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Persistence with bisphosphonates in patients with metastatic breast cancer: a retrospective database analysis



In women with breast cancer and bone metastasis, compliance to antiresorptive treatment is of upmost importance to ensure maximum effectiveness in clinical practice. The aim of our study was to investigate persistence with oral and intravenous bisphosphonates (BIS) in a large group of women with metastatic breast cancer and to identify the determinants of non-persistence.

Patients and methods

We used data from the Disease Analyzer database (IMS Health, Germany), which includes 2,067 general practices and 397 gynaecological practices. From a dataset of 20 million patients, we identified 1,045 patients diagnosed between January 2001 and December 2010 with bone metastasis (ICD 10: C795) following breast cancer (ICD 10: C50) with first-time cancer-related bisphosphonate prescriptions (ATC: M03B4). Of these, 763 patients received intravenous treatment, and 280 patients received oral BIS treatment.


After 1 year, 35.3 % of patients treated with intravenous, and 45.6 % of patients treated with oral bisphosphonates discontinued their therapy (p = 0.002). Multivariate Cox Regression analyses showed a significant increased risk of treatment discontinuation in patients using intravenous BIS (HR: 0.82) compared with oral BIS. Patients younger than 50 (HR: 1.52) were most likely to discontinue treatment compared with the reference group of women over 70. The use of other treatments, such as chemotherapy or hormone therapy, was associated with a decreased risk of treatment discontinuation. Moreover, treatment discontinuation was higher in West Germany compared with East Germany (HR: 1.65) and in patients covered under private health insurance (HR: 1.33).


Persistence with all bisphosphonate treatments in women with breast cancer and bone metastasis is low and needs to be significantly increased to improved outcomes in clinical practice. Further research is required to understand this complex issue.

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  1. Aapro M, Saad F, Costa L (2010) Optimizing clinical benefits of bisphosphonates in cancer patients with bone metastases. Oncologist 11:1147–1158

  2. Andrade SE, Kahler KH, Frech F, Chan KA (2006) Methods for evaluation of medication adherence and persistence using automated databases. Pharmacoepidemiol Drug Saf 15:565–574

  3. Balkrishnan R (2005) The importance of medication adherence in improving chronic-disease related outcomes: what we know and what we need to further know. Med Care 43:517–520

  4. Becher H, Kostev K, Schröder-Bernhardi D (2009) Validity and representativeness of the disease analyzer patient database for use in pharmacoepidemiological and pharmacoeconomic studies. Int J Clin Pharm Ther 47:617–662

  5. Coleman RE (2001) Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27:165–176

  6. Conte P, Guarneri V (2004) Safety of intravenous and oral bisphosphonates and compliance with dosing regiments. Oncologist 9(suppl 4):28–37

  7. Cramer JA, Lynch NO, Gaudin AF et al (2006) The effect of dosing frequency on compliance and persistence with bisphosphonate therapy in postmenopausal women: a comparison of studies in the United States, the United Kingdom, and France. Clin Ther 28:1686–1694

  8. Davidson B, Vogel V, Wickerham L (2007) Oncologist–patient discussion of adjuvant hormonal therapy in breast cancer: results of a linguistic study focusing on adherence and persistence to therapy. J Support Oncol 5:139–143

  9. Dezii CM (2001) Persistence with drug therapy: a practical approach using administrative claims data. Manag Care 10:42–45

  10. Grunfeld EA, Hunter MS, Sikka P et al (2005) Adherence beliefs among breast cancer patients taking tamoxifen. Patient Educ Couns 59:97–102

  11. Hadji P (2010) Improving compliance and persistence to adjuvant tamoxifen and aromatase inhibitor therapy. Crit Rev Oncol Hematol 73(2):156–166

  12. Hadji P, Gnant M, Aapro M (2010) Dosing of zoledronic acid throughout the treatment continuum in patients with breast cancer. Crit Rev Oncol Hematol 79(2):175–188

  13. Hadji P, Aapro M, Costa L, Gnant M (2012a) Antiresorptive treatment options and bone health in cancer patients-safety profiles and clinical considerations. Cancer Treat Rev 38(6):815–824

  14. Hadji P, Claus V, Steinle T et al (2012b) GRAND: the German retrospective cohort analysis on non-adherence and associated risk of fractures in osteoporotic women treated with oral bisphosphonates. Osteoporos Int 23(1):223–231

  15. Hadji P, Kostev K, Schröder-Bernhardi D et al (2012c) Cost comparison of outpatient treatment with granulocyte colony-stimulating factors (G-CSF) in Germany. Int J Clin Pharmacol Ther 50(4):281–289

  16. Hadji P, Ziller V, Kyvernitakis J et al (2013a) Persistence in patients with breast cancer treated with tamoxifen or aromatase inhibitors: a retrospective database analysis. Breast Cancer Res Treat 138(1):185–191

  17. Hadji P, Blettner M, Harbeck N et al (2013b) The patient’s anastrozole compliance to therapy (PACT) programme. A randomized, in-practice study on the impact of a standardized information programme on persistence and compliance to adjuvant endocrine therapy in postmenopausal women with early breast cancer. Ann Oncol [Epub ahead of print]

  18. Haynes RB, Ackloo E, Sahota N et al (2008) Interventions for enhancing medication adherence. Cochrane database. Syst Rev CD000011. doi:10.1002/14651858.CD000011.pub3

  19. Himei A, Okamura T (2006) Discontinuation syndrome associated with paroxetine in depressed patients: a retrospective analysis of factors involved in the occurrence of the syndrome. CNS Drugs 20(8):665–672

  20. Horne R, Weinman J (1999) Patients’ beliefs about prescribed medicines and their role in adherence to treatment in chronic physical illness. J Psychosom Res 47:555–567

  21. Iwamoto J, Miyata A, Sato Y et al (2009) Factors affecting discontinuation of alendronate treatment in postmenopausal Japanese women with osteoporosis. J Chin Med Assoc 72(12):619–624

  22. Kahn KL, Schneider EC, Malin JL et al (2007) Patient centered experiences in breast cancer: predicting long-term adherence to tamoxifen use. Med Care 45:431–439

  23. Kostev K, Haas G (2011) Medical care in Germany. Optimus, Göttingen

  24. Major PP, Cook R (2002) Efficacy of bisphosphonates in the management of skeletal complications of bone metastases and selection of clinical endpoints. Am J Clin Oncol 25(suppl 1):10–18

  25. Mangiapane S, Hoer A, Gothe H et al (2006) Higher persistency with i.v. bisphosphonates in patients with bone metastasis. J Clin Oncol ASCO Ann Meet Proc Part I 24(18S):18623

  26. Motheral B, Brooks J, Clark MA et al (2003) A checklist for retrospective database studies—report of the ISPOR task force on retrospective databases. Value Health 6:90–97

  27. Ogdie A, Langan S, Parkinson J et al (2012) Medical Record Databases. In: Strom BL, Kimmel S, Hennessy S (eds) Pharmacoepidemiology, 5th edn. University of Pennsylvania, Philadelphia, PA, pp 224–243

  28. Osterberg L, Blaschke T (2005) Adherence to medication. N Engl J Med 353:487–497

  29. Partridge AH, Wang PS, Winer EP, Avorn J (2003) Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol 21:6002–6006

  30. Pockett RD, Castellano D, McEwan P, Oglesby A, Barber BL, Chung K (2010) The hospital burden of disease associated with bone metastases and skeletal-related events in patients with breast cancer, lung cancer, or prostate cancer in Spain. Eur J Cancer Care (Engl) 19(6):755–760

  31. Robert Koch Institut (2012) Krebs in Deutschland. Accessed 20 Aug 2012

  32. Rubens RD, Coleman RE (1995) Bone metastases. In: Abeloff MD, Armitage JO, Lichter AS, Niederhuber JE (eds) Clinical oncology. Churchill Livingstone, New York, pp 643–657

  33. Saad F, Lipton A, Cook R et al (2007) Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer 110:1860–1867

  34. Von Moos R (2005) Bisphosphonate treatment recommendations for oncologists. Oncologists 10(suppl 1):19–24

  35. Weinfurt KP, Castel LD, Li Y, Timbie JW, Glendenning GA, Schulman KA (2004) Health-related quality of life among patients with breast cancer receiving zoledronic acid or pamidronate disodium for metastatic bone lesions. Med Care 42:164–175

  36. World Health Organization (2003) Adherence to long-term therapies: evidence for action. World Health Organization, Geneva

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Conflict of interest

PH received speaker’s fee, educational and research funding from Amgen, Astra Zeneca, Elli Lilly, Novartis, Pfizer, and Roche. VZ and YK have no conflicts of interest to declare. KK and NS are employers of IMS with no further conflicts of interest.

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Correspondence to K. Kostev.

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Hadji, P., Ziller, V., Kyvernitakis, J. et al. Persistence with bisphosphonates in patients with metastatic breast cancer: a retrospective database analysis. J Cancer Res Clin Oncol 139, 1149–1155 (2013).

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  • Breast cancer
  • Persistence
  • Bisphosphonates
  • Bone metastasis
  • Compliance