To our knowledge, there have been few previous studies that used the FAERS database to assess sex differences of FRIDs, with most studies focused on the classes of FRIDs. Additionally, in our study, ROR and BCPNN were both used to detect the FRIDs, which made it possible to obtain more reliable results when the number of AEs was low22. According to Table 1, once the adverse event of a fall occurs, there will be a high risk of serious consequences such as hospitalization, life-threatening and even death, regardless of whether they are middle-aged and elderly women or men. Falling results from an interaction between factors within the individual (age-related changes, cognitive deficits, sensory deficits etc.) and the environment (medications, assistive devices, alcohol/drugs etc.)8,23. Therefore, it is very essential to prevent and reduce the occurrence of falls. Meanwhile, drugs with high risk of falls should be taken as little as possible, according to the disease condition and individual characteristics of middle-age and elderly patients.
Most important of all, we have unveiled a potential association between immunomodulatory agents and the increasing risk of falls within the female population. It is well-acknowledged that limb weakness, especially the hands and arms, is believed to be driven by an immune-mediated process in many autoimmune disorders24–26. In contrast to robust elderly and youthful female counterparts, intramuscular total carnitine levels and short-chain acylcarnitine levels are decreased in pre-frail older females, which is associated with reduced physical performance, whereas no differences were observed in males27. Besides, in female but not male older adults, physical weakness was characterized by a higher sex-specific expression of intramuscular inflammatory pathways, coupled with an infiltration of NOX2-expressing immune cells and a concomitant rise in VCAM1 expression28. However, there is a paucity of research examining the relationship between immunomodulators and falls across different genders, necessitating further investigation.
Teriparatide, bisphosphonates and romosozumab are existing drugs for the prevention or treatment of osteoporosis in internationally recognized clinical guidelines29, and cholecalciferol is the preferred form of vitamin D exogenous supplementation30, which were observed to have significant biases towards females in this study. Nevertheless, considering the prevalence of bone diseases such as rheumatoid arthritis31 and osteoporosis32, the sex bias of signals may be associated with significant gender characteristic differences of different indications as shown in Table 1. Research has demonstrated that cholecalciferol-calcium supplementation over an extended period of time reduces the odds of falling in ambulatory older women by 46%, but with a neutral effect in men33. Significantly, there were inconsistent results for Vitamin D supplementation interventions, with a high dose being associated with increasing risks of falls and fractures34–36. The crucial factor in determining the efficacy of vitamin D in preventing falls appears to be the dosage administered to each individual, regardless of gender. Nevertheless, women who take the medications mentioned above might need extra attention and care than men, no matter how the fall risk is brought from bone diseases conditions or high dosages of medications.
In the nervous system, sex differences in drug effects appear to be even more prominent. A recent study demonstrated a significant association between depressive symptoms and both the occurrence of falls and the dread of falling in the elderly. Interestingly, it highlighted a distinct gender disparity, as depression played a stronger role in women37. However, higher drugs use in females compared to males may be one of the reasons why sex differences were reported in some psychotropic drugs, of which antidepressants were the most frequently reported38. Furthermore, over 1000 transcripts with substantial interactions of sex and disease were discovered by Seney39 et al., and these transcripts were impacted in opposite directions in men and women with major depressive disorder, leading to sex differences in the responsiveness to antidepressant medications. Antiparkinsonian medication may worsen cognitive impairment and genders may exhibit various forms of cognitive impairment in Parkinson’s patients. The gender differences may be attributed to differences in brain anatomy, chemistry, and function40. Antipsychotics and hypnotics, and sedatives might increase the risk of falling. Antipsychotic drugs induce falls owing to their negative effects on cognition, blood pressure management, or causing their extrapyramidal motor symptoms such as tremor, rigidity, and bradykinesia41. For psychotropic drugs, haloperidol and quetiapine were observed to be associated with falls, yet pipamperone and risperidone were not, indicating that falls may be associated with particular drugs rather than drug classes42. However, further research is needed to determine which individual drugs cause major sex differences.
By the way, tamsulosin, alfuzosin or other prostate-specific α antagonists in cardiovascular system have a minor but considerable increased risk of falls, fractures, and head injuries, most likely as a result of induced hypotension43. However, there is a lack of sufficient evidence to support the gender difference results observed in our findings.
Some inherent limitations should be taken into consideration when interpreting the findings of our investigation. Firstly, our retrospective study design precludes the establishment of direct causality, which cannot be directly inferred from the observed results. Secondly, due to the lack of denominator data and high risk of selection and self-reporting bias, the ROR or IC025 values were rendered as metric of disproportionality of AE reporting, rather than a quantifier of relative risk. Finally, the FAERS database does not detail temporal information regarding drug exposure and accordingly incidence rate cannot be calculated, and it is impossible to quantify the individual effect of multiple drug exposures. However, to a certain extent, these results can provide reference for general practitioners, nursing staff, and other health professionals when making clinical medical decisions. In summary, to prevent drug-induced falling, we should not only pay attention to FRIDs categories, but drug sensitivity of different genders.