Advertisement

Osteoporosis International

, Volume 29, Issue 2, pp 467–478 | Cite as

Risk of venous thromboembolism among users of different anti-osteoporosis drugs: a population-based cohort analysis including over 200,000 participants from Spain and the UK

  • E. Martín-MerinoEmail author
  • I. Petersen
  • S. Hawley
  • A. Álvarez-Gutierrez
  • S. Khalid
  • A. Llorente-Garcia
  • A. Delmestri
  • M. K. Javaid
  • T. P. Van Staa
  • A. Judge
  • C. Cooper
  • D. Prieto-Alhambra
Original Article

Abstract

Summary

The venous thromboembolism risk among anti-osteoporotics is unknown. In this primary care study, the risk with other bisphosphonates [1.05 (0.94–1.18) and 0.96 (0.78–1.18)], strontium [0.90 (0.61–1.34) and 1.19 (0.82–1.74)], in the UK and Spain respectively, and denosumab [1.77 (0.25–12.66)] and teriparatide [1.27 (0.59–2.71)] in Spain, did not differ versus alendronate.

Introduction

Most of the known adverse drug reactions described for anti-osteoporosis medication (AOM) have been described in studies comparing AOM users to non-users. We aimed to compare the risk of venous thromboembolism (VTE) among incident users of different AOM compared to alendronate (first line therapy).

Methods

Two cohort studies were performed using data from the UK (CPRD) and Spain (BIFAP) primary care records separately. All patients aged ≥ 50 years with at least 1 year of data available and a new prescription or dispensation of AOM (date for therapy initiation) during 2000–2014 (CPRD) or 2001–2013 (BIFAP) were included. Users of raloxifene/bazedoxifene were excluded from both databases. Five exposure cohorts were identified according to first treatment: (1) alendronate, (2) other bisphosphonates, (3) strontium ranelate, (4) denosumab, and (5) teriparatide. Participants were followed from the day after therapy initiation to the earliest of a treated VTE (cases), end of AOM treatment (defined by a refill gap of 180 days), switching to an alternative AOM, drop-out, death, or end of study period. Incidence rates of VTE were estimated by cohort. Adjusted hazard ratios (HR 95%CI) were estimated according to drug used.

Results

Overall, 2035/159,209 (1.28%) in CPRD and 401/83,334 (0.48%) in BIFAP had VTE. Compared to alendronate, adjusted HR of VTE were 1.05 (0.94–1.18) and 0.96 (0.78–1.18) for other bisphosphonates, and 0.90 (0.61–1.34) and 1.19 (0.82–1.74) for strontium in CPRD and BIFAP, respectively; 1.77 (0.25–12.66) for denosumab and 1.27 (0.59–2.71) for teriparatide in BIFAP.

Conclusions

VTE risk during AO therapy did not differ by AOM drug use. Our data does not support an increased risk of VTE associated with strontium ranelate use in the community.

Keywords

Anti-osteoporosis medication Electronic health records Pharmacoepidemiology Primary care Venous thromboembolism 

Notes

Acknowledgements

This study is based in part on data from the Clinical Practice Research Datalink obtained under license from the UK Medicines and Healthcare products Regulatory Agency. The data is provided by patients and collected by the NHS as part of their care and support.

This study is based in part on data from the “Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria” (BIFAP) fully financed by the Spanish Agency on Medicines and Medical Devices (AEMPS). The authors would like to acknowledge the excellent collaboration of the primary care general practitioners, pediatricians, and patients taking part in the primary care records and the support of the regional governments, and they thank Monica Ríos Martinez, for her participation in the review of the clinical profiles.

Funding

Partial funding from UK National Osteoporosis Society (Project Grant).

Compliance with ethical standards

Competing interest

EMM, SH, SK, AAG, AD, and ALG, declare no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, no other relationships or activities that could appear to have influenced the submitted work.

IP supervises a PhD student who is funded by Novo Nordisk.

DPA had an unrestricted research grants from Servier Laboratoires; AMGEN.

MKJ has received honoraria, travel and/or subsistence expenses in the last 5 years from: Amgen, Eli Lilly, Medtronic, Norvartis, Proctor and Gamble, Servier, Shire, Internis, Consilient Health, Stirling Anglia Pharmaceuticals, Mereo Biopharma, Optasia.

TPVS has provided consultancy to GSK, Roche, Laser, and Sanofi.

AJ has received consultancy fees, lecture fees, and honoraria from Servier, UK Renal Registry, Oxford Craniofacial Unit, IDIAP Jordi Gol and Freshfields Bruckhaus Deringer, a member of the Data Safety and Monitoring Board (which involved receipt of fees) from Anthera Pharmaceuticals, Inc., and received consortium research grants from Roche.

CC has received consultancy fees and honoraria from Alliance for Better Bone Health, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda, and UCB.

The interpretation and conclusions contained in this study are those of the author/s alone.

Supplementary material

198_2017_4308_MOESM1_ESM.docx (42 kb)
ESM 1 (DOCX 41.6 kb).

References

  1. 1.
    European Medicines Agency. Protelos. Background information on the procedure [Internet]. 2005 [cited 2017 Mar 13]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Procedural_steps_taken_before_authorisation/human/000560/WC500045523.pdf
  2. 2.
    European Medicines Agency. CHMP Type II variation assessment report. Invented name Protelos. Procedure No. EMEA/H/C/000560/II/0031 [Internet]. 2012 May [cited 2017 Mar 13]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000560/WC500131790.pdf
  3. 3.
    European Medicines Agency. PSUR assessment report. Strontium ranelate. EMA/PRAC/136656/2013 [Internet]. 2013 [cited 2016 Jun 23]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000560/WC500147168.pdf
  4. 4.
    European Medicines Agency. Assessment report for Protelos and Osseor. Review under Article 20 of Regulation (EC) No 726/2004 [Internet]. 2012 May [cited 2016 Jun 23]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000561/WC500131785.pdf
  5. 5.
    European Medicines Agency. Protelos and Osseor-CHMP scientific conclusions and PRAC Assessment report of the Review under Article 20 of Regulation (EC) No 726/2004 [Internet]. 2014 [cited 2017 Mar 13]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Conclusion/human/000560/WC500169913.pdf
  6. 6.
    Agencia Española de Medicamentos y Productos Sanitarios. Ranelato de estroncio (Osseor®, Protelos®): calificado como medicamento de diagnóstico hospitalario [Internet]. Agencia Española de Medicamentos y Productos Sanitarios; 2014 Jul [cited 2015 Jul 28]. Available from: http://www.aemps.gob.es/informa/notasInformativas/medicamentosUsoHumano/seguridad/2014/NI-MUH_FV_09-2014-ranelato.htm
  7. 7.
    Agencia Española de Medicamentos y Productos Sanitarios. Ranelato de estroncio (Osseor®, Protelos®): la revisión europea concluye que el balance beneficio-riesgo es desfavorable [Internet]. Agencia Española de Medicamentos y Productos Sanitarios; 2014 Jan [cited 2015 Jul 28]. Available from: http://www.aemps.gob.es/informa/notasInformativas/medicamentosUsoHumano/seguridad/2014/NI-MUH_FV_01-2014-ranelato-estroncio.htm
  8. 8.
    Medicines & Healthcare products, Regulatory Agency. Strontium ranelate: cardiovascular risk. Restricted indication and new monitoring requirements [Internet]. 2014 [cited 2017 Mar 13]. Available from: https://www.gov.uk/drug-safety-update/strontium-ranelate-cardiovascular-risk
  9. 9.
    Clinical Practice Research Datalink-CPRD [Internet]. [cited 2017 Feb 28]. Available from: https://www.cprd.com/intro.asp
  10. 10.
    Hospital Episode Statistics-NHS Digital [Internet]. [cited 2017 Mar 1]. Available from: http://content.digital.nhs.uk/hes
  11. 11.
    The British National Formulary [Internet]. BNF Publications. [cited 2017 Apr 27]. Available from: https://www.bnf.org/
  12. 12.
    O’Neil M, Payne C, Read J (1995) Read codes version 3: a user led terminology. Methods Inf Med 34(1–2):187–192PubMedGoogle Scholar
  13. 13.
    Stuart-Buttle CD, Read JD, Sanderson HF, Sutton YM (1996) A language of health in action: read codes, classifications and groupings. Proc Conf Am Med Inform Assoc AMIA Fall Symp:75–79Google Scholar
  14. 14.
    Agencia Española del Medicamento y Productos Sanitarios. BIFAP: Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria [Internet]. [cited 2017 Jan 31]. Available from: http://bifap.aemps.es/
  15. 15.
    European Medicines Agency. Evista-Summary of product characteristics [Internet]. [cited 2017 Mar 13]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000184/WC500031011.pdf
  16. 16.
    Gardarsdottir H, Souverein PC, Egberts TCG, Heerdink ER (2010) Construction of drug treatment episodes from drug-dispensing histories is influenced by the gap length. J Clin Epidemiol 63(4):422–427.  https://doi.org/10.1016/j.jclinepi.2009.07.001 CrossRefPubMedGoogle Scholar
  17. 17.
    Venous thromboembolism: reducing the risk for patients in hospital. Guidance and guidelines NICE [Internet]. NICE; 2015 Jun [cited 2016 Jun 17]. Available from: https://www.nice.org.uk/guidance/cg92/chapter/1-recommendations#assessing-the-risks-of-vte-and-bleeding-2
  18. 18.
    Carpenter J, Kenward M (2013) Survival data, skips and large datasets. In: Multiple Imputation and its Application. First Edition. Wiley; p. 167–202Google Scholar
  19. 19.
    Jonville-Bera A-P, Autret-Leca E (2011) Ranélate de strontium (Protelos®) : effets indésirables rapportés en France. Presse Med 40(10):e453–e462.  https://doi.org/10.1016/j.lpm.2011.07.010 CrossRefPubMedGoogle Scholar
  20. 20.
    European Medicines Agency. European Medicines Agency starts review of Protelos/Osseor [Internet]. 2011 [cited 2017 Aug 28]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/10/news_detail_001366.jsp&mid=WC0b01ac058004d5c1
  21. 21.
    Berencsi K, Sanni Ali M, Marinier K, Deltour N, Hawley S, Pedersen L, Rijnbeek P, Duijnhoven RG, Van der Lei J, Lappi F, Simonetti M, Reyes-Reyes C, Sturkenboom M, Prieto-Alhambra D (2017) Impact of risk minimisation measures on the use of strontium ranelate: a multi-national cohort study in 5 EU countries by the EU-ADR alliance. Pharmacoepidemiol Drug Saf 26(Suppl 2):483Google Scholar
  22. 22.
    Breart G, Cooper C, Meyer O, Speirs C, Deltour N, Reginster JY (2010) Osteoporosis and venous thromboembolism: a retrospective cohort study in the UK general practice research database. Osteoporos Int J Establ Result Coop Eur Found Osteoporos Natl Osteoporos Found USA 21(7):1181–1187.  https://doi.org/10.1007/s00198-009-1050-7 CrossRefGoogle Scholar
  23. 23.
    Grosso A, Douglas I, Hingorani A, MacAllister R, Smeeth L (2008) Post-marketing assessment of the safety of strontium ranelate; a novel case-only approach to the early detection of adverse drug reactions. Br J Clin Pharmacol 66(5):689–694.  https://doi.org/10.1111/j.1365-2125.2008.03273.x CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Sanni Ali M, Berencsi K, Marinier K, Deltour N, Hawley S, Pedersen L, Rijnbeek P, Duijnhoven RG, Van der Lei J, Lappi F, Simonetti M, Reyes-Reyes C, Sturkenboom M, Prieto-Alhambra D (2017) Comparative cardiovascular safety of strontium ranelate and bisphosphonates amongst patients with no contraindications: a multi-database study in our European countries by the EU-ADR alliance. Pharmacoepidemiol Drug Saf 26(Suppl 2):47Google Scholar
  25. 25.
    Osborne V, Layton D, Perrio M, Wilton L, Shakir SAW (2010) Incidence of venous thromboembolism in users of strontium ranelate: an analysis of data from a prescription-event monitoring study in England. Drug Saf 33(7):579–591.  https://doi.org/10.2165/11533770-000000000-00000 CrossRefPubMedGoogle Scholar
  26. 26.
    Martín-Merino E, Huerta-Álvarez C, Prieto-Alhambra D, Montero-Corominas D (2017) Cessation rate of anti-osteoporosis treatments and risk factors in Spanish primary care settings: a population-based cohort analysis. Arch Osteoporos 12(1):39.  https://doi.org/10.1007/s11657-017-0331-6 CrossRefPubMedGoogle Scholar
  27. 27.
    Carbonell-Abella C, Pages-Castella A, Javaid MK, Nogues X, Farmer AJ, Cooper C et al (2015) Early (1-year) discontinuation of different anti-osteoporosis medications compared: a population-based cohort study. Calcif Tissue Int 97(6):535–541.  https://doi.org/10.1007/s00223-015-0040-3
  28. 28.
    Penning-van Beest FJA, Goettsch WG, Erkens JA, Herings RMC (2006) Determinants of persistence with bisphosphonates: a study in women with postmenopausal osteoporosis. Clin Ther 28(2):236–242.  https://doi.org/10.1016/j.clinthera.2006.01.002 CrossRefPubMedGoogle Scholar
  29. 29.
    Huerta C, Johansson S, Wallander M-A, García Rodríguez LA (2007) Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med 167(9):935–943.  https://doi.org/10.1001/archinte.167.9.935 CrossRefPubMedGoogle Scholar
  30. 30.
    Lawrenson R, Todd JC, Leydon GM, Williams TJ, Farmer RD (2000) Validation of the diagnosis of venous thromboembolism in general practice database studies. Br J Clin Pharmacol 49(6):591–596CrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2017

Authors and Affiliations

  • E. Martín-Merino
    • 1
    Email author
  • I. Petersen
    • 2
  • S. Hawley
    • 3
  • A. Álvarez-Gutierrez
    • 1
  • S. Khalid
    • 3
  • A. Llorente-Garcia
    • 1
  • A. Delmestri
    • 3
  • M. K. Javaid
    • 4
  • T. P. Van Staa
    • 5
  • A. Judge
    • 3
  • C. Cooper
    • 6
    • 7
  • D. Prieto-Alhambra
    • 3
    • 8
    • 9
  1. 1.BIFAP, Division of Pharmacoepidemiology and PharmacovigilanceSpanish Agency of Medicines and Medical Devices (AEMPS)MadridSpain
  2. 2.Department of Primary Care and Population HealthUniversity College LondonLondonUK
  3. 3.Centre for Statistics in Medicine, Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal SciencesUniversity of OxfordOxfordUK
  4. 4.Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal SciencesUniversity of OxfordOxfordUK
  5. 5.Health eResearch CentreUniversity of ManchesterManchesterUK
  6. 6.MRC Lifecourse Epidemiology Unit, Faculty of MedicineUniversity of SouthamptonSouthamptonUK
  7. 7.Elsie Widdowson Laboratory Oxford NIHR Musculoskeletal Biomedical Research Unit, MRC Human Nutrition ResearchUniversity of OxfordSouthamptonUK
  8. 8.GREMPAL Research Group, Idiap Jordi Gol and CIBERFesUniversitat Autonoma de BarcelonaBarcelonaSpain
  9. 9.Instituto de Salud Carlos IIIMadridSpain

Personalised recommendations