Antipsychotic Use and Risk of Low-Energy Fractures in People With Schizophrenia: A Nationwide Nested Case-Control Study in Finland

Abstract

Abstract Background Low-energy fractures (LEF) are more frequent in people with schizophrenia than the general population, and the role of prolactin-increasing antipsychotics is unknown. Study design We conducted a nested case-control study using Finnish nationwide registers (inpatient, specialized outpatient care, prescription drug purchases). We matched each person with schizophrenia aged 16–85 years and incident LEF (cases) with 5 age/sex/illness duration-matched controls with schizophrenia, but no LEF. We investigated the association between cumulative exposure (duration, and Defined Daily Doses, DDDs) to prolactin-increasing/sparing antipsychotics and LEF. Adjusted conditional logistic regression analyses were performed. Sensitivity analyses were conducted. Study results Out of 61 889 persons with schizophrenia between 1972 and 2014, we included 4960 cases. Compared with 24 451 controls, 4 years or more of exposure to prolactin-increasing antipsychotics was associated with increased risk of LEF (adjusted odds ratio (aOR) from aOR = 1.22, 95%CI = 1.09–1.37 to aOR = 1.38, 95%CI = 1.22–1.57, for 4–<7/>13 years of exposure, respectively), without a significant association for prolactin-sparing antipsychotics. All cumulative doses higher than 1000 DDDs of prolactin-increasing antipsychotics were associated with LEF (from aOR = 1.21, 95%CI = 1.11–1.33, 1000–<3000 DDDs, to aOR = 1.64, 95%CI = 1.44–1.88, >9000 DDDs). Only higher doses of prolactin-sparing antipsychotics reached statistical significance (aOR = 1.24, 95%CI = 1.01–1.52, 6000–<9000 DDDs, aOR = 1.45, 95%CI = 1.13–1.85, >9000 DDDs). Sensitivity analyses confirmed the main analyses for prolactin-increasing antipsychotics. For prolactin-sparing antipsychotics, significant associations were limited to extreme exposure, major LEF, older age group, and males. Conclusions Long-term exposure to prolactin-increasing antipsychotics at any dose, and high cumulative doses of prolactin-sparing antipsychotics is associated with significantly increased odds of LEF. Monitoring and addressing hyperprolactinemia is paramount in people with schizophrenia receiving prolactin-increasing antipsychotics.