal women treated for node-positive early breast cancer with 2 years of goserelin or 6 months of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Osteoporos Int 14:1001–1006PubMedCrossRef
30.
go back to reference Saarto T, Blomqvist C, Välimäki M, Mäkelä P, Sarna S, Elomaa I (1997) Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients. J Clin Oncol 15:1341–1347PubMed Saarto T, Blomqvist C, Välimäki M, Mäkelä P, Sarna S, Elomaa I (1997) Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients. J Clin Oncol 15:1341–1347PubMed
31.
go back to reference Cauley JA, Lucas FL, Kuller LH, Vogt MT, Browner WS, Cummings SR (1996) Bone mineral density and risk of breast cancer in older women: the study of osteoporotic fractures. Study of Osteoporotic Fractures Research Group. JAMA 276:1404–1408PubMedCrossRef Cauley JA, Lucas FL, Kuller LH, Vogt MT, Browner WS, Cummings SR (1996) Bone mineral density and risk of breast cancer in older women: the study of osteoporotic fractures. Study of Osteoporotic Fractures Research Group. JAMA 276:1404–1408PubMedCrossRef
32.
go back to reference Newcomb PA, Trentham-Dietz A, Egan KM, Titus-Ernstoff L, Baron JA, Storer BE et al (2001) Fracture history and risk of breast and endometrial cancer. Am J Epidemiol 153:1071–1078PubMedCrossRef Newcomb PA, Trentham-Dietz A, Egan KM, Titus-Ernstoff L, Baron JA, Storer BE et al (2001) Fracture history and risk of breast and endometrial cancer. Am J Epidemiol 153:1071–1078PubMedCrossRef
33.
go back to reference Newcomb PA, Trentham-Dietz A, Hampton JM (2010) Bisphosphonates for osteoporosis treatment are associated with reduced breast cancer risk. Br J Cancer 102:799–802PubMedCrossRef Newcomb PA, Trentham-Dietz A, Hampton JM (2010) Bisphosphonates for osteoporosis treatment are associated with reduced breast cancer risk. Br J Cancer 102:799–802PubMedCrossRef
34.
go back to reference Vogel V, Costantino J, Wickerham D, Cronin W, Cecchini R, Atkins J et al (2006) Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP study of tamoxifen and raloxifene (STAR) P-2 trial. JAMA 295:2727–2741PubMedCrossRef Vogel V, Costantino J, Wickerham D, Cronin W, Cecchini R, Atkins J et al (2006) Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP study of tamoxifen and raloxifene (STAR) P-2 trial. JAMA 295:2727–2741PubMedCrossRef
35.
go back to reference Cummings S, Eckert S, Krueger K, Grady D, Powles T, Cauley J et al (1999) The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the more randomized trial. Multiple outcomes of raloxifene evaluation. JAMA 281:2189–2197PubMedCrossRef Cummings S, Eckert S, Krueger K, Grady D, Powles T, Cauley J et al (1999) The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the more randomized trial. Multiple outcomes of raloxifene evaluation. JAMA 281:2189–2197PubMedCrossRef
36.
go back to reference Lévesque LE, Hanley JA, Kezouh A, Suissa S (2010) Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes. BMJ 340:b5087PubMedCrossRef Lévesque LE, Hanley JA, Kezouh A, Suissa S (2010) Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes. BMJ 340:b5087PubMedCrossRef
37.
go back to reference Eastell R, Hannon R, Cuzick J, Dowsett M, Clack G, Adams J (2006) Effect of an aromatase inhibitor on BMD and bone turnover markers: 2-year results of the anastrozole, tamoxifen, alone or in combination (ATAC) trial (18233230). J Bone Miner Res 21:1215–1223PubMedCrossRef Eastell R, Hannon R, Cuzick J, Dowsett M, Clack G, Adams J (2006) Effect of an aromatase inhibitor on BMD and bone turnover markers: 2-year results of the anastrozole, tamoxifen, alone or in combination (ATAC) trial (18233230). J Bone Miner Res 21:1215–1223PubMedCrossRef
38.
go back to reference Persson I, Adami H, McLaughlin J, Naessen T, Fraumeni J (1994) Reduced risk of breast and endometrial cancer among women with hip fractures (Sweden). Cancer Causes Control 5:523–528PubMedCrossRef Persson I, Adami H, McLaughlin J, Naessen T, Fraumeni J (1994) Reduced risk of breast and endometrial cancer among women with hip fractures (Sweden). Cancer Causes Control 5:523–528PubMedCrossRef
39.
go back to reference Burshell AL, Song J, Dowsett SA, Mershon JL, Delmas PD, Secrest RJ et al (2008) Relationship between bone mass, invasive breast cancer incidence and raloxifene therapy in postmenopausal women with low bone mass or osteoporosis. Curr Med Res Opin 24:807–813PubMedCrossRef Burshell AL, Song J, Dowsett SA, Mershon JL, Delmas PD, Secrest RJ et al (2008) Relationship between bone mass, invasive breast cancer incidence and raloxifene therapy in postmenopausal women with low bone mass or osteoporosis. Curr Med Res Opin 24:807–813PubMedCrossRef
40.
go back to reference Pocock N, Eisman J, Hopper J, Yeates M, Sambrook P, Eberl S (1987) Genetic determinants of bone mass in adults: a twin study. J Clin Invest 80:706–710PubMedCrossRef Pocock N, Eisman J, Hopper J, Yeates M, Sambrook P, Eberl S (1987) Genetic determinants of bone mass in adults: a twin study. J Clin Invest 80:706–710PubMedCrossRef
Metadata
Title
Use of Bisphosphonates and Risk of Breast Cancer
Authors
Peter Vestergaard
Lone Fischer
Marco Mele
Leif Mosekilde
Peer Christiansen
Publication date
01-04-2011
Publisher
Springer-Verlag
Published in
Calcified Tissue International / Issue 4/2011
Print ISSN: 0171-967X
Electronic ISSN: 1432-0827
DOI
https://doi.org/10.1007/s00223-011-9463-7

Other articles of this Issue 4/2011

Calcified Tissue International 4/2011 Go to the issue