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Risk of hip, subtrochanteric, and femoral shaft fractures among mid and long term users of alendronate: nationwide cohort and nested case-control study

BMJ 2016; 353 doi: (Published 28 June 2016) Cite this as: BMJ 2016;353:i3365
  1. Bo Abrahamsen, professor, consultant endocrinologist1 2,
  2. Pia Eiken, consultant endocrinologist, clinical associate professor3 4,
  3. Daniel Prieto-Alhambra, associate professor, NIHR clinician scientist5 6,
  4. Richard Eastell, professor7
  1. 1Odense Patient Data Explorative Network, Department of Clinical Research, University of Southern Denmark, J.B. Winsløws Vej 9 A, 3. Sal, DK-5000, Odense, Denmark
  2. 2Department of Medicine, Holbæk Hospital, Smedelundsgade 60, 4300 Holbæk, Denmark
  3. 3Department of Cardiology, Nephrology and Endocrinology, Hillerød Hospital, Dyrehavevej 29, 3400 Hillerød, Denmark, Pia Eiken
  4. 4Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark, Pia Eiken
  5. 5Oxford NIHR Musculoskeletal Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeltal Sciences (NDORMS), University of Oxford, Botnar Research Centre, Oxford OX3 7LD, UK
  6. 6Musculoskeletal Research Unit, IMIM-Parc de Salut Mar and RETICEF, Universitat Autònoma de Barcelona and Instituto Carlos III (FEDER Research Funds), Passeig Marítim 25-29, 08003 Barcelona, Spain,
  7. 7Academic Unit of Bone Metabolism (AUBM), Northern General Hospital and University of Sheffield, Sheffield S5 7AU, UK
  1. Correspondence to: D Prieto-Alhambra, Botnar Research Centre, NDORMS, University of Oxford, Nuffield Orthopaedics Centre, Oxford OX3 7LD, UK Daniel.prietoalhambra{at}
  • Accepted 16 May 2016


Objectives To determine the skeletal safety and efficacy of long term (≥10 years) alendronate use in patients with osteoporosis.

Design Open register based cohort study containing two nested case control studies.

Setting Nationwide study of population of Denmark.

Participants 61 990 men and women aged 50-94 at the start of treatment, who had not previously taken alendronate, 1996-2007.

Interventions Treatment with alendronate.

Main outcome measures Incident fracture of the subtrochanteric femur or femoral shaft (ST/FS) or the hip. Non-fracture controls from the cohort were matched to fracture cases by sex, year of birth, and year of initiation of alendronate treatment. Conditional logistic regression models were fitted to calculate odds ratios with and without adjustment for comorbidity and comedications. Sensitivity analyses investigated subsequent treatment with other drugs for osteoporosis.

Results 1428 participants sustained a ST/FS (incidence rate 3.4/1000 person years, 95% confidence interval 3.2 to 3.6), and 6784 sustained a hip fracture (16.2/1000 person years, 15.8 to 16.6). The risk of ST/FS was lower with high adherence to treatment with alendronate (medication possession ratio (MPR, a proxy for compliance) >80%) compared with poor adherence (MPR <50%; odds ratio 0.88, 0.77 to 0.99; P=0.05). Multivariable adjustment attenuated this association (adjusted odds ratio 0.88, 0.77 to 1.01; P=0.08). The risk was no higher in long term users (≥10 dose years; 0.70, 0.44 to 1.11; P=0.13) or in current compared with past users (0.91, 0.79 to 1.06; P=0.22). Similarly, MPR >80% was associated with a decreased risk of hip fracture (0.73, 0.68 to 0.78; P<0.001) as was longer term cumulative use for 5-10 dose years (0.74, 0.67 to 0.83; P<0.001) or ≥10 dose years (0.74, 0.56 to 0.97; P=0.03).

Conclusions These findings support an acceptable balance between benefit and risk with treatment with alendronate in terms of fracture outcomes, even for over 10 years of continuous use.


  • Contributors: All authors contributed to the design of the study, the interpretation of the results, and reviewed the manuscript. BA performed the statistical analysis and is guarantor. BA and DP-A wrote the first draft of the manuscript. RE and DP-A are joint senior authors.

  • Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: no support from any organisation for the submitted work; BA receives institutional research grants and has contracts with Novartis and UCB, past institutional research contracts with Amgen and NPS Pharmaceuticals, and past payment for membership of advisory boards from Nycomed, Merck, and Amgen; PE reports grant support from Eli Lilly and payment for educational presentations for Amgen and Eli Lilly, pro bono educational presentations for Boehringer Ingelheim, payment for membership of advisory boards from Amgen, Eli Lilly, and Merck, and stock ownership in Novo Nordisk; DP-A reports institutional research grants from Amgen and Servier and support for conference attendance and speaker fees paid to his institution; RE reports institutional research grants and personal fees from Amgen, IDS, Alexian, and Roche, institutional research grants from Astra Zeneca, and speaker or consulting fees from Bayer, Fonterra, Janssen, Eli Lilly, Ono Pharma, Alere, Teijin Pharm, D-STAR, and GSK nutrition.

  • Ethical approval: The study was approved by Statistics Denmark (project 702538) and by the Medicines Agency branch of the Danish National Board of Health. Analyses were conducted via VPN exclusively on de-identified microdata hosted with Statistics Denmark with no access to patients’ names, social security numbers, or other identifiers.

  • Transparency: The lead authors affirm that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • Data sharing: No additional data available.

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