Calcified Tissue International

, Volume 90, Issue 1, pp 22–29 | Cite as

Acute Myocardial Infarction and Atherosclerosis of the Coronary Arteries in Patients Treated with Drugs Against Osteoporosis: Calcium in the Vessels and not the Bones?

Original Research

Abstract

We studied the association between bisphosphonate use and risk of acute myocardial infarction (AMI) or atherosclerosis of the coronary vessels using a nationwide retrospective cohort from Denmark. All users of bisphosphonates and other drugs against osteoporosis between 1996 and 2006 (n = 103,562) comprised the exposed group and three age- and gender-matched controls from the general population (n = 310,683), the unexposed group. The main outcomes were occurrence of AMI or atherosclerosis of the coronary vessels. An excess risk of AMI was seen in users of alendronate compared to the unexposed. However, an inverse dose–response relationship was seen, with an increased risk in those with low adherence (≤0.66 DDD, HR = 1.50, 95% CI 1.24–1.82) and a nonsignificantly decreased risk in those who were adherent to the drug (≥1 DDD, HR = 0.80, 95% CI 0.59–1.09; P for trend <0.01). For etidronate and raloxifene, no excess risk was present and no dose–response relationship was seen. For atherosclerosis of the coronary vessels, a similar trend as for AMI was seen for alendronate but a protective effect was present at high doses (≥1 DDD, HR = 0.58, 95% CI 0.49–0.70). For etidronate, an increased risk of atherosclerosis was seen at all doses, with no dose–response relationship. For raloxifene, no excess of atherosclerosis was observed. At high doses of alendronate a decreased risk of atherosclerosis of the coronary vessels was seemingly present, whereas at low doses an increased risk was present. The finding may be spurious due to the “healthy user” effect, but a causal relationship cannot be excluded.

Keywords

Bisphosphonate Alendronate Etidronate Raloxifene Acute myocardial infarction Angina pectoris Atherosclerosis 

Notes

Acknowledgments

This study was funded by an unrestricted grant from the A.P. Møller Foundation (Fonden til Lægevidenskabens Fremme), Servier Denmark, and the Dandy Foundation.

References

  1. 1.
    Bolland MJ, Barber PA, Doughty RN, Mason B, Horne A, Ames R, Gamble GD, Grey A, Reid IR (2008) Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ 336:262–266PubMedCrossRefGoogle Scholar
  2. 2.
    Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, Reid IR (2010) Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 341:c3691PubMedCrossRefGoogle Scholar
  3. 3.
    Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR (2011) Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ 342:d2040PubMedCrossRefGoogle Scholar
  4. 4.
    Reid IR, Bolland MJ, Avenell A, Grey A (2011) Cardiovascular effects of calcium supplementation. Osteoporos Int 22:1649–1658PubMedCrossRefGoogle Scholar
  5. 5.
    World Health Organization (2003) Prevention and management of osteoporosis. WHO technical report series 921. WHO, GenevaGoogle Scholar
  6. 6.
    Lambrinoudaki I, Armeni E, Georgiopoulos G, Kazani M, Kouskouni E, Creatsa M, Alexandrou A, Fotiou S, Papamichael C, Stamatelopoulos K (2011) Subclinical atherosclerosis in menopausal women with low to medium calculated cardiovascular risk. Int J Cardiol [Epub ahead of print]Google Scholar
  7. 7.
    Women’s Health Initiative (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288:321–333CrossRefGoogle Scholar
  8. 8.
    Manson J, Hsia J, Johnson K, Rossouw J, Assaf A, Lasser N, Trevisan M, Black H, Heckbert S, Detrano R, Strickland O, Wong N, Crouse J, Stein E, Cushman M (2003) Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 349:523–534PubMedCrossRefGoogle Scholar
  9. 9.
    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 291:1701–1712CrossRefGoogle Scholar
  10. 10.
    EMEA (2003) EMEA public statement on recent publications regarding hormone replacement therapy. http://www.emea.eu.int/pdfs/human/press/pus/3306503en.pdf. Accessed 3 December 2003
  11. 11.
    Vogt M, Cauley J, Kuller L, Nevitt M (1997) Bone mineral density and blood flow to the lower extremities: the study of osteoporotic fractures. J Bone Miner Res 12:283–289PubMedCrossRefGoogle Scholar
  12. 12.
    Sanada M, Taguchi A, Higashi Y, Tsuda M, Kodama I, Yoshizumi M, Ohama K (2004) Forearm endothelial function and bone mineral loss in postmenopausal women. Atherosclerosis 176:387–392PubMedCrossRefGoogle Scholar
  13. 13.
    Divers J, Register TC, Langefeld CD, Wagenknecht LE, Bowden DW, Carr JJ, Hightower RC, Xu J, Hruska KA, Freedman BI (2011) Relationships between calcified atherosclerotic plaque and bone mineral density in African Americans with type 2 diabetes. J Bone Miner Res 26:1554–1560PubMedCrossRefGoogle Scholar
  14. 14.
    Tanko LB, Bagger YZ, Christiansen C (2003) Low bone mineral density in the hip as a marker of advanced atherosclerosis in elderly women. Calcif Tissue Int 73:15–20PubMedCrossRefGoogle Scholar
  15. 15.
    Barrett-Connor E, Grady D, Sashegyi A, Anderson P, Cox D, Hoszowski K, Rautaharju P, Harper K (2002) Raloxifene and cardiovascular events in osteoporotic postmenopausal women: four-year results from the MORE (multiple outcomes of raloxifene evaluation) randomized trial. JAMA 287:847–857PubMedCrossRefGoogle Scholar
  16. 16.
    Barrett-Connor E, Mosca L, Collins P, Geiger M, Grady D, Kornitzer M, McNabb M, Wenger N (2006) Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 355:125–137PubMedCrossRefGoogle Scholar
  17. 17.
    Roijers RB, Debernardi N, Cleutjens JPM, Schurgers LJ, Mutsaers PHA, van der Vusse GJ (2011) Microcalcifications in early intimal lesions of atherosclerotic human coronary arteries. Am J Pathol 178:2879–2887PubMedCrossRefGoogle Scholar
  18. 18.
    Adami S, Passeri M, Ortolani S, Broggini M, Carratelli L, Caruso I, Gandolini G, Gnessi L, Laurenzi M, Lombardi A et al (1995) Effects of oral alendronate and intranasal salmon calcitonin on bone mass and biochemical markers of bone turnover in postmenopausal women with osteoporosis. Bone 17:383–390PubMedCrossRefGoogle Scholar
  19. 19.
    Meunier PJ, Confavreux E, Tupinon I, Hardouin C, Delmas PD, Balena R (1997) Prevention of early postmenopausal bone loss with cyclical etidronate therapy (a double-blind, placebo-controlled study and 1-year follow-up). J Clin Endocrinol Metab 82:2784–2791PubMedCrossRefGoogle Scholar
  20. 20.
    Bjarnason NH, Sarkar S, Duong T, Mitlak B, Delmas PD, Christiansen C (2001) Six and twelve month changes in bone turnover are related to reduction in vertebral fracture risk during 3 years of raloxifene treatment in postmenopausal osteoporosis. Osteoporos Int 12:922–930PubMedCrossRefGoogle Scholar
  21. 21.
    Gulhan I, Bilgili S, Gunaydin R, Gulhan S, Posaci C (2008) The effect of strontium ranelate on serum insulin like growth factor-1 and leptin levels in osteoporotic post-menopausal women: a prospective study. Arch Gynecol Obstet 278:437–441PubMedCrossRefGoogle Scholar
  22. 22.
    Kostenuik PJ, Smith SY, Jolette J, Schroeder J, Pyrah I, Ominsky MS (2011) Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody. Bone 49:151–161PubMedCrossRefGoogle Scholar
  23. 23.
    Madsen M, Balling H, Eriksen L (1990) The validity of the diagnosis of acute myocardial infarction in 2 registries: the Heart Registry compared to the National Patient Registry [in Danish]. Ugeskr Laeger 152:308–314PubMedGoogle Scholar
  24. 24.
    Andersen T, Madsen M, Jørgensen J, Mellemkjær L, Olsen J (1999) The Danish National Hospital Register. Dan Med Bull 46:263–268PubMedGoogle Scholar
  25. 25.
    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 157:3741–3745PubMedGoogle Scholar
  26. 26.
    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:b5087PubMedCrossRefGoogle Scholar
  27. 27.
    Curtis JR, Larson JC, Delzell E, Brookhart MA, Cadarette SM, Chlebowski R, Judd S, Safford M, Solomon DH, Lacroix AZ (2011) Placebo adherence, clinical outcomes, and mortality in the Women’s Health Initiative randomized hormone therapy trials. Med Care 49:427–435PubMedCrossRefGoogle Scholar
  28. 28.
    Schuetz P, Mueller B, Christ-Crain M, Dick W, Haas H (2005) Amino-bisphosphonates in heterotopic ossification: first experience in five consecutive cases. Spinal Cord 43:604–610PubMedCrossRefGoogle Scholar
  29. 29.
    Haran M, Bhuta T, Lee B (2004) Pharmacological interventions for treating acute heterotopic ossification. Cochrane Database Syst Rev (4): CD003321Google Scholar
  30. 30.
    Fleisch H (ed) (1995) Bisphosphonates in bone disease: from the laboratory to the patient. Parthenon, New YorkGoogle Scholar
  31. 31.
    Budoff MJ, Nasir K, Katz R, Takasu J, Carr JJ, Wong ND, Allison M, Lima JAC, Detrano R, Blumenthal RS, Kronmal R (2011) Thoracic aortic calcification and coronary heart disease events: the multi-ethnic study of atherosclerosis (MESA). Atherosclerosis 215:196–202PubMedCrossRefGoogle Scholar
  32. 32.
    Vestergaard P, Mosekilde L (2003) Fracture risk associated with smoking—a meta-analysis. J Intern Med 254:572–583PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.The Osteoporosis Clinic, Department of Endocrinology and Internal Medicine (MEA)Aarhus University Hospital THGAarhus CDenmark

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