Examining the role of tricyclic antidepressants in osteoporotic fractures

Osteoporotic fractures can cause severe disability and death, especially in older adults. Although multiple researchers have sought to establish an association between treatment with tricyclic antidepressants (TCAs) and increased fracture risk, much of the research performed to date has yielded conflicting results, making it difficult to draw conclusions about the role of TCAs in osteoporotic fractures.

To address this issue, a team of Mayo Clinic researchers conducted a comprehensive meta-analysis, published in the Journal of Bone and Mineral Research, that examines the association between TCA treatment and risk of fracture.

Wenchun Qu, M.D., M.S., Ph.D., from Physical Medicine and Rehabilitation at Mayo Clinic's campus in Minnesota, and a research biostatistician at Mayo Clinic's campus in Arizona, quantitatively assessed all available qualified studies that have examined the effect of TCAs on fracture risk to gather more accurate and precise information about this effect.

"We hypothesized that TCA treatment would be associated with an increased risk of fractures," says Dr. Qu. "We also examined whether the effect varied by sex, study design, anatomical site of fracture, dose, exposure duration, geographic location, or adjustment for bone mineral density (BMD) or depression."


From a list of more than 1,500 studies involving human participants, use of TCA as exposure, and BMD or fracture as outcome, Dr. Qu's team identified 12 eligible studies — five cohort studies and seven case-control studies. No related randomized controlled trials were found. From this meta-analysis, Mayo researchers found that the relative risk of fracture was increased by 45 percent in TCA users compared with non-TCA users.

This moderate, but clinically relevant increase in fracture risk was consistent in multiple sensitivity analyses and in subgroup analyses. After Dr. Qu and colleagues adjusted for possible publication bias, the increased risk associated with TCA treatment (RR, 1.36; 95 percent CI, 1.24-1.50; p < 0.001) remained moderate and clinically important, although slightly weaker.

"These findings strongly suggest that TCA use is associated with an increased risk of fractures," says Dr. Qu. "But the underlying mechanism for the association between TCA use and fractures remains unclear."

Dr. Qu says that it's important to remember that both bone loss and a higher propensity to fall contribute to increased fracture risk. The fact that antidepressant use has been linked with increased falls risk among the elderly may also explain the association between TCA use and fractures.

TCAs can cause decreased blood pressure, increased heart rate (especially during the initial phase of treatment), increased body sway and decreased postural balance. All of these reported and potentially adverse effects can increase the potential for fractures caused by falls.

Mayo researchers had several other findings that also strongly suggest that TCAs may increase the propensity for falling rather than causing bone loss:

  • Adjusting for bone mineral density (BMD) did not decrease the estimates, which suggests that TCA use may increase fracture risk independent of BMD reduction.
  • While increased fracture risk was associated with current TCA use, it was not associated with past use. This suggests that the effect of TCAs is to increase falls instead of affecting skeletal strength.
  • The incidence of hip fractures, which are typically linked to falls, was greater than the incidence of other types of fractures.
  • The increased fracture risk was much higher among patients who underwent a shorter duration of TCA treatment (< six weeks) than among patients who underwent extended treatment (≥ six weeks).
  • Even low-dose TCAs (< 0.5 defined daily dose) were associated with an increased fracture risk.

Study limitations

Dr. Qu acknowledges several study limitations, including the absence of a multivariate meta-regression analysis to further investigate the sources of heterogeneity presented, due to the small number of studies included; the inability to assess risks of falling, because few individual studies accounted for falls; and the limited use of claims data, which may lack information on nutrients, physical functioning, cognition or other potential confounders.


The increased fracture risk associated with TCAs is moderate and independent of depression and BMD. Because this increased risk may have a substantial clinical impact, physicians prescribing even low-dose TCAs should monitor fall risk in patients, especially during the initial treatment period, and consider offering fall prevention education, especially for older patients.

For more information

Wu Q, et al. Tricyclic antidepressant use and risk of fractures: A meta-analysis of cohort and case-control studies. Journal of Bone and Mineral Research. 2013;28:753.