Osteoporosis International

, Volume 25, Issue 8, pp 2109–2116 | Cite as

Adherence to oral bisphosphonates and the risk of subtrochanteric and femoral shaft fractures among female medicare beneficiaries

  • Z. Wang
  • M. M. Ward
  • L. Chan
  • T. Bhattacharyya
Original Article



Previous studies have shown an association between duration of bisphosphonate use and atypical femur fractures. This cohort study showed an increasingly higher risk of subtrochanteric and femoral shaft fractures among those who were more adherent to oral bisphosphonates.


Long-term use of oral bisphosphonates has been implicated in an increased risk of atypical femur fractures located in subtrochanteric and femoral shaft regions. Another measure of drug exposure, medication adherence, however, has not been investigated.


Among all Medicare fee-for-service female beneficiaries from 2006–2010, we followed 522,287 new bisphosphonate users from their index prescription until being censored or having a primary diagnosis of closed subtrochanteric/femoral shaft or intertrochanteric/femoral neck fractures. Data about radiographs of fracture site and features were not available. Adherence was classified according to the medication possession ratio (MPR) as the following: MPR < 1/3 as less compliant, MPR ≥ 1/3– < 2/3 as compliant, and MPR ≥ 2/3 as highly compliant. Alternative cutoff points at 50 and 80 % were also used. Survival analysis was used to determine the cumulative incidence and hazard of subtrochanteric/femoral shaft or intertrochanteric/femoral neck fractures.


There was a graded increase in incidence of subtrochanteric/femoral shaft fractures as the level of adherence increased (Gray’s test, P < 0.001). The adjusted hazard ratio (HR) for the highly compliant vs. the less compliant was 1.23 (95 % Confidence Interval [CI] 1.06–1.43) overall, became significant after 2 years of follow-up (HR = 1.51, 95 % CI 1.06–2.15) and reached the highest risk in the fifth year (HR = 4.06, 95 % CI 1.47–11.19). However, age-adjusted incidence rates of intertrochanteric/femoral neck fractures were significantly lower among highly compliant beneficiaries, compared to less compliant users (HR = 0.69, 95 % CI 0.66–0.73). Similar results were obtained when the cutoff points for being compliant and highly compliant were set at 50 and 80 %, respectively.


Subtrochanteric/femoral shaft fractures, unlike intertrochanteric/femoral neck fractures, are positively associated with higher adherence to long-term (≥3 years) oral bisphosphonates in the elderly female Medicare population.


Bisphosphonates Fracture Osteoporosis Atypical femur fracture 



This study was funded by the Intramural Research Program at NIAMS/NIH. We want to thank Shannon Pietzsch from General Dynamic Information Technology, Inc., Drs. Elizabeth Rasch and Alex Constantin from Department of Rehabilitation Medicine of NIH Clinical Center, and Dr. Seo Young Kim from Brigham and Woman’s hospital for their supports.

Author’s roles: ZW, MW, and TB had full access to the study details and output but limited access to the data due to the CMS ENCLAVE data user agreement, and will take responsibility for the integrity of the data and the accuracy of data analysis. Conception and design: ZW, MW, TB and LC. Data acquisition: ZW and LC. Analysis and interpretation: ZW, MW, and TB. Drafting of manuscript: ZW. Critical revision of the manuscript: ZW, MW, LC, and TB. Statistical analysis: ZW and MW.

Conflicts of interest



  1. 1.
    Gedmintas L, Solomon DH, Kim SC (2013) Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis. J Bone Miner Res 28(8):1729–1737PubMedCrossRefGoogle Scholar
  2. 2.
    Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD et al (2010) Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 25(11):2267–2294PubMedCrossRefGoogle Scholar
  3. 3.
    Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM et al (2014) Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American society for bone and mineral research. J Bone Miner Res 29(1):1–23, Epub 2013/05/29PubMedCrossRefGoogle Scholar
  4. 4.
    Schilcher J, Koeppen V, Ranstam J, Skripitz R, Michaelsson K, Aspenberg P (2013) Atypical femoral fractures are a separate entity, characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls. Bone 52(1):389–392PubMedCrossRefGoogle Scholar
  5. 5.
    Wang Z, Bhattacharyya T (2011) Trends in incidence of subtrochanteric fragility fractures and bisphosphonate use among the US elderly, 1996–2007. J Bone Miner Res 26(3):553–560PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Ng AC, Drake MT, Clarke BL, Sems SA, Atkinson EJ, Achenbach SJ et al (2012) Trends in subtrochanteric, diaphyseal, and distal femur fractures, 1984–2007. Osteoporos Int 23(6):1721–1726PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Yoon BH, Lee YK, Kim SC, Kim SH, Ha YC, Koo KH (2013) Epidemiology of proximal femoral fractures in South Korea. Arch Osteoporos 8(1–2):157PubMedCrossRefGoogle Scholar
  8. 8.
    Meier RP, Perneger TV, Stern R, Rizzoli R, Peter RE (2012) Increasing occurrence of atypical femoral fractures associated with bisphosphonate use. Arch Intern Med 172(12):930–936PubMedCrossRefGoogle Scholar
  9. 9.
    Feldstein AC, Black D, Perrin N, Rosales AG, Friess D, Boardman D et al (2012) Incidence and demography of femur fractures with and without atypical features. J Bone Miner Res 27(5):977–986PubMedCrossRefGoogle Scholar
  10. 10.
    Dell RM, Adams AL, Greene DF, Funahashi TT, Silverman SL, Eisemon EO et al (2012) Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res 27(12):2544–2550PubMedCrossRefGoogle Scholar
  11. 11.
    Park-Wyllie LY, Mamdani MM, Juurlink DN, Hawker GA, Gunraj N, Austin PC et al (2011) Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. Jama 305(8):783–789PubMedCrossRefGoogle Scholar
  12. 12.
    Abrahamsen B, Eiken P, Eastell R (2010) Cumulative alendronate dose and the long-term absolute risk of subtrochanteric and diaphyseal femur fractures: a register-based national cohort analysis. J Clin Endocrinol Metab 95(12):5258–5265PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Abrahamsen B, Eiken P, Eastell R (2009) Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res 24(6):1095–1102PubMedCrossRefGoogle Scholar
  14. 14.
    Hsiao FY, Huang WF, Chen YM, Wen YW, Kao YH, Chen LK et al (2011) Hip and subtrochanteric or diaphyseal femoral fractures in alendronate users: a 10-year, nationwide retrospective cohort study in Taiwanese women. Clin Ther 33(11):1659–1667PubMedCrossRefGoogle Scholar
  15. 15.
    Kim SY, Schneeweiss S, Katz JN, Levin R, Solomon DH (2011) Oral bisphosphonates and risk of subtrochanteric or diaphyseal femur fractures in a population-based cohort. J Bone Miner Res 26(5):993–1001PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Vestergaard P, Schwartz F, Rejnmark L, Mosekilde L (2011) Risk of femoral shaft and subtrochanteric fractures among users of bisphosphonates and raloxifene. Osteoporos Int 22(3):993–1001PubMedCrossRefGoogle Scholar
  17. 17.
    Lenart BA, Neviaser AS, Lyman S, Chang CC, Edobor-Osula F, Steele B et al (2009) Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study. Osteoporos Int 20(8):1353–1362PubMedCrossRefGoogle Scholar
  18. 18.
    Girgis CM, Sher D, Seibel MJ (2010) Atypical femoral fractures and bisphosphonate use. N Engl J Med 362(19):1848–1849PubMedCrossRefGoogle Scholar
  19. 19.
    Giusti A, Hamdy NA, Dekkers OM, Ramautar SR, Dijkstra S, Papapoulos SE (2011) Atypical fractures and bisphosphonate therapy: a cohort study of patients with femoral fracture with radiographic adjudication of fracture site and features. Bone 48(5):966–971PubMedCrossRefGoogle Scholar
  20. 20.
    Schilcher J, Michaelsson K, Aspenberg P (2011) Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med 364(18):1728–1737PubMedCrossRefGoogle Scholar
  21. 21.
    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(9):1435–1441PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Siris ES, Harris ST, Rosen CJ, Barr CE, Arvesen JN, Abbott TA et al (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(8):1013–1022PubMedCrossRefGoogle Scholar
  23. 23.
    Pazianas M, Abrahamsen B, Wang Y, Russell RG (2012) Incidence of fractures of the femur, including subtrochanteric, up to 8 years since initiation of oral bisphosphonate therapy: a register-based cohort study using the US MarketScan claims databases. Osteoporos Int 23(12):2873–2884PubMedCrossRefGoogle Scholar
  24. 24.
    Fay MP, Feuer EJ (1997) A semi-parametric estimate of extra-Poisson variation for vital rates. Stat Med 16(21):2389–2401PubMedCrossRefGoogle Scholar
  25. 25.
    Gray RJ (1988) A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16(3):1141–1154CrossRefGoogle Scholar
  26. 26.
    Gagne JJ, Glynn RJ, Avorn J, Levin R, Schneeweiss S (2011) A combined comorbidity score predicted mortality in elderly patients better than existing scores. J Clin Epidemiol 64(7):749–759PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Narongroeknawin P, Patkar NM, Shakoory B, Jain A, Curtis JR, Delzell E et al (2012) Validation of diagnostic codes for subtrochanteric, diaphyseal, and atypical femoral fractures using administrative claims data. J Clin Densitom 15(1):92–102PubMedCrossRefGoogle Scholar

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2014

Authors and Affiliations

  • Z. Wang
    • 1
  • M. M. Ward
    • 1
  • L. Chan
    • 2
  • T. Bhattacharyya
    • 1
    • 3
  1. 1.Intramural Research Program, National Institute of Arthritis, Musculoskeletal and Skin DiseasesNational Institutes of HealthBethesdaUSA
  2. 2.Department of Rehabilitation Medicine, the Clinical CenterNational Institutes of HealthBethesdaUSA
  3. 3.BethesdaUSA

Personalised recommendations