Fraser L, Liu K, Naylor KL, Hwang YJ, Dixon SN, Shariff SZ, Garg AX. Falls and Fractures With Atypical Antipsychotic Medication UseA Population-Based Cohort Study. JAMA Intern Med. 2015;175(3):450-452. doi:10.1001/jamainternmed.2014.6930
Antipsychotic medications are commonly used in elderly persons to treat dementia and other behavioral disturbances.1 Several articles have linked these medications to an increased risk of fracture.2,3 It is unclear whether this fracture risk is limited to older conventional antipsychotic medications or if the risk extends to newer atypical antipsychotics4 because the newer drugs remain associated with orthostatic hypotension, gait abnormalities, and sedation (all of which may increase the risk of falling).5 We conducted a population-based study to better understand the risk of falls and fracture associated with atypical antipsychotic medications.
We used linked health care administrative databases housed at the Institute for Clinical Evaluative Sciences in the province of Ontario, Canada, which provides universal health care for its citizens. Hwang et al6 recently examined the association between the use of atypical antipsychotics and kidney injury (the study methods are fully described in that article); we used this same cohort for the current study. In brief, adults 65 years and older who received a new outpatient prescription for an oral atypical antipsychotic (quetiapine, risperidone, or olanzapine) between June 1, 2003, and December 31, 2011, were matched 1 to 1 with individuals who did not receive such a prescription. The cohort was followed up for 90 days to assess fracture and fall outcomes with hospital presentation, identified by diagnosis and procedure codes in hospital discharge, same-day surgery, and ambulatory care databases. We followed a prespecified protocol that was approved by the research ethics board at Sunnybrook Health Sciences Centre (Toronto, Ontario, Canada). Patient informed consent was not required for this study.
A total of 195 554 individuals were studied. As described previously, matching resulted in 2 well-balanced groups that showed no meaningful differences in 91 measured baseline characteristics. Additional characteristics relating to fracture risk were also well balanced (Table 1). New outpatient atypical antipsychotic medication use was associated with an increased 90-day risk of nonvertebral osteoporotic fracture, hip fracture, a broader definition of fractures, and hospital visit with a fall (Table 2; see footnote for outcome definitions). Subgroup analyses found that the risk of fracture and falling was unaffected by the specific atypical antipsychotic medication used, high vs low dosage, or whether the individual lived in a long-term care facility or in the community.
In this population-based study of older adults, we found that receiving a new prescription of an atypical antipsychotic medication was associated with a 52% increased risk of a serious fall and a 50% increased risk of a nonvertebral osteoporotic fracture.
Although previous results have been mixed, several articles2,3 have identified fall and fracture risk as complications of new antipsychotic medication use. Our findings complement these articles and confirm the association with a large study involving almost 200 000 individuals. Similarly, there has been previous disagreement about the type of antipsychotic medications associated with fracture risk2- 4; we confirm that risk exists among the atypical antipsychotic class.
We identified a similar increase in hospital visits with falls and osteoporotic fractures. Atypical antipsychotic medications have been found previously to be associated with hypotension, sedation, and gait abnormalities5,6; therefore, it is possible that falls are the mechanism by which these drugs increase fracture risk.
Our large population-based study provides estimates of associations with narrow 95% CIs. Although this study was limited in that the 2 groups were matched (on baseline morbidity) to assess renal outcomes, the groups were similar with respect to fracture-specific risk factors at baseline. Our study was observational; while the 2 groups were well matched on important prognostic factors such as dementia and psychoses, the associations may be subject to confounding by indication in which the reason for prescription of an atypical antipsychotic medication (eg, behavioral disturbances) may predispose patients to falls and fractures.
In summary, these findings call into question the widespread off-label use of atypical antipsychotic medications and support increasing evidence of safety concerns regarding their use in older adults.
Corresponding Author: Lisa-Ann Fraser, MD, MSc, Department of Medicine, University of Western Ontario, 268 Grosvenor’s St, London, ON N6A 4V2, Canada.
Published Online: January 12, 2015. doi:10.1001/jamainternmed.2014.6930.
Author Contributions: Dr Shariff had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Fraser, Shariff, Garg.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Fraser.
Critical revision of the manuscript for important intellectual content: Liu, Naylor, Hwang, Dixon, Shariff, Garg.
Statistical analysis: Liu, Hwang, Dixon, Shariff.
Obtained funding: Garg.
Administrative, technical, or material support: Fraser, Naylor, Garg.
Study supervision: Shariff.
Conflict of Interest Disclosures: Dr Garg reports receiving an investigator-initiated grant from Astellas and Roche to support a Canadian Institutes of Health Research study in living kidney donors, and that his institution received unrestricted research funding from Pfizer. No other disclosures were reported.
Funding/Support: This study was supported by the Institute for Clinical Evaluative Sciences (ICES) Western Site. ICES is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. The ICES Western Site is funded by an operating grant from the Academic Medical Organization of Southwestern Ontario, the Schulich School of Medicine and Dentistry at Western University, and the Lawson Health Research Institute.
Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The study design and conduct, opinions, results, and conclusions in this article are those of the authors and are independent of the funding sources.