Skip to main content
Erschienen in: Osteoporosis International 11/2012

01.11.2012 | Original Article

Reduced colon cancer incidence and mortality in postmenopausal women treated with an oral bisphosphonate—Danish National Register Based Cohort Study

verfasst von: M. Pazianas, B. Abrahamsen, P. A. Eiken, R. Eastell, R. Graham G. Russell

Erschienen in: Osteoporosis International | Ausgabe 11/2012

Einloggen, um Zugang zu erhalten

Abstract

Summary

In this Danish national register-based cohort study, we examined the effects of alendronate on the development of colon cancers and survival. The incidence of colon cancer and mortality rate, once colon cancer had been diagnosed, were lower in patients treated with alendronate, posing the question whether alendronate acts as chemopreventive.

Introduction

When bisphosphonates are given by mouth, around 99% remains non-absorbed in the intestine. Based on their biochemical actions, we predicted that oral bisphosphonates might prevent colon cancers.

Methods

This is a Danish national register-based cohort study. We identified 30,606 women aged 50+, mean age 71.9 years, who had not previously taken treatments for osteoporosis, who began to take alendronate in 1996–2005, and assigned 124,424 individually age- and gender-matched control subjects. The main outcome measure was colorectal cancers incidence and post-diagnosis survival in patients taking oral alendronate for osteoporosis.

Results

Cox proportional hazards analysis of death due to colon cancer showed lower risk in alendronate users, crude hazard ratio (HR) 0.69 (95% CI 0.59–0.81) with an adjusted HR of 0.62 (95% CI 0.52–0.72). The reduction in risk comprised both a lower incidence of colon cancer-adjusted HR 0.69 (95% CI 0.60–0.79) and a lower mortality once colon cancer had been diagnosed, adjusted HR 0.82 (95% CI 0.70–0.97). Weekly alendronate was associated with a greater risk reduction than daily alendronate. The main findings were unaffected by excluding patients from the analysis who had pulmonary disease, a major co-morbid condition in users of alendronate and an important cause of death.

Conclusions

The risk of overall deaths from cancer and in particular death caused by colon cancer was significantly and substantially decreased (40%) in patients treated with alendronate, with survival curves deviating progressively after 2 years. Also, the incidence of colon cancer was lower in those patients.
Literatur
1.
Zurück zum Zitat Russell RG, Watts NB, Ebetino FH, Rogers MJ (2008) Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 19:733–759PubMedCrossRef Russell RG, Watts NB, Ebetino FH, Rogers MJ (2008) Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 19:733–759PubMedCrossRef
2.
Zurück zum Zitat Fritz G, Just I, Kaina B (1999) Rho GTPases are over-expressed in human tumors. Int J Cancer 81:682–687PubMedCrossRef Fritz G, Just I, Kaina B (1999) Rho GTPases are over-expressed in human tumors. Int J Cancer 81:682–687PubMedCrossRef
3.
Zurück zum Zitat Clark EA, Golub TR, Lander ES, Hynes RO (2000) Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406(6795):532–535, Erratum in: Nature 2001 21;411(6840):974PubMedCrossRef Clark EA, Golub TR, Lander ES, Hynes RO (2000) Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406(6795):532–535, Erratum in: Nature 2001 21;411(6840):974PubMedCrossRef
4.
Zurück zum Zitat Pruitt K, Der CJ (2001) Ras and Rho regulation of the cell cycle and oncogenesis. Cancer Lett 171:1–10PubMedCrossRef Pruitt K, Der CJ (2001) Ras and Rho regulation of the cell cycle and oncogenesis. Cancer Lett 171:1–10PubMedCrossRef
5.
Zurück zum Zitat Vigil D, Cherfils J, Rossman KL, Der CJ (2010) Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer 10:842–857PubMedCrossRef Vigil D, Cherfils J, Rossman KL, Der CJ (2010) Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Nat Rev Cancer 10:842–857PubMedCrossRef
6.
Zurück zum Zitat Suri S, Mönkkönen J, Taskinen M et al (2001) Nitrogen-containing bisphosphonates induce apoptosis of Caco-2 cells in vitro by inhibiting the mevalonate pathway: a model of bisphosphonate-induced gastrointestinal toxicity. Bone 29:336–343PubMedCrossRef Suri S, Mönkkönen J, Taskinen M et al (2001) Nitrogen-containing bisphosphonates induce apoptosis of Caco-2 cells in vitro by inhibiting the mevalonate pathway: a model of bisphosphonate-induced gastrointestinal toxicity. Bone 29:336–343PubMedCrossRef
7.
Zurück zum Zitat Sewing L, Steinberg F, Schmidt H, Göke R (2008) The bisphosphonate zoledronic acid inhibits the growth of HCT-116 colon carcinoma cells and induces tumor cell apoptosis. Apoptosis 13:782–789PubMedCrossRef Sewing L, Steinberg F, Schmidt H, Göke R (2008) The bisphosphonate zoledronic acid inhibits the growth of HCT-116 colon carcinoma cells and induces tumor cell apoptosis. Apoptosis 13:782–789PubMedCrossRef
8.
Zurück zum Zitat Todaro M, D'Asaro M, Caccamo N et al (2009) Efficient killing of human colon cancer stem cells by gammadelta T lymphocytes. J Immunol 182:7287–7296PubMedCrossRef Todaro M, D'Asaro M, Caccamo N et al (2009) Efficient killing of human colon cancer stem cells by gammadelta T lymphocytes. J Immunol 182:7287–7296PubMedCrossRef
9.
Zurück zum Zitat Hosmer DW, Lemeshow S (1999) Applied survival analysis: regression modeling of time to event data, vol 6. Wiley, New York Hosmer DW, Lemeshow S (1999) Applied survival analysis: regression modeling of time to event data, vol 6. Wiley, New York
10.
Zurück zum Zitat Machado M, Cruz LS, Tannus G, Fonseca M (2009) Efficacy of clodronate, pamidronate, and zoledronate in reducing morbidity and mortality in cancer patients with bone metastasis: a meta-analysis of randomized clinical trials. Clin Ther 31:962–979PubMedCrossRef Machado M, Cruz LS, Tannus G, Fonseca M (2009) Efficacy of clodronate, pamidronate, and zoledronate in reducing morbidity and mortality in cancer patients with bone metastasis: a meta-analysis of randomized clinical trials. Clin Ther 31:962–979PubMedCrossRef
11.
Zurück zum Zitat Bolland MJ, Grey AB, Gamble GD, Reid IR (2010) Effect of osteoporosis treatment on mortality: a meta-analysis. J Clin Endocrinol Metab 95(3):1174–1181PubMedCrossRef Bolland MJ, Grey AB, Gamble GD, Reid IR (2010) Effect of osteoporosis treatment on mortality: a meta-analysis. J Clin Endocrinol Metab 95(3):1174–1181PubMedCrossRef
12.
Zurück zum Zitat Lyles KW, Colón-Emeric CS, Magaziner JS, For the HORIZON Recurrent Fracture Trial et al (2007) Zoledronic acid in reducing clinical fracture and mortality after hip fracture. N Engl J Med 357:nihpa40967PubMedCrossRef Lyles KW, Colón-Emeric CS, Magaziner JS, For the HORIZON Recurrent Fracture Trial et al (2007) Zoledronic acid in reducing clinical fracture and mortality after hip fracture. N Engl J Med 357:nihpa40967PubMedCrossRef
13.
Zurück zum Zitat Colon-Emeric CS, Mesenbrink P, Lyles KW et al (2010) Potential mediators of the mortality reduction with zoledronic acid after hip fracture. J Bone Miner Res 25:91–97PubMedCrossRef Colon-Emeric CS, Mesenbrink P, Lyles KW et al (2010) Potential mediators of the mortality reduction with zoledronic acid after hip fracture. J Bone Miner Res 25:91–97PubMedCrossRef
14.
Zurück zum Zitat Sambrook PN, Cameron ID, Chen JS, March LM, Simpson JM, Cumming RG, Seibel MJ (2011) Oral bisphosphonates are associated with reduced mortality in frail older people: a prospective five-year study. Osteoporos Int 22(9):2551–2556, Epub 2010 Oct 20PubMedCrossRef Sambrook PN, Cameron ID, Chen JS, March LM, Simpson JM, Cumming RG, Seibel MJ (2011) Oral bisphosphonates are associated with reduced mortality in frail older people: a prospective five-year study. Osteoporos Int 22(9):2551–2556, Epub 2010 Oct 20PubMedCrossRef
15.
Zurück zum Zitat Rennert G, Pinchev M, Rennert HS, Gruber SB (2011) Use of bisphosphonates and reduced risk of colorectal cancer. J Clin Oncol 29(9):1146–1150PubMedCrossRef Rennert G, Pinchev M, Rennert HS, Gruber SB (2011) Use of bisphosphonates and reduced risk of colorectal cancer. J Clin Oncol 29(9):1146–1150PubMedCrossRef
16.
Zurück zum Zitat Green J, Czanner G, Reeves G et al (2010) Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case–control analysis within a UK primary care cohort. BMJ 341:4444CrossRef Green J, Czanner G, Reeves G et al (2010) Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case–control analysis within a UK primary care cohort. BMJ 341:4444CrossRef
17.
Zurück zum Zitat Cardwell CR, Abnet CC, Cantwell MM, Murray LJ (2010) Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA 304:657–663PubMedCrossRef Cardwell CR, Abnet CC, Cantwell MM, Murray LJ (2010) Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA 304:657–663PubMedCrossRef
18.
Zurück zum Zitat Clézardin P, Ebetino FH, Fournier PG (2005) Bisphosphonates and cancer-induced bone disease: beyond their antiresorptive activity. Cancer Res 65:4971–4974PubMedCrossRef Clézardin P, Ebetino FH, Fournier PG (2005) Bisphosphonates and cancer-induced bone disease: beyond their antiresorptive activity. Cancer Res 65:4971–4974PubMedCrossRef
19.
Zurück zum Zitat Guenther A, Gordon S, Tiemann M et al (2010) The bisphosphonate zoledronic acid has antimyeloma activity in vivo by inhibition of protein prenylation. Int J Cancer 126:239–246PubMedCrossRef Guenther A, Gordon S, Tiemann M et al (2010) The bisphosphonate zoledronic acid has antimyeloma activity in vivo by inhibition of protein prenylation. Int J Cancer 126:239–246PubMedCrossRef
20.
Zurück zum Zitat Walker K, Olson MF (2005) Targeting Ras and Rho GTPases as opportunities for cancer therapeutics. Curr Opin Genet Dev 15:62–68PubMedCrossRef Walker K, Olson MF (2005) Targeting Ras and Rho GTPases as opportunities for cancer therapeutics. Curr Opin Genet Dev 15:62–68PubMedCrossRef
21.
Zurück zum Zitat (2010) Statins lose prevention ground. Nat Rev Cancer 10:385 (2010) Statins lose prevention ground. Nat Rev Cancer 10:385
22.
Zurück zum Zitat Bertagnolli MM, Hsu M, Hawk ET, Eagle CJ, Zauber AG (2010) Adenoma Prevention with Celecoxib (APC) Study Investigators. Statin use and colorectal adenoma risk: results from the adenoma prevention with celecoxib trial. Cancer Prev Res (Phila Pa) 3:588–596CrossRef Bertagnolli MM, Hsu M, Hawk ET, Eagle CJ, Zauber AG (2010) Adenoma Prevention with Celecoxib (APC) Study Investigators. Statin use and colorectal adenoma risk: results from the adenoma prevention with celecoxib trial. Cancer Prev Res (Phila Pa) 3:588–596CrossRef
23.
Zurück zum Zitat Dietz HC (2010) New therapeutic approaches to Mendelian disorders. N Engl J Med 363:852–863PubMedCrossRef Dietz HC (2010) New therapeutic approaches to Mendelian disorders. N Engl J Med 363:852–863PubMedCrossRef
24.
Zurück zum Zitat Varela I, Pereira S, Ugalde AP et al (2008) Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat Med 14:767–772PubMedCrossRef Varela I, Pereira S, Ugalde AP et al (2008) Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nat Med 14:767–772PubMedCrossRef
25.
Zurück zum Zitat Pavli P, Maxwell L, van de Pol E, Doe WF (1995) Distribution of human colonic dendritic cells and macrophages—functional implications. Adv Exp Med Biol 378:121–123PubMedCrossRef Pavli P, Maxwell L, van de Pol E, Doe WF (1995) Distribution of human colonic dendritic cells and macrophages—functional implications. Adv Exp Med Biol 378:121–123PubMedCrossRef
26.
Zurück zum Zitat Coffelt SB, Hughes R, Lewis CE (2009) Tumor-associated macrophages: effectors of angiogenesis and tumor progression. Biochim Biophys Acta 1796:11–18PubMed Coffelt SB, Hughes R, Lewis CE (2009) Tumor-associated macrophages: effectors of angiogenesis and tumor progression. Biochim Biophys Acta 1796:11–18PubMed
27.
Zurück zum Zitat Jedinak A, Dudhgaonkar S, Sliva D (2010) Activated macrophages induce metastatic behavior of colon cancer cells. Immunobiology 215:242–249PubMedCrossRef Jedinak A, Dudhgaonkar S, Sliva D (2010) Activated macrophages induce metastatic behavior of colon cancer cells. Immunobiology 215:242–249PubMedCrossRef
28.
Zurück zum Zitat Roelofs AJ, Coxon FP, Ebetino FH et al (2010) Fluorescent risedronate analogues reveal bisphosphonate uptake by bone marrow monocytes and localization around osteocytes in vivo. J Bone Miner Res 25:606–616PubMedCrossRef Roelofs AJ, Coxon FP, Ebetino FH et al (2010) Fluorescent risedronate analogues reveal bisphosphonate uptake by bone marrow monocytes and localization around osteocytes in vivo. J Bone Miner Res 25:606–616PubMedCrossRef
29.
Zurück zum Zitat Grimm MC, Pavli P, Van de Pol E, Doe WF (1995) Evidence for a CD14+ population of monocytes in inflammatory bowel disease mucosa—implications for pathogenesis. Clin Exp Immunol 100:291–297PubMedCrossRef Grimm MC, Pavli P, Van de Pol E, Doe WF (1995) Evidence for a CD14+ population of monocytes in inflammatory bowel disease mucosa—implications for pathogenesis. Clin Exp Immunol 100:291–297PubMedCrossRef
30.
Zurück zum Zitat Ballester I, Daddaoua A, López-Posadas R et al (2007) The bisphosphonate alendronate improves the damage associated with trinitrobenzenesulfonic acid-induced colitis in rats. Br J Pharmacol 151:206–215PubMedCrossRef Ballester I, Daddaoua A, López-Posadas R et al (2007) The bisphosphonate alendronate improves the damage associated with trinitrobenzenesulfonic acid-induced colitis in rats. Br J Pharmacol 151:206–215PubMedCrossRef
31.
Zurück zum Zitat Sassa S, Okabe H, Nemoto N et al (2009) Icadronate may prevent colorectal carcinogenesis in mice with ulcerative colitis. Anticancer Res 29:4615–4619PubMed Sassa S, Okabe H, Nemoto N et al (2009) Icadronate may prevent colorectal carcinogenesis in mice with ulcerative colitis. Anticancer Res 29:4615–4619PubMed
32.
Zurück zum Zitat Roelofs AJ, Jauhiainen M, Mönkkönen H et al (2009) Peripheral blood monocytes are responsible for γδ T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP. Br J Haematol 144:245–250PubMedCrossRef Roelofs AJ, Jauhiainen M, Mönkkönen H et al (2009) Peripheral blood monocytes are responsible for γδ T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP. Br J Haematol 144:245–250PubMedCrossRef
34.
Zurück zum Zitat Kunzmann V, Wilhelm M (2005) Anti-lymphoma effect of gammadelta T cells. Leuk Lymphoma 46:671–680PubMedCrossRef Kunzmann V, Wilhelm M (2005) Anti-lymphoma effect of gammadelta T cells. Leuk Lymphoma 46:671–680PubMedCrossRef
36.
Zurück zum Zitat Eberhart CE, Coffey RJ, Radhika A et al (1994) Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107:1183–1188PubMed Eberhart CE, Coffey RJ, Radhika A et al (1994) Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107:1183–1188PubMed
37.
Zurück zum Zitat Sheehan KM, Sabah M, Cummins RJ et al (2003) Cyclooxygenase-2 expression in stromal tumors of the gastrointestinal tract. Hum Pathol 34:1242–1246PubMedCrossRef Sheehan KM, Sabah M, Cummins RJ et al (2003) Cyclooxygenase-2 expression in stromal tumors of the gastrointestinal tract. Hum Pathol 34:1242–1246PubMedCrossRef
38.
Zurück zum Zitat Liu ES, Shin VY, Ye YN et al (2005) Cyclooxygenase-2 in cancer cells and macrophages induces colon cancer cell growth by cigarette smoke extract. Eur J Pharmacol 518:47–55PubMedCrossRef Liu ES, Shin VY, Ye YN et al (2005) Cyclooxygenase-2 in cancer cells and macrophages induces colon cancer cell growth by cigarette smoke extract. Eur J Pharmacol 518:47–55PubMedCrossRef
39.
Zurück zum Zitat Cuzick J, Otto F, Baron JA et al (2009) Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol 10:501–507PubMedCrossRef Cuzick J, Otto F, Baron JA et al (2009) Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol 10:501–507PubMedCrossRef
40.
Zurück zum Zitat Chan AT, Ogino S, Fuchs CS (2007) Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 356:2131–2142PubMedCrossRef Chan AT, Ogino S, Fuchs CS (2007) Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med 356:2131–2142PubMedCrossRef
41.
Zurück zum Zitat Rothwell PM, Wilson M, Elwin C et al (2010) Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376:1741–1750PubMedCrossRef Rothwell PM, Wilson M, Elwin C et al (2010) Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376:1741–1750PubMedCrossRef
42.
Zurück zum Zitat Pazianas M, Abrahamsen B (2011) Safety of bisphosphonates. Bone 49(1):103–110, Epub 2011 Jan 12PubMedCrossRef Pazianas M, Abrahamsen B (2011) Safety of bisphosphonates. Bone 49(1):103–110, Epub 2011 Jan 12PubMedCrossRef
43.
Zurück zum Zitat Abrahamsen B, Pazianas M, Eiken P, Russell RG, Eastell R (2011) Esophageal and gastric cancer incidence and mortality in alendronate users. J Bone Miner Res. doi:10.1002/jbmr.1481 [Epub ahead of print] Abrahamsen B, Pazianas M, Eiken P, Russell RG, Eastell R (2011) Esophageal and gastric cancer incidence and mortality in alendronate users. J Bone Miner Res. doi:10.​1002/​jbmr.​1481 [Epub ahead of print]
44.
Zurück zum Zitat Solomon DH, Patrick A, Brookhart MA (2009) More on reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 360:1789–1790PubMedCrossRef Solomon DH, Patrick A, Brookhart MA (2009) More on reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 360:1789–1790PubMedCrossRef
45.
Zurück zum Zitat Pazianas M, Russell RGG (2011) Potential therapeutic effects of oral bisphosphonates on the intestine. Ann N Y Acad Sci. [Epub ahead of print] Pazianas M, Russell RGG (2011) Potential therapeutic effects of oral bisphosphonates on the intestine. Ann N Y Acad Sci. [Epub ahead of print]
46.
Zurück zum Zitat Manson JE, Mayne ST, Clinton SK (2011) Vitamin D and prevention of cancer—ready for prime time? N Engl J Med 364(15):1385–1387PubMedCrossRef Manson JE, Mayne ST, Clinton SK (2011) Vitamin D and prevention of cancer—ready for prime time? N Engl J Med 364(15):1385–1387PubMedCrossRef
47.
Zurück zum Zitat Fleisch H, Russell RG, Francis MD (1969) Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science 165(899):1262–1264PubMedCrossRef Fleisch H, Russell RG, Francis MD (1969) Diphosphonates inhibit hydroxyapatite dissolution in vitro and bone resorption in tissue culture and in vivo. Science 165(899):1262–1264PubMedCrossRef
Metadaten
Titel
Reduced colon cancer incidence and mortality in postmenopausal women treated with an oral bisphosphonate—Danish National Register Based Cohort Study
verfasst von
M. Pazianas
B. Abrahamsen
P. A. Eiken
R. Eastell
R. Graham G. Russell
Publikationsdatum
01.11.2012
Verlag
Springer-Verlag
Erschienen in
Osteoporosis International / Ausgabe 11/2012
Print ISSN: 0937-941X
Elektronische ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-012-1902-4

Weitere Artikel der Ausgabe 11/2012

Osteoporosis International 11/2012 Zur Ausgabe

Arthropedia

Grundlagenwissen der Arthroskopie und Gelenkchirurgie. Erweitert durch Fallbeispiele, Videos und Abbildungen. 
» Jetzt entdecken

Update Orthopädie und Unfallchirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.