Falls represent a significant global public health issue, with more than 40% of people over 65 years of age experiencing at least one fall per year (1), resulting in a variety of consequences including death, fractures and other problems, significantly impacting quality of life and imposing a substantial burden on healthcare systems worldwide (2, 3). Interest in the prevention and management of falls is growing with the increasing global population aging (4). Wrist fractures, particularly distal radius fractures (DRFs), are the most common type of osteoporotic fractures and are usually caused by straightening of the hand during a forward or backward fall (5). Several studies, including the guidelines for falls prevention and management for older adults by the World Falls Guidelines Task Force, emphasize the need to reduce the incidence of medication-induced falls in the older adult in clinical practice (2, 6), Medication-induced osteoporotic fractures have also long been a concern (7).

Although diuretics are widely used for the treatment of hypertension, heart failure, and kidney disease to reduce extracellular fluid volume and lower blood pressure, they may also pose some potential risks, such as inducing hypotension, electrolyte imbalances, or deterioration of kidney function (8, 9). Several studies have confirmed that the use of diuretics, especially loop diuretics (LDs), increases the risk of falls and fractures in patients (10, 11), but there is a lack of genetic evidence for this association. Therefore, there is a need to investigate whether there is evidence of association through a Mendelian randomization (MR) study. Another important question to answer is whether diuretics have a further effect on the occurrence of DRFs.

Mendelian randomization analysis is a method for causal inference in epidemiology that relies on genome-wide association studies (GWASs) and uses one or more genetic variants as instrumental variables (IVs), which can be independent of confounding factors since they are randomly assigned during gamete formation and are independent of environmental and lifestyle factors (12, 13). MR analysis has been widely used to investigate the association between drug factors and various diseases (14–16). We aimed to use two-sample MR analysis to determine whether genetically predicted use of diuretics is a risk factor for falls and wrist fractures, with the goal of providing evidence-based recommendations for fall prevention from the perspective of drug use.

In the MR analysis results, the exposure was considered a risk factor for the outcome if OR > 1, and was considered a protective factor if OR < 1. Results are presented as odds ratios (OR) and 95% confidence intervals (95% CIs). The corresponding p-values were used to determine their statistical significance.

This study revealed the causal relationships between three types of genetically proxied diuretics and the risk of falls and wrist fractures. MR analysis predicted that the use of LDs and PSDs increases the risk of falls, and neither of the two diuretics has an impact on the risk of wrist fractures. However, these findings mainly indicate a potential association. The use of TDs does not affect the incidence of falls, but it can reduce the risk of wrist fracture by an average of 16.67%.

Diuretics are considered as clinically important antihypertensive drugs, and the latest guidelines emphasize their significance in the treatment of antihypertension, particularly in refractory hypertension where they play an irreplaceable role (25). The three most commonly used diuretics have different mechanisms of action, and irrational use will cause some complications. Falls have become the most unpredictable injuries in the older adult and are closely associated with psychiatric disorders, cerebrovascular disease, and skeletal muscle disease, etc. Several meta-analyses studies have demonstrated the risk of falls from neurological medications, cardiovascular/circulatory system medications, and other medications (10, 26–28). Among them, LDs have been identified as a significant factor in increasing the risk of falls, which is consistent with our study. First, it is evident that the use of diuretics can easily lead to insufficient blood volume, particularly in older adult patients, resulting in orthostatic hypotension or syncope, thereby increasing the risk of falls (29). Second, the action of all diuretics affects the electrolyte balance. LDs such as furosemide inhibit the active reabsorption of NaCl by blocking the Na + -K + -Cl− co-transporter, resulting in hyponatremia, hypokalemia, and hypocalcemia (30), causing muscle pain, spasms, and instability in walking, leading to falls. Additionally, PSDs may cause hyperkalemia, and TDs increase calcium reabsorption, leading to hypercalcemia. Bumetanide (an LD) impairs myogenic differentiation and exercise-induced muscle hypertrophy, leading to muscle wasting (31), and also has a sedative effect (32), which can cause patients to faint after taking the medication, thus increasing the risk of falls. Finally, the frequency of patient urination increases after treatment with diuretics, studies have shown that environmental factors such as bed height, toilet handles, and slippery and uneven surfaces, also influence the probability of falling (3), leading to more falls during the process of walking from the bed to the toilet. Although we concluded that diuretics increased fracture risk, the OR value was modest, compared to 1.185 for diuretics (33) or 1.36 for LDs (10). In our study, TDs had no impact on the risk of falls, which remains controversial. A study by Ravioli et al. (34) suggests that the risk of falls increased after the use of TDs, while another meta-analysis combining multiple studies found no evidence of such risk (10). World guidelines for falls prevention and management for older adults recommend to identify and appropriate deprescribing fall risk increasing drugs (6).

In orthopedic research, the risk of wrist fractures, represented by DRFs, is associated with falls (5). Although diuretics increase the risk of falls, current research indicates that they do not increase the incidence of DRFs (35), but the existence of a positive correlation between TDs and hip fractures has been reported, and the effect disappears within 4 months after use is discontinued (36). In contrast, our MR analysis suggests that the use of TDs can reduce the occurrence of wrist fractures, possibly due to their positive effect on bone health and structure. The direct effects of TDs include stimulating the production of runt-related transcription factor 2 (RUNX2) and osteopontin to promote osteoblast differentiation while reducing the production of osteoclasts (37). Indirectly, TDs increases blood calcium (38) and enhances the formation of mineralized nodules (39). In certain patient populations, such as those with hyperparathyroidism and hypercalciuria, TDs can normalize parathyroid hormone levels, thereby slowing down bone resorption and the dissolution of bone matrix (40). DRF is a common osteoporotic fracture, and prevention of osteoporosis is an effective measure to reduce this type of fractures. An MR study found a positive correlation between TDs and calcaneal bone density (41), which partly explains the reduction in the occurrence of wrist fractures with TDs.

Fall prevention has become a critical public health issue, with peak of concentrations reached within 0.5–2 h of taking LDs (42). The daily dose of diuretics needs to be strictly controlled, as it is significantly associated with adverse outcomes (43). The side effects of the drug must be closely monitored, such as hypokalemia, upright hypotension and dizziness, must be closely monitored, with the moment of standing up being the most dangerous. Additionally, regular review of electrolyte levels for medication adjustment is an effective measure to prevent falls (30). Regarding the issue of increased urination frequency, the authors believe that emptying the bladder before taking the medication can help avoid an increased risk of falling after taking the medication. If the patients feel weakness in the limbs after taking the medication, it is best to use a bedside commode. For patients at high risk of hypertension combined with osteoporosis, TDs are more recommended in the selection of diuretics (44).

This study has inherent limitations in MR analysis. For instance, the genetic instrumental variables obtained from GWAS may not be the same as those in clinical practice, thus the main purpose of our MR analysis was to assess causality rather than quantify the effect size, the influence of the study’s objective on clinical practice still needs to be further demonstrated. Although evidence of the association of the use of diuretics being with falls was observed in our study, it was better suitable for older persons, the estimation of the genetic effects of the medication cannot be explained as the clinical effects of the medication, especially in the case of initial use or dosage adjustments. The MR analysis cannot evaluate the effect indicators of the risk of falls for the choice between intravenous injection or oral medication, or for combination therapy with multiple drugs. For non-European populations, we did not perform the analysis due to the lack of appropriate outcome data, and the effects of this result on other ethnic groups remain to be investigated.

The results of our study indicate that diuretics, a classical medication, such as LDs and PSDs increase the risk of falls occurrence but does not have an effect on wrist fractures incidence. In contrast, TDs may not be causally related to the occurrence of falls and may reduce the risk of wrist fractures. MR analysis is not limited by the short follow-up period of clinical trials. It is necessary to further investigate the impact of diuretics on falls and guide clinical practice to avoid diuretic-induced falls as much as possible through rational use of drugs, patient education, and other means.