Antipsychotic Drugs and Risk of Hip Fracture in People Aged 60 and Older in Norway

Marit S. Bakken, MD, PhD; Jan Schjøtt, MD, PhD; Anders Engeland, MSc, PhD; Lars B. Engesæter, MD, PhD; Sabine Ruths, MD, PhD


J Am Geriatr Soc. 2016;64(6):1203-1209. 

In This Article

Abstract and Introduction


Objectives: To examine associations between exposure to various subgroups of antipsychotic drugs and risk of hip fracture in older adults.

Design: Nationwide cohort study.

Setting: Norway, 2005–2010.

Participants: Everyone living in Norway born before 1945 (N = 906,422).

Measurements: Information was obtained on all prescriptions of antipsychotic drugs dispensed from 2004 to 2010 (Norwegian Prescription Database) and data on all primary hip fractures from 2005 to 2010 (Norwegian Hip Fracture Registry). Incidence rates of hip fracture during person-time exposed and unexposed to antipsychotic drugs were compared by calculating the standardized incidence ratio (SIR).

Results: Thirty-nine thousand nine hundred thirty-eight (4.4%) participants experienced a primary hip fracture. Greater risk of hip fracture was associated with exposure to any antipsychotic (SIR = 2.1, 95% confidence interval (CI) = 1.9–2.1), first-generation antipsychotics (SIR = 2.0, 95% CI = 1.8–2.2), second-generation antipsychotics (SIR = 2.2, 95% CI = 1.9–2.4), prolactin-sparing antipsychotics (SIR = 2.4, 95% CI = 1.8–3.1) and prolactin-elevating antipsychotics (SIR = 2.0, 95% CI = 1.9–2.2).

Conclusion: In people aged 60 and older in Norway, those who took an antipsychotic drug had twice the risk of sustaining a hip fracture during exposure than during nonexposure. Although confounding by indication, comorbidity, or other drugs used cannot be excluded, this association is relevant for clinical practice because hip fracture and antipsychotic drug use are prevalent in vulnerable older individuals. Clinical studies examining mechanisms or causality of the observed association between antipsychotic drug use and excess risk of hip fracture are needed.


Hip fractures are highly prevalent in older people, with implications for morbidity and mortality.[1,2] Numerous factors (e.g., medical conditions, drug use, lifestyle) affect the risk of hip fracture. Most hip fractures result from a combination of low bone mineral density and a fall,[3] and low bone mineral density and falls are both multifactorial in origin. Use of psychotropic drugs (antidepressant, anxiolytic, hypnotic, antipsychotic drugs) is an independent, and potentially modifiable, risk factor for falls in older people.[4] Their effects on bone metabolism differ; whereas antidepressants with serotonergic properties negatively affect bone metabolism,[5–7] there is no evidence that anxiolytics or hypnotics do, and the results are conflicting regarding antipsychotics.[8,9]

Schizophrenia and other psychotic disorders and symptoms are the main indications for treatment with antipsychotic drugs,[10] often involving long-term drug treatment.[11] Off-label prescribing is widespread, especially for behavioral and psychiatric symptoms of dementia in nursing home residents such as agitation and restlessness.[12–14] Treatment effects are limited in these conditions, severe adverse effects are common,[12] and antipsychotic drugs can be withdrawn from most residents without adversely affecting their behavior.[14] Antipsychotics are prescribed to 4% to 10% of community-dwelling people aged 70 and older[15,16] and 20% to 50% of nursing home residents worldwide.[17–20] Whereas prescription rates of antipsychotics for community-dwelling people are stable, they are declining in nursing homes; prescription rates in Norway are in the lowest parts of the range.[16,21]

Observational studies have shown associations between antipsychotic drug use and hip fracture; which subgroup is associated with the greatest excess risk is unclear,[8,13,22,23] as are the mechanisms involved.

It is thought that antipsychotic drugs have their antipsychotic effect by occupying dopaminergic receptors in the brain, although a contribution from serotonergic effects cannot be excluded.[24] All antipsychotics have prolactin-elevating potential, primarily associated with dopaminergic D2 receptor occupancy in the pituitary and the drugs' ability to penetrate the blood–brain barrier.[25] First-generation antipsychotics (FGAs) have high affinity for dopaminergic receptors, whereas dopaminergic affinity varies among second-generation antipsychotics (SGAs). The latter also show variable binding to serotonergic (5-hydroxytryptamine; 5-HT), adrenergic, histaminergic, and muscarinic receptors.[26] Serotonin levels and serotonergic neurotransmission may influence prolactin secretion.[27] Thus, SGAs could be associated with greater prolactin secretion, although antidopaminergic activity varies within this subgroup of antipsychotics.

Antipsychotic drugs probably affect bone tissue indirectly through prolactin-induced hypogonadism. Recent studies suggest that they may also directly affect bone homeostasis.[8,9,27–30] An example is risperidone, which is thought to affect bone formation and resorption through its ability to block 5-HT2B and α1-adrenoceptors.[31]

Aims of the Study

The aim of the study was to examine associations between exposure to various subgroups of antipsychotic drugs and the risk of hip fracture in older people. The subgroups were FGAs or SGAs and prolactin-sparing or prolactin-elevating antipsychotics. If associations were found, the goal was to estimate the attributable risk of hip fracture.