Research ArticleClinical Studies
Open Access

Relationship Between Overactive Bladder and Bone Fracture Risk in Female Patients

SHINTARO MORI, TOMOHIRO MATSUO, HIROYUKI HONDA, KYOHEI ARAKI, KENSUKE MITSUNARI, KOJIRO OHBA and RYOICHI IMAMURA
In Vivo July 2024, 38 (4) 2031-2040; DOI: https://doi.org/10.21873/invivo.13661

Abstract

Background/Aim: Overactive bladder (OAB) has recently been recognized as an independent risk factor for falls and fractures. This study aimed to predict fracture risk in female patients with OAB symptoms. Patients and Methods: We assessed and compared the fracture risk in newly diagnosed female patients with OAB to those without OAB using the Fracture Risk Assessment Tool (FRAX), and investigated the relationship between fracture risk and OAB severity. Results: The present single-center, cross-sectional study included 177 female participants (79 with OAB, 98 without OAB). The OAB group was older (p=0.033) and shorter (p=0.010) compared to the non-OAB group. Compared to the non-OAB group, the OAB group had more patients with hypertension (p<0.001) and diabetes mellitus (p=0.011), as well as higher risks for major fractures (non-OAB group: 15.2±13.2%; OAB group: 23.6±14.1%; p<0.001) and hip fractures (non-OAB group: 6.3±11.0%; OAB group: 10.6±10.0%; p=0.007). In addition, those with moderate/severe OAB had the most significantly elevated risks for both major fractures (non-OAB group: 15.2±13.2%, mild-OAB: 17.6±12.5%, moderate/sever-OAB: 26.4±14.0%; p<0.001) and hip fractures (non-OAB group: 6.3±11.0%, mild-OAB: 6.5±7.6%, moderate/sever-OAB: 12.5±10.4%; p<0.001). Among the OAB symptoms, nocturia had the strongest correlation with fracture risk (major fracture, ρ=0.534; hip fracture, ρ=0.449; all p<0.001). Conclusion: Patients with severe OAB, and particularly severe nocturia, should be closely monitored with timely and aggressive symptom management; however, an interventional study incorporating the management of OAB symptoms is required to confirm whether the proactive management of OAB symptoms reduces the risk of fractures in older females.

Key Words:

Lower urinary tract symptoms (LUTS), including overactive bladder (OAB), have a significant impact on the quality of life of females, including negative physical, social, emotional, and sleep effects (1). OAB is a syndrome characterized primarily by urinary urgency, with or without urinary incontinence, and is often but not always associated with nocturia and increased urinary frequency (2). OAB impacts roughly one in six women worldwide, with its prevalence increasing as age advances (3, 4). Recent studies indicate that the onset of LUTS, including OAB in elderly women, is linked to frailty. Moreover, it has been identified as an independent risk factor for falls and fractures (5, 6).

Falls and fractures in older patients with LUTS are common and can significantly reduce their activities of daily living and often lead to life-threatening events such infections and progression of weakness in clinical practice. Nocturia, which is one of the components of OAB symptoms, can be particularly bothersome for patients, as it can result in poor sleep quality, affect daytime activities, and increase the risk of falls (7); the latter, in particular, provides a plausible connection between urinary symptoms and fracture risk. A method that could predict the risk of fractures in this population would be of profound value to reduce morbidity and mortality, as well as improve quality of life. The World Health Organization (WHO) has recently developed a fracture risk assessment tool (FRAX) to predict the risk of fracture occurrence over the next 10 years (8). The Studies using FRAX suggest that there is some association between the incidence of lifestyle-related diseases and fracture risk (9, 10), which are associated with the prevalence of OAB. However, to our knowledge, there has been no previous clinical study attempting to predict the risk of fractures in female patients with LUTS, including OAB, using a simple and useful tool.

Hence, the primary aim of this study was to predict the fracture risk in female patients with OAB using the FRAX tool. Moreover, the study aimed to examine the association between each OAB symptom and fracture risk in detail.

Patients and Methods

Patients and study design. This cross-sectional, retrospective clinical study was conducted at a single center between January 2017 and March 2019 and included female patients who were newly diagnosed with OAB. This study was approved by the ethics review board of Nagasaki University Hospital, Nagasaki, Japan (registration number: 11120267), and conducted in accordance with the principles of the Declaration of Helsinki. All participants provided written informed consent. Participants with a urinary urgency [Question (Q)3] score of 2 or more and those with a total score of 3 or more on the overactive bladder symptom score (OABSS) were defined as having OAB (11). The exclusion criteria were males, patients under the age of 40 or over 90 years, individuals currently undergoing treatment for a fracture, those with acute urinary tract infection, and those with a neurogenic bladder.

FRAX. We evaluated the risk of osteoporotic fractures in patients with OAB using FRAX, which has also been validated and used in some studies in Japan (12-14). The FRAX has been adopted in the age range between 40 and 90 years and includes 11 items: age, sex, body height, body weight, history of previous osteoporotic fracture, parental hip fracture, current smoking, use of glucocorticoids, rheumatoid arthritis, secondary osteoporosis, and alcohol consumption. In addition, the measurement of bone mineral density is not mandatory for evaluating the FRAX score (12). The FRAX score estimates an individual’s prospective 10-year risk of major osteoporotic and hip fractures. We set up a control group of female participants without OAB to compare the differences in subjective and objective parameters with those of the patients with OAB. The primary endpoint of this study was to compare the differences in FRAX scores, including risks of major osteoporotic and hip fracture, between the two groups stratified based on the presence or absence of OAB.

OABSS. Additionally, the participants were categorized into three groups based on their OABSS scores: non-OAB (0-2), mild OAB (3-5), and moderate/severe OAB (6-15). Furthermore, the differences in the LUTS and FRAX scores were assessed among the three groups.

Evaluation of vital signs. Hypertension was defined as a systolic blood pressure of 140 mmHg or more, diastolic blood pressure of 90 mmHg or more, or treatment with oral medication. Chronic renal dysfunction was defined when estimated glomerular filtration was less than 60 ml/min/1.73 m2. For diabetes and dyslipidemia, the presence or absence of disease was determined based on whether the patient was administered therapeutic drugs.

Statistical analyses. All statistical analyses were performed using JMP 16 software (SAS Institute, Cary, NC, USA). All data are presented as means±standard deviations. The Student’s t-test and Mann–Whitney U-test were used to compare the OAB and non-OAB groups, as needed. The Kruskal–Wallis test was used to analyze the association between OAB severity and fracture risk, and the Steel–Dwass method was used to evaluate multiple comparisons. Spearman’s rank correlation coefficient analysis (ρ) was used to evaluate the relationship between the continuous variables, and the corresponding p-values are shown. All tests were two-sided, and statistical significance was set at a p-value of less than 0.05. The number of samples was determined on the basis of previous reports (9, 15, 16). Hence, we set a power of 80%, and an effect size of 0.5. We estimated that the ideal number of participants for this study should be at least 148 (74 patients in non-OAB group and 74 in OAB group each).

Results

Patient characteristics and OAB symptoms. Figure 1 shows the flow chart of patient selection and Table I shows the demographic details of the patients in this study. The total number of patients available for the analysis was 177, comprising 79 patients with OAB and 98 without. The mean age was 68.9±10.8 years. When examining the two groups based on OAB status, the OAB group was found to be older than the non-OAB group (non-OAB group: 67.4±11.3 years; OAB group: 70.7±9.9 years; p=0.033). In terms of body height, the OAB group’s height was significantly shorter than that of the non-OAB group (non-OAB group: 152.5±5.8 cm; OAB group: 149.7±7.0 cm; p=0.010). When participants were categorized into three groups based on OAB symptom severity, the moderate/severe OAB group had the highest average age and the shortest average body height among all the groups (Table II). Both the OAB groups had a significantly higher proportion of patients with hypertension and diabetes mellitus compared with the non-OAB group (Table I, Table II).

Figure 1.
Figure 1.

Flow chart of patient selection. OAB: Overactive bladder; LUTS: lower urinary tract symptom.

View this table:
Table I.

General characteristics of the patients included in this study.

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Table II.

Patient characteristics according to overactive bladder (OAB) severity.

All four items of the OABSS and the total score were significantly higher in the OAB group compared with the non-OAB group (Table III). Moreover, with an increase in the severity of OAB, there was a corresponding increase in all the questionnaire items and total scores (Table IV).

View this table:
Table III.

Differences in the overactive bladder (OAB) symptom score between the two groups.

View this table:
Table IV.

Differences in overactive bladder symptom score (OABSS) according to OAB severity.

Differences in osteoporotic risk factors between the groups. Table V shows the results of the FRAX questionnaire, with the exception of age, sex, body weight, and height, which are listed in Table I. A significantly higher number of patients in the OAB group had a history of fractures, rheumatoid arthritis, and secondary osteoporosis compared with those in the non-OAB group. However, no differences were observed between the two groups regarding a history of a parent with a fractured hip, current smoking, use of glucocorticoids, and alcohol consumption (Table V).

View this table:
Table V.

Differences in fracture risk factors by the fracture risk assessment tool between the two groups.

When participants were categorized into three groups based on OAB severity, the occurrences of previous fractures were higher in both the mild and moderate/severe OAB groups compared with the non-OAB group (all p<0.001). Statistically significant differences in secondary osteoporosis were observed between the moderate/severe OAB group and the non-OAB group, while the mild OAB group did not differ significantly from the non-OAB group (Table VI). Differences in fracture risks. Figure 2 shows the major and hip fracture risks in the non-OAB and OAB groups based on FRAX (A; major fracture risk, B; hip fracture risk). Both fracture risks in the OAB group were significantly higher than those in the non-OAB group (major fracture risk, p<0.001; hip fracture risk, p=0.007). In terms of OAB severity and fracture risk, there was no significant difference in the major and hip fracture risk between the non-OAB and mild OAB groups. However, the moderate/severe OAB group exhibited a significantly higher fracture risk than the other two groups (Figure 3).

View this table:
Table VI.

The differences of fracture risk factors by the fracture risk assessment tool according to overactive bladder (OAB) severity.

Figure 2.
Figure 2.

The relationship between overactive bladder (OAB) and fracture risk. A) Major fracture risk; B) hip fracture risk. The risk of major fracture in the OAB group was higher than that in the non-OAB group (non-OAB group: 15.2±13.2%; OAB group: 23.6±14.1%; p<0.001). The risk of hip fracture in the OAB group was higher than that in the non-OAB group (non-OAB group: 6.3±11.0%; OAB group: 10.6±10.0%; p=0.007).

Figure 3.
Figure 3.

The relationship between overactive bladder (OAB) severity and fracture risk. A) Major fracture risk; B) hip fracture risk. The risk of major fracture in moderate/severe OAB group was highest in all groups (non-OAB group, 15.2±13.2%; mild OAB group, 17.6±12.5%; moderate/severe OAB group, 26.4±14.0%; p<0.001). The risk of hip fracture in moderate/severe OAB group was highest in all groups (non-OAB group, 6.3±11.0%; mild OAB group, 6.5±7.6%; moderate/severe OAB group, 12.5±10.4%; p<0.001).

Correlation between fracture risk and OABSS. The correlations between the two fracture risks and each OABSS questionnaire score are presented in Table VII. Among the OABSS questionnaire items, Q2 (nighttime frequency) showed the highest correlation with fracture risk (major fracture risk, ρ=0.534, p<0.001; hip fracture risk, ρ=0.449, p<0.001). Furthermore, a moderate and statistically significant positive correlation was observed between the OABSS total score and both fracture risks (major fracture risk, ρ=0.444, p<0.001; hip fracture risk, ρ=0.354, p<0.001).

View this table:
Table VII.

Relationship between overactive bladder symptom score (OABSS) and fracture risk.

Discussion

This clinical study demonstrated an association between the presence of OAB and osteoporotic risk factors. Furthermore, we observed a positive correlation between the severity of OAB and the risk of major and hip fractures, as indicated by the FRAX score in this study. Notably, among the OABSS questionnaire items, nocturia exhibited the strongest association with the FRAX score.

The symptoms of OAB have a profound effect on women’s well-being due to the negative physical, social, emotional, and sleep effects, among others (1). Despite encouraging evidence of reduced mortality of hip fractures over the past 60 years (17), possibly due to improvements in preoperative planning, medical management, specialized care facilities, and expedited surgery, hip and other bone fractures still present a significant morbidity and mortality risk for females. Therefore, there is a great need to fully understand the relationship between urinary symptoms such as OAB and fracture risk in older females in order to optimize preventive strategies and management approaches in this vulnerable population. Our findings indicate that nocturia is a particularly concerning symptom for fracture risk and should be a focus for management approaches attempting to reduce fracture risk in older females.

OAB is a common LUTS in older people (18). In addition, several previous studies have shown that the presence of OAB is significantly associated with metabolic syndrome and lifestyle-related diseases such as hypertension and diabetes in female patients (19, 20). These results are similar to those obtained in this study. Furthermore, we found that OAB severity was associated with age and presence of hypertension. The reduction in estrogen levels post-menopause has been associated with a range of systemic comorbidities that tend to escalate with age, particularly among older women (21, 22). The details of the patients’ systemic comorbidities in the current study are unknown; however, as in previous reports (23, 24), the severity of comorbidities, which increases with age, might also have affected the severity of OAB.

Several studies have suggested a link between lifestyle-related diseases, which are also risk factors for OAB and osteoporosis (25, 26). For instance, individuals with hypertension and diabetes may be more prone to bone density loss and fractures due to disruption of the processes involved in bone metabolism and formation (27-29). In addition, frail patients with muscle weakness, a risk factor for OAB, are also at risk of falls (30). Furthermore, falls caused by OAB have been shown to increase the risk of fractures (6, 31, 32). Nonetheless, to the best of our knowledge, no comprehensive studies have used straightforward tools to investigate OAB and its potential association with future fracture risk.

The FRAX is a fracture risk assessment questionnaire with 11 questions, some of which include OAB risk factors, such as age, sex, weight, smoking, and rheumatoid arthritis (33). In addition, it has been reported that the FRAX is a useful fracture prediction tool for lifestyle-related diseases, including type 2 diabetes mellitus (9) and chronic kidney disease (34). On the other hand, there are reports that the presence of lifestyle-related diseases is associated with bone marrow density, but does not reflect the occurrence of fractures (35). Therefore, the use of the FRAX for the risk assessment of fractures in lifestyle-related diseases remains controversial.

The present study, which targeted only female participants, showed that patients with OAB had more risk factors for fractures, such as a history of fracture, rheumatoid arthritis, and secondary osteoporosis, than the non-OAB group. These results were likely associated with an increase in two parameters of the FRAX score (major osteoporosis and hip fracture) in the OAB group. Furthermore, when examined according to the severity of OAB, the moderate/severe OAB group had the highest risk factors for fracture not only because the patients in the group had lifestyle-related diseases, but also because they were the oldest and shortest regarding body height than any other group in the items of FRAX. In addition, the moderate/severe OAB group had more secondary osteoporosis than the other groups, which likely contributed to their increased risk of fracture based on the FRAX score. There is some uncertainty regarding why there were more patients with secondary osteoporosis in the moderate/severe OAB group. However, causes of secondary osteoporosis include type 1 diabetes, osteogenesis imperfecta, hyperthyroidism, and premature menopause (<45 years of age). Particularly in the case of premature menopause, estrogen depletion triggers a variety of systemic diseases, which have been pointed out to be very closely related to the development of LUTS (36, 37). In fact, three (3.1%) participants in the non-OAB group, three (12.0%) in the mild OAB group, and 10 (18.5%) in the moderate/severe OAB group had early menopause in this study, with the moderate/severe OAB group being the most frequent (p=0.005). Moreover, body height was the lowest in patients with moderate/severe OAB. We hypothesized that this group might include patients with shortened stature due to unrecognized compression fractures caused by long-term estrogen depletion due to aging or early menopause, resulting in decreased bone density. In other words, we believe that the differences in FRAX scores between the groups in this study were found as a result of various systemic changes caused by aging and estrogen deficiency, both of which are risk factors for the development of OAB.

Of the four symptoms in the OABSS in this study, nocturia had the strongest correlation with fracture risk. Several studies have suggested an association between OAB, including urinary urgency and nocturia, and fractures of the buttocks and thighs (5, 6, 31, 32). However, to the best of our knowledge, the OABSS categories and risk of fracture have not been examined in detail previously as in the present study. Although the detailed mechanism by which patients with OAB are at a higher risk of fracture than healthy individuals is not known completely, many patients with OAB have frailty, which indicates reduced muscle strength (30), and are at a higher risk of falling (5, 38). In particular, it is generally known that the risk of fracture, which is triggered by urinary urgency and falls during toilet transfers due to nocturia, is higher than that in healthy individuals. Additionally, various systemic complications resulting from fractures have been reported to affect life expectancy (31, 32). This suggests that patients with OAB, including nocturia, should be treated with necessary pharmacological and behavioral therapies depending on the risk of fracture. However, it is worth noting that anticholinergic drugs commonly used to treat OAB are associated with dizziness and an increased risk of falls due to their cognitive effects (39, 40). Therefore, behavioral therapy, including exercise, should be intensified, especially in fragile older patients with OAB, and the use of β3-adrenoceptor stimulants should be considered when pharmacotherapy is used.

Osteoporosis treatment is indicated when the major fracture risk is 15% or higher (41). In this study, the major fracture risk exceeded this criterion in 41.8% of the non-OAB group and 64.6% of the OAB group, probably because many of the participants were relatively older. Furthermore, according to the severity of OAB, 56.0% of patients in the mild OAB group and 68.5% in the moderate/severe OAB group showed an increase in the number of patients indicated for osteoporosis treatment as the severity of OAB increased. Based on these results, we believe that there is a strong need for close collaboration with related departments, such as orthopedic surgeons, especially in older female patients with OAB who tend to be at a higher risk of complications of osteoporosis and consequent fractures.

It is commonly known that the lower dietary intake observed in older people and the reduced remodeling function of bone formation are associated with higher urinary calcium excretion (42, 43). Urinary calcium excretion also increases along with urinary sodium excretion, especially in patients with hypertension related to excessive salt intake (44). Such a series of changes in bone metabolism triggered by hypertension have a significant influence on the development of osteoporosis (10, 44). Previously, we also investigated the association between urinary sodium and calcium excretion and LUTS, and found that increased urinary excretion of both was associated with nocturia and nocturnal polyuria rather than urinary urgency (45). In the present study, most patients with OAB had hypertension, and this tendency was associated with OAB severity. In addition, estrogen deficiency in older women significantly affects calcium metabolism (46). Although urinary parameters were not measured in this study, it is possible that the OAB group, which included more hypertensive and older participants, may have included patients with more severe nocturia, with a consequent increased risk of fractures correlated with the severity of OAB, as well as an increased excretion of urinary calcium. However, this study did not analyze the daily and nocturnal urinary volume in a detailed manner using a voiding diary or frequency volume chart, and further investigation is necessary to address this issue.

Study limitations. First, the sample size was relatively small. Since there are no studies on the association of the FRAX with OAB, the number of participants recruited was set with reference to previous studies on the prevalence of OAB and fracture, and on the FRAX and various systemic comorbidities (9, 15, 16). Furthermore, given that participants were drawn from a specific population (new patients presenting at Nagasaki University Hospital), a convenience sampling method was used. This is a non-probability sampling technique that selects participants based on their likelihood and willingness to participate. However, this type of sampling may introduce bias because it may not be representative of the broader population. Hence, the present study may have introduced sampling bias and our findings may not be generalizable to a broader population. Therefore, it is essential to design a larger and more thorough study that enables a detailed analysis of the relationship between OAB severity and fracture prediction, which could not be clarified in this study. Furthermore, the severity of systemic comorbidities and their treatment may have influenced the results of this study. The incidence and severity of lifestyle-related diseases may affect urinary calcium and sodium excretion, which are closely related to osteoporosis. In addition, we did not perform bone densitometry studies due to the issue of radiation exposure. Moreover, we did not study voiding symptoms in detail because we mainly investigated the relationship between OAB and the FRAX. Therefore, detailed research using questionnaires including the International Prostate Symptom Score and frequency volume chart are also needed. In addition, objective findings require a detailed pressure flow study also be performed. This should be addressed in future large studies with sufficient statistical power to perform such analyses.

Conclusion

The results of this study indicate that female patients with OAB have a higher fracture risk than those without OAB, and the risk of fracture was correlated with the severity of OAB symptoms. In addition, this is the first study to reveal that the severity of nocturia was the factor most associated with fracture risk. These results indicate that patients with severe OAB, and particularly severe nocturia, are at especially high risk of fractures and should be closely monitored in the clinical setting with timely and aggressive management of OAB symptoms; in addition to improvements in their quality of life. This approach could potentially reduce their risk of fractures. However, further research is required to confirm our findings in a large, prospective cohort, and an interventional study addressing OAB symptoms is required to evaluate whether proactive management of OAB symptoms is associated with a clinically meaningful reduction in the risk of fractures in older females.

Acknowledgements

The Authors thank Editage (www.editage.com) for English language editing.

Footnotes

  • Authors’ Contributions

    Conceptualization, S.M. and T.M.; methodology, T.M. and K.M.; formal analysis, K.O.; investigation, S.M., T.M., H.H., and K.A.; writing – original draft preparation, S.M. and T.M; writing – review and editing, T.M., K.M., K.O., and R.I.; supervision, project administration, R.I. All Authors have read and agreed to the published version of the manuscript.

  • Conflicts of Interest

    The Authors declare no conflicts of interest in relation to this study.

  • Funding

    This research received no external funding.

  • Received April 19, 2024.
  • Revision received May 19, 2024.
  • Accepted May 20, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Relationship Between Overactive Bladder and Bone Fracture Risk in Female Patients
SHINTARO MORI, TOMOHIRO MATSUO, HIROYUKI HONDA, KYOHEI ARAKI, KENSUKE MITSUNARI, KOJIRO OHBA, RYOICHI IMAMURA
In Vivo Jul 2024, 38 (4) 2031-2040; DOI: 10.21873/invivo.13661
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