Risk of acute myocardial infarction among new users of bisphosphonates: a nested case–control study

Abstract

Objective

To test the hypothesis that bisphosphonates reduce AMI risk among new users and to assess whether the effect depends on the duration of treatment.

Methods

Case–control study nested in a primary cohort composed of patients aged 40 to 99 years, with at least 1-year registry in the BIFAP database throughout the study period 2002–2015. Out of this cohort, incident AMI cases were identified and five controls per case were randomly selected, matched by exact age, sex, and index date. The association of AMI with current, recent and past use of bisphosphonates was assessed by computing adjusted odds ratios (AOR) and their corresponding 95% confidence interval (CI) through an unconditional logistic regression. Only initiators of bisphosphonates were considered.

Results

A total of 23,590 cases of AMI and 117,612 controls were included. The mean age was 66.8 (SD 13.4) years, and 72.52% was male, in both groups. About 276 (1.17%) cases and 1458 (1.24%) controls were current users of bisphosphonates yielding an AOR of 0.98 (95% CI 0.854–1.14). Recent and past use were not associated with a reduced risk, either, nor was it found a reduction with treatment duration (AOR less than 1 year = 0.92; 95% CI 0.73–1.15; AOR more than 1 year = 1.03; 95% CI 0.86–1.23). Stratified analysis by age, sex and background cardiovascular risk did not show an effect modification by these variables.

Conclusion

The results do not support a cardioprotective effect of bisphosphonates regardless of the duration of treatment, age, sex or background cardiovascular risk. However, a small protective effect could have been masked if patients with osteoporosis have had a background higher risk of AMI.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

References

  1. 1.

    Barengolts EI, Berman M, Kukreja SC, Kouznetsova T, Lin C, Chomka EV (1998) Osteoporosis and coronary atherosclerosis in asymptomatic postmenopausal women. Calcif Tissue Int 62:209–213

    CAS  Article  Google Scholar 

  2. 2.

    Shaffer JR, Kammerer CM, Rainwater DL, O'Leary DH, Bruder JM, Bauer RL, Mitchell BD (2007) Decreased bone mineral density is correlated with increased subclinical atherosclerosis in older, but not younger, Mexican American women and men: the San Antonio Family Osteoporosis Study. Calcif Tissue Int 81:430–441. https://doi.org/10.1007/s00223-007-9079-0

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    van der Klift M, Pols HA, Hak AE, Witteman JC, Hofman A, de Laet CE (2002) Bone mineral density and the risk of peripheral arterial disease: the Rotterdam Study. Calcif Tissue Int 70:443–449. https://doi.org/10.1007/s00223-001-2076-9

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Kiel DP, Kauppila LI, Cupples LA, Hannan MT, O'Donnell CJ, Wilson PW (2001) Bone loss and the progression of abdominal aortic calcification over a 25 year period: the Framingham Heart Study. Calcif Tissue Int 68:271–276

    CAS  Article  Google Scholar 

  5. 5.

    Browner WS, Seeley DG, Vogt TM, Cummings SR (1991) Non-trauma mortality in elderly women with low bone mineral density. Study of Osteoporotic Fractures Research Group. Lancet 338:355–358 DOI 0140-6736(91)90489-C [pii]

    CAS  Article  Google Scholar 

  6. 6.

    Kado DM, Browner WS, Blackwell T, Gore R, Cummings SR (2000) Rate of bone loss is associated with mortality in older women: a prospective study. J Bone Miner Res 15:1974–1980. https://doi.org/10.1359/jbmr.2000.15.10.1974

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    von der Recke P, Hansen MA, Hassager C (1999) The association between low bone mass at the menopause and cardiovascular mortality. Am J Med 106:273–278 DOI S0002934399000285 [pii]

    Article  Google Scholar 

  8. 8.

    Veronese N, Stubbs B, Crepaldi G, Solmi M, Cooper C, Harvey NC, Reginster JY, Rizzoli R, Civitelli R, Schofield P, Maggi S, Lamb SE (2017) Relationship between low bone mineral density and fractures with incident cardiovascular disease: a systematic review and meta-analysis. J Bone Miner Res 32:1126–1135. https://doi.org/10.1002/jbmr.3089

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Demer LL, Tintut Y (2003) Mineral exploration: search for the mechanism of vascular calcification and beyond: the 2003 Jeffrey M. Hoeg award lecture. Arterioscler Thromb Vasc Biol 23:1739–1743. https://doi.org/10.1161/01.ATV.0000093547.63630.0F

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Anagnostis P, Karagiannis A, Kakafika AI, Tziomalos K, Athyros VG, Mikhailidis DP (2009) Atherosclerosis and osteoporosis: age-dependent degenerative processes or related entities? Osteoporos Int 20:197–207. https://doi.org/10.1007/s00198-008-0648-5

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    McFarlane SI, Muniyappa R, Shin JJ, Bahtiyar G, Sowers JR (2004) Osteoporosis and cardiovascular disease: brittle bones and boned arteries, is there a link? Endocrine 23:1–10 DOI ENDO:23:1:01 [pii]

    CAS  Article  Google Scholar 

  12. 12.

    Szekanecz Z, Raterman HG, Petho Z, Lems WF (2019) Common mechanisms and holistic care in atherosclerosis and osteoporosis. Arthritis Res Ther 21:15–17. https://doi.org/10.1186/s13075-018-1805-7

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Schor AM, Allen TD, Canfield AE, Sloan P, Schor SL (1990) Pericytes derived from the retinal microvasculature undergo calcification in vitro. J Cell Sci 97(Pt 3):449–461

    PubMed  Google Scholar 

  14. 14.

    Doherty MJ, Ashton BA, Walsh S, Beresford JN, Grant ME, Canfield AE (1998) Vascular pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res 13:828–838. https://doi.org/10.1359/jbmr.1998.13.5.828

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Jeziorska M, McCollum C, Wooley DE (1998) Observations on bone formation and remodelling in advanced atherosclerotic lesions of human carotid arteries. Virchows Arch 433:559–565

    CAS  Article  Google Scholar 

  16. 16.

    Nitta K, Akiba T, Suzuki K, Uchida K, Watanabe R, Majima K, Aoki T, Nihei H (2004) Effects of cyclic intermittent etidronate therapy on coronary artery calcification in patients receiving long-term hemodialysis. Am J Kidney Dis 44:680–688 DOI S0272638604009370 [pii]

    CAS  Article  Google Scholar 

  17. 17.

    Kawahara T, Nishikawa M, Kawahara C, Inazu T, Sakai K, Suzuki G (2013) Atorvastatin, etidronate, or both in patients at high risk for atherosclerotic aortic plaques: a randomized, controlled trial. Circulation 127:2327–2335. https://doi.org/10.1161/CIRCULATIONAHA.113.001534

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Kang JH, Keller JJ, Lin HC (2012) A population-based 2-year follow-up study on the relationship between bisphosphonates and the risk of stroke. Osteoporos Int 23:2551–2557. https://doi.org/10.1007/s00198-012-1894-0

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Kang JH, Keller JJ, Lin HC (2013) Bisphosphonates reduced the risk of acute myocardial infarction: a 2-year follow-up study. Osteoporos Int 24:271–277. https://doi.org/10.1007/s00198-012-2213-5

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Wolfe F, Bolster MB, O'Connor CM, Michaud K, Lyles KW, Colon-Emeric CS (2013) Bisphosphonate use is associated with reduced risk of myocardial infarction in patients with rheumatoid arthritis. J Bone Miner Res 28:984–991. https://doi.org/10.1002/jbmr.1792

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Pittman CB, Davis LA, Zeringue AL, Caplan L, Wehmeier KR, Scherrer JF, Xian H, Cunningham FE, McDonald JR, Arnold A, Eisen SA (2014) Myocardial infarction risk among patients with fractures receiving bisphosphonates. Mayo Clin Proc 89:43–51. https://doi.org/10.1016/j.mayocp.2013.08.021

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Kim DH, Rogers JR, Fulchino LA, Kim CA, Solomon DH, Kim SC (2015) Bisphosphonates and risk of cardiovascular events: a meta-analysis. PLoS One 10:e0122646. https://doi.org/10.1371/journal.pone.0122646

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Kranenburg G, Bartstra JW, Weijmans M, de Jong PA, Mali WP, Verhaar HJ, Visseren FLJ, Spiering W (2016) Bisphosphonates for cardiovascular risk reduction: a systematic review and meta-analysis. Atherosclerosis 252:106–115 DOI S0021-9150(16)30284-2 [pii]

    CAS  Article  Google Scholar 

  24. 24.

    Fiore CE, Pennisi P, Pulvirenti I, Francucci CM (2009) Bisphosphonates and atherosclerosis. J Endocrinol Investig 32:38–43

    CAS  Google Scholar 

  25. 25.

    Santos LL, Cavalcanti TB, Bandeira FA (2012) Vascular effects of bisphosphonates-a systematic review. Clin Med Insights Endocrinol Diabetes 5:47–54. https://doi.org/10.4137/CMED.S10007

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Ray WA (2003) Evaluating medication effects outside of clinical trials: new-user designs. Am J Epidemiol 158:915–920. https://doi.org/10.1093/aje/kwg231

    Article  PubMed  Google Scholar 

  27. 27.

    BIFAP Base de Datos para la Investigación Farmacoepidemiológica en Atención Primaria. Available online: http://www.bifap.org (accessed on 28 December 2019)

  28. 28.

    Juutilainen A, Lehto S, Ronnemaa T, Pyorala K, Laakso M (2005) Type 2 diabetes as a “coronary heart disease equivalent”: an 18-year prospective population-based study in Finnish subjects. Diabetes Care 28:2901–2907 DOI 28/12/2901 [pii]

    Article  Google Scholar 

  29. 29.

    Altman DG, Bland JM (2003) Interaction revisited: the difference between two estimates. BMJ 326:219. https://doi.org/10.1136/bmj.326.7382.219

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Azur MJ, Stuart EA, Frangakis C, Leaf PJ (2011) Multiple imputation by chained equations: what is it and how does it work? Int J Methods Psychiatr Res 20:40–49. https://doi.org/10.1002/mpr.329

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Jackson B, Gee AN, Guyon-Gellin Y, Niesor E, Bentzen CL, Kerns WD, Suckling KE (2000) Hypocholesterolaemic and antiatherosclerotic effects of tetra-iso-propyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl-1,1-diphosphonate (SR-9223i). Arzneimittelforschung 50:380–386. https://doi.org/10.1055/s-0031-1300217

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Ylitalo R, Oksala O, Yla-Herttuala S, Ylitalo P (1994) Effects of clodronate (dichloromethylene bisphosphonate) on the development of experimental atherosclerosis in rabbits. J Lab Clin Med 123:769–776

    CAS  PubMed  Google Scholar 

  33. 33.

    Ylitalo R, Syvala H, Tuohimaa P, Ylitalo P (2002) Suppression of immunoreactive macrophages in atheromatous lesions of rabbits by clodronate. Pharmacol Toxicol 90:139–143. https://doi.org/10.1034/j.1600-0773.2002.900305.x

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Hollander W, Paddock J, Nagraj S, Colombo M, Kirkpatrick B (1979) Effects of anticalcifying and antifibrobrotic drugs on pre-established atherosclerosis in the rabbit. Atherosclerosis 33:111–123 DOI 0021-9150(79)90202-8 [pii]

    CAS  Article  Google Scholar 

  35. 35.

    Koshiyama H, Nakamura Y, Tanaka S, Minamikawa J (2000) Decrease in carotid intima-media thickness after 1-year therapy with etidronate for osteopenia associated with type 2 diabetes. J Clin Endocrinol Metab 85:2793–2796. https://doi.org/10.1210/jcem.85.8.6748

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Ikeda K, Takahashi T, Yamada H, Matsui K, Sawada T, Nakamura T, Matsubara H, (for the PEACE Investigators) (2013) Effect of intensive statin therapy on regression of carotid intima-media thickness in patients with subclinical carotid atherosclerosis (a prospective, randomized trial: PEACE (Pitavastatin Evaluation of Atherosclerosis Regression by Intensive Cholesterol-lowering Therapy) study). Eur J Prev Cardiol 20:1069–1079 DOI https://doi.org/10.1177/2047487312451539

    Article  PubMed  Google Scholar 

  37. 37.

    Crouse JR, Raichlen JS, Riley WA, Evans GW, Palmer MK, O'Leary DH, Grobbee DE, Bots ML, METEOR Study Group (2007) Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA 297:1344–1353 297.12.1344 [pii]

    CAS  Article  Google Scholar 

  38. 38.

    Celiloglu M, Aydin Y, Balci P, Kolamaz T (2009) The effect of alendronate sodium on carotid artery intima-media thickness and lipid profile in women with postmenopausal osteoporosis. Menopause 16:689–693

    Article  Google Scholar 

  39. 39.

    Toussaint ND, Lau KK, Strauss BJ, Polkinghorne KR, Kerr PG (2010) Effect of alendronate on vascular calcification in CKD stages 3 and 4: a pilot randomized controlled trial. Am J Kidney Dis 56:57–68. https://doi.org/10.1053/j.ajkd.2009.12.039

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Tanko LB, Qin G, Alexandersen P, Bagger YZ, Christiansen C (2005) Effective doses of ibandronate do not influence the 3-year progression of aortic calcification in elderly osteoporotic women. Osteoporos Int 16:184–190. https://doi.org/10.1007/s00198-004-1662-x

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Blumenthal RS, Kapur NK (2006) Can a potent statin actually regress coronary atherosclerosis? JAMA 295:1583–1584 DOI 295.13.jed60019 [pii]

    CAS  Article  Google Scholar 

  42. 42.

    Sing CW, Wong AY, Kiel DP, Cheung EY, Lam JK, Cheung TT, Chan EW, Kung AW, Wong IC, Cheung CL (2018) Association of alendronate and risk of cardiovascular events in patients with hip fracture. J Bone Miner Res 33:1422–1434. https://doi.org/10.1002/jbmr.3448

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Kanazawa I, Yamaguchi T, Yano S, Yamamoto M, Yamauchi M, Kurioka S, Sugimoto T (2010) Baseline atherosclerosis parameter could assess the risk of bone loss during pioglitazone treatment in type 2 diabetes mellitus. Osteoporos Int 21:2013–2018

    CAS  Article  Google Scholar 

  44. 44.

    Reid IR, Horne AM, Mihov B, Stewart A, Garratt E, Wong S, Wiessing KR, Bolland MJ, Bastin S, Gamble GD (2018) Fracture prevention with zoledronate in older women with osteopenia. N Engl J Med 379:2407–2416. https://doi.org/10.1056/NEJMoa1808082

    CAS  Article  PubMed  Google Scholar 

  45. 45.

    Reid IR, Horne AM, Mihov B, Stewart A, Garratt E, Bastin S, Gamble GD (2020) Effects of zoledronate on cancer, cardiac events, and mortality in Osteopenic older women. J Bone Miner Res 35:20–27. https://doi.org/10.1002/jbmr.3860

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study’s authors would like to thank the excellent collaboration of primary care practitioners participating in BIFAP. We also owe a debt of gratitude to the staff members of the BIFAP Unit.

Funding

BIFAP is funded and operated by the Spanish Agency for Medicines and Medical Devices (AEMPS, by its Spanish acronym). This study was supported by a research grant from Instituto de Salud Carlos IIIMinisterio de Ciencia e Innovación (# PI16/01353), granted to F.d.A., co-funded by FEDER.

Author information

Affiliations

Authors

Corresponding author

Correspondence to F.J. de Abajo.

Ethics declarations

Conflicts of interest

None

Additional information

Outcomes, discussion, and conclusions have been issued by the authors of this study and do not necessarily reflect the position of AEMPS.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 42.9 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mazzucchelli, R., Rodríguez-Martín, S., García-Vadillo, A. et al. Risk of acute myocardial infarction among new users of bisphosphonates: a nested case–control study. Osteoporos Int 31, 2403–2412 (2020). https://doi.org/10.1007/s00198-020-05538-2

Download citation

Keywords

  • Acute myocardial infarction
  • Antiresorptive agents, osteoporosis
  • Bisphosphonates