Increased Risk of Hip Fracture Among Older People Using Antidepressant Drugs

Data From the Norwegian Prescription Database and the Norwegian Hip Fracture Registry

Marit Stordal Bakken; Anders Engeland; Lars B. Engesæter; Anette Hylen Ranhoff; Steinar Hunskaar; Sabine Ruths


Age Ageing. 2013;42(4):514-520. 

In This Article


Excess Risk of Hip Fracture Among Exposed People

Our results showing excess risk of hip fracture in persons using antidepressants, especially SSRIs and other antidepressants with high or intermediate serotonergic properties (e.g. venlafaxine or mirtazapine), are in accordance with previous studies.[10,12,13,21,22] About 5% of the hip fractures in the study period were attributable to antidepressant drug use.

We found a higher excess risk of hip fracture among persons on recently started treatment with antidepressants when compared with all users of SSRIs and other antidepressants with high or intermediate serotonergic effects. The numbers of hip fractures are small and these findings must be interpreted with caution, but they support previous research.[10,12] The relationships between the dose[21,22] and duration[10,13] of SSRI use and the risk of hip fracture have been shown earlier.

Other studies suggest that tolerance for TCAs evolves after a few weeks of use, while the risk of hip fracture remains elevated over time among older people using SSRIs.[10,11]

It is reasonable to suspect that SSRIs adversely affect bone strength. A meta-analysis of epidemiological studies indicates that using SSRIs is associated with an increased risk of fracture, although when SSRI use was adjusted for depression and bone mineral density at baseline, it was non-significantly associated with bone loss.[23] A recent case–control study demonstrated associations between using SSRIs and osteoporosis, independent of depression and concomitant use of medication affecting bone metabolism, while using TCAs was associated with higher bone mineral density.[24] Although functional 5-hydroxytryptamine (5-HT) receptors and 5-HT transporters have been localised to osteoblasts and osteocytes, and 5-HT seems to modulate the skeletal effects of parathyroid hormone and mechanical stimulation,[13] the detailed effects of serotonin on bone metabolism remain unknown.[25] SSRIs and other drugs with serotonergic properties may possibly contribute to an increased risk of hip fracture through falls in recently initiated treatment, due to hyponatraemia and haemodynamic disturbances,[26] and through effects on bone physiology, assumedly impairing bone architecture and bone strength, in longer-lasting treatment.

The excess risk of hip fracture in our study was higher among exposed men than exposed women, supporting the findings of a previous study.[27] As hip fracture and antidepressant drug use are less prevalent among men than among women, exposure to antidepressants will affect the hip fracture risk among men relatively more. Attenuation of the impact of antidepressant drug use with advancing age is possibly due to 'dilution' of the effect by other factors giving rise to an increased risk of hip fracture, such as comorbidities, frailty and concomitant drug use.

Methodological Considerations

The national health registries provided us a unique opportunity to link complete data on antidepressant drugs purchased by a nationwide unselected community-dwelling older population with all primary hip fractures registered in Norway. The 6-year follow-up period revealed high numbers of cases, and the nationwide prospective study design prevented selection and information bias. In addition, the conservative definition of exposed person-days, not allowing for such factors as non-adherence, yields conservative risk estimates.

The databases have some limitations. The NorPD lacks individual information on medication dispensed to nursing home residents, leading to systematic misclassification of ~40,000 people at any time as drug non-users. The prevalence of both antidepressant use[28] and hip fracture is high among nursing home residents, and the excess risk of hip fracture has been underestimated in exposed people. The Norwegian Hip Fracture Registry comprises >80% of all hip fracture operations in Norway,[15] with somewhat lower completeness during the first years.

The most important limitation of our study is the lack of clinical information such as depression, comorbidities, frailty, concomitant drug use and life style. Thus, we do not know whether people purchasing prescriptions for antidepressants were actually diagnosed with depression or not. Low-dosage TCAs are also prescribed for chronic pain and SSRIs for neuropsychiatric symptoms among people with dementia. Confounding by indication must be taken into account when interpreting the results. Most importantly, both depression itself and antidepressants may influence muscle strength, psychomotor function, activity level and bone mineral density and thus interfere with the risk of falls and fractures. However, previous studies have shown that associations between an increased risk of hip fracture among individuals using antidepressants remain even when adjusted for depression.[24,29] Further, a large population-based cohort study among older people diagnosed with depression in the UK adjusted for patient characteristics revealed no evidence that using SSRIs is safer than using TCAs regarding all-cause mortality.[12]

Since antidepressants are predominantly used on a daily basis, we considered the number of days corresponding to the number of DDDs dispensed the best proxy for the number of drug-exposed person-days. Studies of psychotropic drug prescribing for older people in Sweden in 2006[30] and the UK 1996–2007[12] showed that the actually prescribed mean daily dose of SSRI was nearly 1.0 DDD; the latter study also demonstrated that the mean prescribed daily dose of TCAs was <0.5 DDD.[12] Thus, our study may have underestimated the assumed number of person-days exposed to TCAs and the effect on the risk of hip fracture. However, the risk of hip fracture remained largely stable when the SIR was calculated for different assumed exposure times.

Implications for Practice

Since the risk of hip fracture increases with age, demographic changes will contribute to an increasing number of hip fractures. SSRIs are the most widely prescribed antidepressants for older people. We found a marked overrepresentation of hip fractures among people using SSRIs and other antidepressants with serotonergic properties compared both with people not using antidepressants and with people using TCAs. At the population level, the excess risk of hip fracture corresponds to ~1,900 fractures during the study period. These associations need to be explored further in clinical studies. The growing evidence of SSRIs and other antidepressants not being necessarily safer than TCAs requires conscientious evaluation of the potential risks and benefits when prescribing antidepressants for older people and careful follow-up.