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Levothyroxine dose and risk of fractures in older adults: nested case-control study

BMJ 2011; 342 doi: (Published 28 April 2011) Cite this as: BMJ 2011;342:d2238
  1. Marci R Turner, medical resident1,
  2. Ximena Camacho, analyst2,
  3. Hadas D Fischer, epidemiologist2,
  4. Peter C Austin, senior scientist2,
  5. Geoff M Anderson, professor3,
  6. Paula A Rochon, senior scientist4,
  7. Lorraine L Lipscombe, scientist4
  1. 1Department of Medicine, University of Toronto, Canada
  2. 2Institute for Clinical Evaluative Sciences, Toronto, Canada
  3. 3Department of Health Policy Management and Evaluation, University of Toronto, Canada
  4. 4Women’s College Research Institute, 790 Bay Street, Toronto, ON, Canada M5G 1N8
  1. Correspondence to: L L Lipscombe lorraine.lipscombe{at}
  • Accepted 28 February 2011


Objective To quantify the effect of levothyroxine dose on risk of fractures in older adults.

Design Nested case-control study.

Setting Population based health databases, Ontario, Canada.

Participants Adults aged 70 or more prescribed levothyroxine between 1 April 2002 and 31 March 2007 and followed for fractures until 31 March 2008. Cases were cohort members admitted to hospital for any fracture, matched with up to five controls from within the cohort who had not yet had a fracture.

Main outcome measure Primary outcome was fracture (wrist or forearm, shoulder or upper arm, thoracic spine, lumbar spine and pelvis, hip or femur, or lower leg or ankle) in relation to levothyroxine use (current, recent past, remote). Risk among current users was compared between those prescribed high, medium, and low cumulative levothyroxine doses in the year before fracture.

Results Of 213 511 prevalent levothyroxine users identified, 22 236 (10.4%) experienced a fracture over a mean 3.8 years of follow-up, 18 108 (88%) of whom were women. Compared with remote levothyroxine use, current use was associated with a significantly higher risk of fracture (adjusted odds ratio 1.88, 95% confidence interval 1.71 to 2.05), despite adjustment for numerous risk factors. Among current users, high and medium cumulative doses (>0.093 mg/day and 0.044-0.093 mg/day) were associated with a significantly increased risk of fracture compared with low cumulative doses (<0.044 mg/day): 3.45 (3.27 to 3.65) and 2.62 (2.50 to 2.76), respectively.

Conclusion Among adults aged 70 or more, current levothyroxine treatment was associated with a significantly increased risk of fracture, with a strong dose-response relation. Ongoing monitoring of levothyroxine dose is important to avoid overtreatment in this population.


  • This work was supported by a team grant (OTG-88591) from the Canadian Institutes of Health Research (CIHR) and by a CIHR interdisciplinary capacity enhancement grant (HOA-80075). LLL is supported by a Canadian Diabetes Association/CIHR clinician scientist award. PCA is supported by a career investigator award from the Heart and Stroke Foundation of Ontario. GMA is supported by the University of Toronto chair in health management strategies.

  • Contributors: MRT and LLL designed the study, interpreted the data, and drafted the original manuscript. They are the guarantors. XC assisted with the study design and data acquisition and edited the manuscript. HDF assisted with the study design and edited the manuscript. PCA, GMA, and PAR assisted with the study design and interpretation of the data and edited the manuscript. All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The opinions, results, and conclusions are those of the authors and no endorsement by the Ministry of Health and Long-Term Care or by the Institute for Clinical Evaluative Sciences is intended or should be inferred.

  • Competing interests: All authors have completed the Unified Competing Interest form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; and no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: This project was approved by the institutional review board at Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

  • Data sharing: The technical appendix, statistical code, and dataset are available from the corresponding author at lorraine.lipscombe{at}

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