Calcified Tissue International

, Volume 86, Issue 3, pp 202–210 | Cite as

Potential Clinical and Economic Impact of Nonadherence with Osteoporosis Medications

  • Mickaël Hiligsmann
  • Véronique Rabenda
  • Henry-Jean Gathon
  • Olivier Ethgen
  • Jean-Yves Reginster


This study aims to estimate the potential clinical and economic implications of therapeutic adherence to bisphosphonate therapy. A validated Markov microsimulation model was used to estimate the impact of varying adherence to bisphosphonate therapy on outcomes (the number of fractures and the quality-adjusted life-years [QALYs]), health-care costs, and the cost-effectiveness of therapy compared with no treatment. Adherence was divided into persistence and compliance, and multiple scenarios were considered for both concepts. Analyses were performed for women aged 65 years with a bone mineral density T-score of −2.5. Health outcomes and the cost-effectiveness of therapy improved significantly with increasing compliance and/or persistence. In the case of real-world persistence and with a medical possession ratio (MPR; i.e., the number of doses taken divided by the number of doses prescribed) of 100%, the QALY gain and the number of fractures prevented represented only 48 and 42% of the values estimated assuming full persistence, respectively. These proportions fell to 27 and 23% with an MPR value of 80%. The costs per QALY gained, for branded bisphosphonates (and generic alendronate), were estimated at €19,069 (€4,871), €32,278 (€11,985), and €64,052 (€30,181) for MPR values of 100, 80, and 60%, respectively, assuming real-world persistence. These values were €16,997 (€2,215), €24,401 (€6,179), and €51,750 (€20,569), respectively, assuming full persistence. In conclusion, poor compliance and failure to persist with osteoporosis medications results not only in deteriorating health outcomes, but also in a decreased cost-effectiveness of drug therapy. Adherence therefore remains an important challenge for health-care professionals treating osteoporosis.


Adherence Burden Compliance Cost-effectiveness Osteoporosis Persistence 


  1. 1.
    Osterberg L, Blaschke T (2005) Adherence to medication. N Engl J Med 353:487–497CrossRefPubMedGoogle Scholar
  2. 2.
    Hughes DA, Bagust A, Haycox A, Walley T (2001) The impact of non-compliance on the cost-effectiveness of pharmaceuticals: a review of the literature. Health Econ 10:601–615CrossRefPubMedGoogle Scholar
  3. 3.
    Cleemput I, Kesteloot K, DeGeest S (2002) A review of the literature on the economics of noncompliance. Room for methodological improvement. Health Policy 59:65–94CrossRefPubMedGoogle Scholar
  4. 4.
    Hughes D, Cowell W, Koncz T, Cramer J (2007) Methods for integrating medication compliance and persistence in pharmacoeconomic evaluations. Value Health 10:498–509CrossRefPubMedGoogle Scholar
  5. 5.
    Huybrechts KF, Ishak KJ, Caro JJ (2006) Assessment of compliance with osteoporosis treatment and its consequences in a managed care population. Bone 38:922–928CrossRefPubMedGoogle Scholar
  6. 6.
    Rabenda V, Mertens R, Fabri V, Vanoverloop J, Sumkay F, Vannecke C, Deswaef A, Verpooten GA, Reginster JY (2008) Adherence to bisphosphonates therapy and hip fracture risk in osteoporotic women. Osteoporos Int 19:811–818CrossRefPubMedGoogle Scholar
  7. 7.
    Siris ES, Harris ST, Rosen CJ, Barr CE, Arvesen JN, Abbott TA, Silverman S (2006) Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc 81:1013–1022CrossRefPubMedGoogle Scholar
  8. 8.
    Weycker D, Macarios D, Edelsberg J, Oster G (2006) Compliance with drug therapy for postmenopausal osteoporosis. Osteoporos Int 17:1645–1652CrossRefPubMedGoogle Scholar
  9. 9.
    World Health Organization (1994) Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser 843:1–129Google Scholar
  10. 10.
    Cramer JA, Roy A, Burrell A, Fairchild CJ, Fuldeore MJ, Ollendorf DA, Wong PK (2008) Medication compliance and persistence: terminology and definitions. Value Health 11:44–47PubMedGoogle Scholar
  11. 11.
    Cleemput I, van Wilder P, Huybrechts M, Vrijens F (2009) Belgian methodological guidelines for pharmacoeconomic evaluations: toward standardization of drug reimbursement requests. Value Health 12:441–449CrossRefPubMedGoogle Scholar
  12. 12.
    Hiligsmann M, Bruyere O, Ethgen O, Gathon HJ, Reginster JY (2008) Lifetime absolute risk of hip and other osteoporotic fracture in Belgian women. Bone 43:991–994CrossRefPubMedGoogle Scholar
  13. 13.
    Reginster JY, Gillet P, Gosset C (2001) Secular increase in the incidence of hip fractures in Belgium between 1984 and 1996: need for a concerted public health strategy. Bull World Health Organ 79:942–946PubMedGoogle Scholar
  14. 14.
    Kanis JA, Brazier JE, Stevenson M, Calvert NW, Lloyd Jones M (2002) Treatment of established osteoporosis: a systematic review and cost-utility analysis. Health Technol Assess 6:1–146PubMedGoogle Scholar
  15. 15.
    Johnell O, Gullberg B, Kanis JA (1997) The hospital burden of vertebral fracture in Europe: a study of national register sources. Osteoporos Int 7:138–144CrossRefPubMedGoogle Scholar
  16. 16.
    Kanis JA, Johnell O, Oden A, Dawson A, De Laet C, Jonsson B (2001) Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds. Osteoporos Int 12:989–995CrossRefPubMedGoogle Scholar
  17. 17.
    Singer BR, McLauchlan GJ, Robinson CM, Christie J (1998) Epidemiology of fractures in 15,000 adults: the influence of age and gender. J Bone Joint Surg Br 80:243–248CrossRefPubMedGoogle Scholar
  18. 18.
    Melton LJ 3rd, Crowson CS, O’Fallon WM (1999) Fracture incidence in Olmsted County, Minnesota: comparison of urban with rural rates and changes in urban rates over time. Osteoporos Int 9:29–37CrossRefPubMedGoogle Scholar
  19. 19.
    Institut National de Statistique (2006) Démographie mathématique. Tables de mortalité 2004 et 2002–2004. Direction Générale Statistique et Information Economique, BelgiqueGoogle Scholar
  20. 20.
    Oden A, Dawson A, Dere W, Johnell O, Jonsson B, Kanis JA (1998) Lifetime risk of hip fractures is underestimated. Osteoporos Int 8:599–603CrossRefPubMedGoogle Scholar
  21. 21.
    Kanis JA, Oden A, Johnell O, De Laet C, Jonsson B (2004) Excess mortality after hospitalisation for vertebral fracture. Osteoporos Int 15:108–112CrossRefPubMedGoogle Scholar
  22. 22.
    Kanis JA, Oden A, Johnell O, De Laet C, Jonsson B, Oglesby AK (2003) The components of excess mortality after hip fracture. Bone 32:468–473CrossRefPubMedGoogle Scholar
  23. 23.
    Reginster JY, Gillet P, Ben Sedrine W, Brands G, Ethgen O, de Froidmont C, Gosset C (1999) Direct costs of hip fractures in patients over 60 years of age in Belgium. Pharmacoeconomics 15:507–514CrossRefPubMedGoogle Scholar
  24. 24.
    Autier P, Haentjens P, Bentin J, Baillon JM, Grivegnee AR, Closon MC, Boonen S (2000) Costs induced by hip fractures: a prospective controlled study in Belgium. Belgian Hip Fracture Study Group. Osteoporos Int 11:373–380CrossRefPubMedGoogle Scholar
  25. 25.
    Bouee S, Lafuma A, Fagnani F, Meunier PJ, Reginster JY (2006) Estimation of direct unit costs associated with non-vertebral osteoporotic fractures in five European countries. Rheumatol Int 26:1063–1072CrossRefPubMedGoogle Scholar
  26. 26.
    Gabriel SE, Tosteson AN, Leibson CL, Crowson CS, Pond GR, Hammond CS, Melton LJ 3rd (2002) Direct medical costs attributable to osteoporotic fractures. Osteoporos Int 13:323–330CrossRefPubMedGoogle Scholar
  27. 27.
    Melton LJ 3rd, Gabriel SE, Crowson CS, Tosteson AN, Johnell O, Kanis JA (2003) Cost-equivalence of different osteoporotic fractures. Osteoporos Int 14:383–388CrossRefPubMedGoogle Scholar
  28. 28.
    Hiligsmann M, Ethgen O, Richy F, Reginster JY (2008) Utility values associated with osteoporotic fracture: a systematic review of the literature. Calcif Tissue Int 82:288–292CrossRefPubMedGoogle Scholar
  29. 29.
    Hiligsmann M, Ethgen O, Bruyère O, Richy F, Gathon HJ, Reginster JY (2009) Development and validation of a Markov microsimulation model for the economic evaluation of treatments in osteoporosis. Value Health 12:687–696CrossRefGoogle Scholar
  30. 30.
    Hiligsmann M, Bruyere O, Reginster JY (2010) Cost-utility of long-term strontium ranelate treatment for postmenopausal osteoporotic women. Osteoporos Int 21:157–165CrossRefPubMedGoogle Scholar
  31. 31.
    Kanis JA, Johnell O, Oden A, Jonsson B, De Laet C, Dawson A (2000) Risk of hip fracture according to the World Health Organization criteria for osteopenia and osteoporosis. Bone 27:585–590CrossRefPubMedGoogle Scholar
  32. 32.
    National Institute for Health and Clinical Excellence (2008) Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women. Available via DIALOG at: Accessed 15 June 2009
  33. 33.
    Greenspan SL, Emkey RD, Bone HG, Weiss SR, Bell NH, Downs RW, McKeever C, Miller SS, Davidson M, Bolognese MA, Mulloy AL, Heyden N, Wu M, Kaur A, Lombardi A (2002) Significant differential effects of alendronate, estrogen, or combination therapy on the rate of bone loss after discontinuation of treatment of postmenopausal osteoporosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 137:875–883PubMedGoogle Scholar
  34. 34.
    Stock JL, Bell NH, Chesnut CH 3rd, Ensrud KE, Genant HK, Harris ST, McClung MR, Singer FR, Yood RA, Pryor-Tillotson S, Wei L, Santora AC 2nd (1997) Increments in bone mineral density of the lumbar spine and hip and suppression of bone turnover are maintained after discontinuation of alendronate in postmenopausal women. Am J Med 103:291–297CrossRefPubMedGoogle Scholar
  35. 35.
    Strom O, Borgstrom F, Sen SS, Boonen S, Haentjens P, Johnell O, Kanis JA (2007) Cost-effectiveness of alendronate in the treatment of postmenopausal women in 9 European countries—an economic evaluation based on the fracture intervention trial. Osteoporos Int 18:1047–1061CrossRefPubMedGoogle Scholar
  36. 36.
    Belgian Centre for Pharmacotherapeutic Information (2009). Available via DIALOG at: Accessed 15 June 2009
  37. 37.
    Kanis J, Burlet N, Cooper C, Delmas PD, Reginster JY, Borgstrom F, Rizzoli R (2008) European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 19:399–428CrossRefPubMedGoogle Scholar
  38. 38.
    Lekkerkerker F, Kanis JA, Alsayed N, Bouvenot G, Burlet N, Cahall D, Chines A, Delmas P, Dreiser RL, Ethgen D, Hughes N, Kaufman JM, Korte S, Kreutz G, Laslop A, Mitlak B, Rabenda V, Rizzoli R, Santora A, Schimmer R, Tsouderos Y, Viethel P, Reginster JY (2007) Adherence to treatment of osteoporosis: a need for study. Osteoporos Int 18:1311–1317CrossRefPubMedGoogle Scholar
  39. 39.
    Briggs A, Sculpher M, Claxton K (2006) Modelling methods for health economic evaluation. Oxford University Press, New YorkGoogle Scholar
  40. 40.
    Siris ES, Selby PL, Saag KG, Borgstrom F, Herings RM, Silverman SL (2009) Impact of osteoporosis treatment adherence on fracture rates in North America and Europe. Am J Med 122:S3–S13CrossRefPubMedGoogle Scholar
  41. 41.
    Curtis JR, Westfall AO, Cheng H, Lyles K, Saag KG, Delzell E (2008) Benefit of adherence with bisphosphonates depends on age and fracture type: results from an analysis of 101,038 new bisphosphonate users. J Bone Miner Res 23:1435–1441CrossRefPubMedGoogle Scholar
  42. 42.
    Cotte FE, Fautrel B, De Pouvourville G (2009) A Markov model simulation of the impact of treatment persistence in postmenopausal osteoporosis. Med Decis Making 29:125–139CrossRefPubMedGoogle Scholar
  43. 43.
    Sambrook P (2006) Compliance with treatment in osteoporosis patients—an ongoing problem. Aust Fam Phys 35:135–137Google Scholar
  44. 44.
    International Osteoporosis Foundation (2009) Adherence. Available via DIALOG at: Accessed 15 June 2009
  45. 45.
    Claxton AJ, Cramer J, Pierce C (2001) A systematic review of the associations between dose regimens and medication compliance. Clin Ther 23:1296–1310CrossRefPubMedGoogle Scholar
  46. 46.
    Cramer JA, Gold DT, Silverman SL, Lewiecki EM (2007) A systematic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos Int 18:1023–1031CrossRefPubMedGoogle Scholar
  47. 47.
    Roerholt C, Eiken P, Abrahamsen B (2009) Initiation of anti-osteoporotic therapy in patients with recent fractures: a nationwide analysis of prescription rates and persistence. Osteoporos Int 20:299–307CrossRefPubMedGoogle Scholar
  48. 48.
    Strom O, Borgstrom F, Kanis JA, Jonsson B (2009) Incorporating adherence into health economic modelling of osteoporosis. Osteoporos Int 20:23–34CrossRefPubMedGoogle Scholar
  49. 49.
    Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR (2007) Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 356:1809–1822CrossRefPubMedGoogle Scholar
  50. 50.
    Brookhart MA, Avorn J, Katz JN, Finkelstein JS, Arnold M, Polinski JM, Patrick AR, Mogun H, Solmon DH (2007) Gaps in treatment among users of osteoporosis medications: the dynamics of noncompliance. Am J Med 120:251–256CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Mickaël Hiligsmann
    • 1
    • 2
  • Véronique Rabenda
    • 2
  • Henry-Jean Gathon
    • 1
  • Olivier Ethgen
    • 2
  • Jean-Yves Reginster
    • 2
  1. 1.HEC-ULg Management SchoolUniversity of LiègeLiègeBelgium
  2. 2.Department of Public Health, Epidemiology and Health EconomicsUniversity of LiègeLiègeBelgium

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