Increased Risk of Sudden Sensory Neural Hearing Loss in Osteoporosis: A Longitudinal Follow-Up Study

Increased Risk of Sudden Sensory Neural Hearing Loss in Osteoporosis: A Longitudinal Follow-Up Study Abstract Context The results of a previous population cohort study suggested an association between osteoporosis and sudden sensory neural hearing loss (SSNHL). Objectives To use a nationwide cohort in the Korean population to investigate the risk of SSNHL in patients with osteoporosis. Design, Setting, and Participants Data entered from 2002 to 2013 were collected from the Korean National Health Insurance Service-National Sample Cohort. A total of 68,241 patients with osteoporosis aged ≥50 years were matched with 68,241 control individuals. The crude (simple) and adjusted hazard ratios (HRs) of SSNHL in those with osteoporosis were analyzed using the Cox proportional hazard model. A subgroup analysis was performed according to age and sex. Results The risk of SSNHL was greater in the osteoporosis group than in the control group (adjusted HR, 1.56; 95% CI, 1.37 to 1.78; P < 0.001). The risk of SSNHL in those with osteoporosis was greater in patients aged <60 years, regardless of sex. Women aged ≥60 years had a higher HR for SSNHL in the presence of osteoporosis (women aged 60 to 69 years: adjusted HR, 1.67; 95% CI, 1.34 to 2.08; P < 0.001; women aged ≥70 years: adjusted HR, 1.90; 95% CI, 1.29 to 2.79; P < 0.001). Conclusions The risk of SSNHL was greater for patients with osteoporosis aged ≥50 years. Middle-age adults, as well as the elderly, are at an increased risk of SSNHL in the presence of osteoporosis. Osteoporosis is a metabolic bone disorder characterized by low bone mineral density and microarchitectural deterioration of the bone, which increases susceptibility to fracturing. In the United States, its prevalence in individuals aged ≥50 years has been estimated at 16.0% in men and 29.9% in women (1). In Korea, of those aged ≥50 years, ~37.3% of women and ~7.5% of men have osteoporosis (2). In those with osteoporosis, bone resorption exceeds bone formation. This imbalance in bone metabolism can be caused by many factors, including age-related metabolic changes in calcium and vitamin D and estrogen deficiency (3). Chronic disorders, such as diabetes mellitus and dyslipidemia, also increase the risk of osteoporosis (4). In addition to fragility and the associated risk of falls and fracture, osteoporosis has been reported as a risk factor for hypertension, coronary heart disease, cerebral stroke, and dyslipidemia (5). Sudden sensory neural hearing loss (SSNHL) is defined as the abrupt onset of sensorineural hearing loss and must be urgently treated. The prevalence of SSNHL increases with age and has shown no sex preference. Its annual incidence has been reported as 27 per 100,000 persons in the United States and 15 per 100,000 persons in Korea (6, 7). Both perturbation of the perilymphatic flow of the cochlea and auditory nerve dysfunction can cause SSNHL. More than 50% of SSNHL cases are idiopathic (6). Many factors, such as vascular and metabolic dysfunction, have been suggested as risk factors for SSNHL (7). The cochlea and internal auditory nerve are encased in hard and compact petrous temporal bone (8). In addition, the calcium ionic flow in the cochlea and stereocilia of the cochlea orchestrate their activities to maintain mechanoelectrical transduction in the cochlea. Therefore, it might be that bone metabolism has a crucial effect on auditory function. In line with this hypothesis, several previous studies have proposed an association between osteoporosis and hearing impairment (9–11). In the present study, we hypothesized that osteoporosis increases the risk of SSNHL independently of confounders, including age, sex, income, region of residence, and medical history. Previously, several studies have suggested a relationship between osteoporosis and hearing impairment, although only a single cohort study reported an association between osteoporosis and SSNHL (9). To verify this association, we searched the PubMed and Embase databases for relevant studies using the keywords “(osteoporosis) AND ([hearing] OR [sudden hearing loss])” and limited the results to human-based studies reported in English before March 2018. The purpose of the present study was to evaluate the association between osteoporosis and SSNHL in the Korean adult population using a national sample cohort. A control group matched and adjusted for age, sex, income, region of residence, and pertinent medical history was used to investigate the risk of SSNHL in the presence of osteoporosis. Additionally, the age- and sex-specific risk of SSNHL in those osteoporosis was evaluated in a subgroup analysis. Materials and Methods Study population and data collection The ethics committee of Hallym University (2014-I148) approved the use of the presented data. The institutional review board exempted the present study from the requirement for written informed consent. The present national cohort study relied on data obtained from the Korean Health Insurance Review and Assessment Service – National Patient Sample. The Korean National Health Insurance Service (NHIS) selects samples directly from a database comprising the entire population to prevent nonsampling errors. Approximately 2% of the samples (1 million) were selected from the entire Korean population (50 million). These selected data were classified at 1476 levels [i.e., age (18 categories), sex (2 categories), and income level (41 categories)] using randomized stratified systematic sampling methods via proportional allocation to represent the entire population. After data selection, the appropriateness of the sample was verified by a statistician who compared the data for the entire Korean population to the sample data. The details related to the methods used to perform these procedures were provided by the National Health Insurance Sharing Service (12). This cohort database included (1) personal information; (2) health insurance claim codes (procedures and prescriptions); (3) diagnostic codes according to the International Classification of Diseases, 10th Revision (ICD-10); (4) death records from the Korean National Statistical Office (according to the Korean Standard Classification of Disease); (5) socioeconomic data (residence and income); and (6) medical examination data for each participant for the period ranging from 2002 to 2013. Because each Korean citizen is recognized by a 13-digit resident registration number from birth to death, exact population statistics can be determined using this database. It is mandatory for all Koreans to enroll in the NHIS. All Korean hospitals and clinics use this 13-digit resident registration number to register individual patients in the medical insurance system. Therefore, the risk of overlapping medical records is minimal, even when a patient has moved from one place to another. Moreover, all medical treatments performed in Korea are, without exception, tracked by the Korean Health Insurance Review and Assessment Service system. In Korea, notice of death to an administrative entity is legally required before a funeral can be held. The cause and date of death are recorded by medical doctors on the death certificate. Participant selection Of 1,125,691 cases with 114,369,638 medical claim codes, we included all participants with a diagnosis of osteoporosis. Patients with osteoporosis were those receiving a diagnosis of osteoporosis from 2002 to 2013 using the ICD-10 codes M80 (osteoporosis with pathological fracture), M81 (osteoporosis without pathological fracture), and M82 (osteoporosis in diseases classified elsewhere). Among the identified patients, we selected participants who had been treated two or more times or had received a diagnosis of osteoporosis because of bone density test results using radiography or computed tomography (claim codes E7001 to E7004 and HC341 to HC345; n = 94,912). SSNHL was considered diagnosed if the medical record had the ICD-10 code H912. Among these patients, we included only those participants who had undergone an audiometry examination (claim codes E6931 to E6937 and F6341 to F6348) and had been treated with steroids. From 2002 through 2013, we identified and included 5244 such SSNHL participants. The participants with osteoporosis were matched 1:1 with participants (control group) in this cohort who had never had osteoporosis diagnosed from 2002 through 2013. The control groups were selected from the mother population (n = 1,030,779). The matches were processed for age, group, sex, income group, region of residence, and medical history (e.g., hypertension, diabetes, and dyslipidemia). To prevent selection bias when selecting matched participants, the control group participants were sorted using a random number order, and they were then selected from top to bottom. It was assumed that the matched control participants were involved at the same time as each matched osteoporosis participant (index date). Therefore, the individuals in the control group who had died before the index date were excluded. In both the osteoporosis and the control groups, the participants with a history of SSNHL before the index date were excluded. In the osteoporosis group, 367 such participants were excluded. The participants with osteoporosis for whom we could not identify enough matching participants were also excluded (n = 11,690). We excluded participants who were aged <50 years because we sought to analyze the effect of osteoporosis (n = 14,614). Finally, 1:1 matching resulted in the inclusion of 68,241 participants with osteoporosis and 68,241 control participants (Fig. 1). These participants were not matched for ischemic heart disease, cerebral stroke, or a history of depression because strict matching would have increased participant removal by the lack of control participants. Figure 1. View largeDownload slide A schematic illustration of the participant selection process used in the present study. Of a total of 1,125,691 participants, 68,241 participants with osteoporosis were matched with 68,241 control participants by age group, sex, income group, region of residence, and medical history. Figure 1. View largeDownload slide A schematic illustration of the participant selection process used in the present study. Of a total of 1,125,691 participants, 68,241 participants with osteoporosis were matched with 68,241 control participants by age group, sex, income group, region of residence, and medical history. Variables The age-matched groups were classified using 5-year intervals as follows: 50 to 54, 55 to 59, 60 to 64, 65 to 69, 70 to 74, 75 to 79, 80 to 84, and ≥85 years, for a total of 8 age groups. The income groups were initially divided into 41 classes (1 health aid class, 20 self-employment health insurance classes, and 20 employment health insurance classes). These groups were recategorized into 5 classes [class 1 (lowest income) to class 5 (highest income)]. The region of residence was divided into 16 areas according to the administrative district. These regions were regrouped into urban (Seoul, Busan, Daegu, Incheon, Gwangju, Daejeon, and Ulsan) and rural (Gyeonggi, Gangwon, Chungcheongbuk, Chungcheongnam, Jeollabuk, Jeollanam, Gyeongsangbuk, Gyeongsangnam, and Jeju) areas. The medical histories of the participants were evaluated using ICD-10 codes. To improve the accuracy of the diagnosis, hypertension (codes I10 and I15), diabetes (codes E10 to E14), and dyslipidemia (code E78) were checked to select participants who had been treated two or more times. Ischemic heart disease (codes I24 and I25) and cerebral stroke (codes I60 to I66) were checked to identify those participants who had been treated one or more times. Depression was defined using the ICD-10 codes F31 (bipolar affective disorder) through F39 (unspecified mood disorder) and was diagnosed by a psychiatrist from 2002 through 2013. Among these patients, we selected participants who had been treated two or more times. Statistical analysis To analyze the hazard ratio (HR) of osteoporosis in SSNHL, a Cox proportional hazard model was used. In this analysis, crude (simple) and adjusted (age, sex, income, region of residence, and history of hypertension, diabetes, dyslipidemia, ischemic heart disease, cerebral stroke, and depression) models were used. A 95% CI was calculated. For the subgroup analyses, we divided the participants according to age (<60, 60 to 69, and ≥70 years) and sex (male and female). Two-tailed analyses were conducted, and P values < 0.05 were considered to indicate statistical significance. The results were analyzed statistically using SPSS, version 22.0 (IBM, Armonk, NY). Results Of the 67,665 and 67,881 participants in the osteoporosis and control groups, 576 (0.8%) and 360 (0.5%) experienced SSNHL, respectively (P < 0.001; Table 1). Age, sex, level of income, region of residence, and medical history of hypertension, diabetes, and dyslipidemia were matched between the osteoporosis and control groups. The prevalence of ischemic heart disease, cerebral stroke, and depression was greater in the osteoporosis group than in the control group (P < 0.001 for each). The osteoporosis group had higher HRs for SSNHL compared with the control group (crude HR, 1.60; 95% CI, 1.40 to 1.83; P < 0.001; Table 2). This risk of SSNHL was also greater in the adjusted model (adjusted HR, 1.56; 95% CI, 1.37 to 1.78; P < 0.001). Table 1. General Characteristics of Participants Characteristic Osteoporosis Group, n (%) Control Group, n (%) P Value Age, y 1.000  50–54 12,753 (18.7) 12,753 (18.7)  55–59 12,448 (18.2) 12,448 (18.2)  60–64 12,463 (18.3) 12,463 (18.3)  65–69 11,060 (16.2) 11,060 (16.2)  70–74 8511 (12.5) 8511 (12.5)  75–79 5767 (8.5) 5767 (8.5)  80–84 3260 (4.8) 3260 (4.8)  ≥85 1979 (2.9) 1979 (2.9) Sex 1.000  Male 9692 (14.2) 9692 (14.2)  Female 58,549 (85.8) 58,549 (85.8) Income 1.000  1 (lowest) 13,547 (19.9) 13,547 (19.9)  2 9137 (13.4) 9137 (13.4)  3 10,715 (15.7) 10,715 (15.7)  4 14,242 (20.9) 14,242 (20.9)  5 (highest) 20,600 (30.2) 20,600 (30.2) Region of residence 1.000  Urban 29,976 (43.9) 29,976 (43.9)  Rural 38,265 (56.1) 38,265 (56.1) Comorbidity  Hypertension 39,819 (58.4) 39,819 (58.4) 1.000  Diabetes 19,125 (28.0) 19,125 (28.0) 1.000  Dyslipidemia 24,965 (36.6) 24,965 (36.6) 1.000  Ischemic heart disease 7315 (10.7) 6202 (9.1) < 0.001a  Cerebral stroke 13,357 (19.6) 12,027 (17.6) < 0.001a  Depression 10,398 (15.2) 6936 (10.2) < 0.001a SSNHL 576 (0.8) 360 (0.5) < 0.001a Characteristic Osteoporosis Group, n (%) Control Group, n (%) P Value Age, y 1.000  50–54 12,753 (18.7) 12,753 (18.7)  55–59 12,448 (18.2) 12,448 (18.2)  60–64 12,463 (18.3) 12,463 (18.3)  65–69 11,060 (16.2) 11,060 (16.2)  70–74 8511 (12.5) 8511 (12.5)  75–79 5767 (8.5) 5767 (8.5)  80–84 3260 (4.8) 3260 (4.8)  ≥85 1979 (2.9) 1979 (2.9) Sex 1.000  Male 9692 (14.2) 9692 (14.2)  Female 58,549 (85.8) 58,549 (85.8) Income 1.000  1 (lowest) 13,547 (19.9) 13,547 (19.9)  2 9137 (13.4) 9137 (13.4)  3 10,715 (15.7) 10,715 (15.7)  4 14,242 (20.9) 14,242 (20.9)  5 (highest) 20,600 (30.2) 20,600 (30.2) Region of residence 1.000  Urban 29,976 (43.9) 29,976 (43.9)  Rural 38,265 (56.1) 38,265 (56.1) Comorbidity  Hypertension 39,819 (58.4) 39,819 (58.4) 1.000  Diabetes 19,125 (28.0) 19,125 (28.0) 1.000  Dyslipidemia 24,965 (36.6) 24,965 (36.6) 1.000  Ischemic heart disease 7315 (10.7) 6202 (9.1) < 0.001a  Cerebral stroke 13,357 (19.6) 12,027 (17.6) < 0.001a  Depression 10,398 (15.2) 6936 (10.2) < 0.001a SSNHL 576 (0.8) 360 (0.5) < 0.001a a χ2 test; statistical significance set at P < 0.05. View Large Table 1. General Characteristics of Participants Characteristic Osteoporosis Group, n (%) Control Group, n (%) P Value Age, y 1.000  50–54 12,753 (18.7) 12,753 (18.7)  55–59 12,448 (18.2) 12,448 (18.2)  60–64 12,463 (18.3) 12,463 (18.3)  65–69 11,060 (16.2) 11,060 (16.2)  70–74 8511 (12.5) 8511 (12.5)  75–79 5767 (8.5) 5767 (8.5)  80–84 3260 (4.8) 3260 (4.8)  ≥85 1979 (2.9) 1979 (2.9) Sex 1.000  Male 9692 (14.2) 9692 (14.2)  Female 58,549 (85.8) 58,549 (85.8) Income 1.000  1 (lowest) 13,547 (19.9) 13,547 (19.9)  2 9137 (13.4) 9137 (13.4)  3 10,715 (15.7) 10,715 (15.7)  4 14,242 (20.9) 14,242 (20.9)  5 (highest) 20,600 (30.2) 20,600 (30.2) Region of residence 1.000  Urban 29,976 (43.9) 29,976 (43.9)  Rural 38,265 (56.1) 38,265 (56.1) Comorbidity  Hypertension 39,819 (58.4) 39,819 (58.4) 1.000  Diabetes 19,125 (28.0) 19,125 (28.0) 1.000  Dyslipidemia 24,965 (36.6) 24,965 (36.6) 1.000  Ischemic heart disease 7315 (10.7) 6202 (9.1) < 0.001a  Cerebral stroke 13,357 (19.6) 12,027 (17.6) < 0.001a  Depression 10,398 (15.2) 6936 (10.2) < 0.001a SSNHL 576 (0.8) 360 (0.5) < 0.001a Characteristic Osteoporosis Group, n (%) Control Group, n (%) P Value Age, y 1.000  50–54 12,753 (18.7) 12,753 (18.7)  55–59 12,448 (18.2) 12,448 (18.2)  60–64 12,463 (18.3) 12,463 (18.3)  65–69 11,060 (16.2) 11,060 (16.2)  70–74 8511 (12.5) 8511 (12.5)  75–79 5767 (8.5) 5767 (8.5)  80–84 3260 (4.8) 3260 (4.8)  ≥85 1979 (2.9) 1979 (2.9) Sex 1.000  Male 9692 (14.2) 9692 (14.2)  Female 58,549 (85.8) 58,549 (85.8) Income 1.000  1 (lowest) 13,547 (19.9) 13,547 (19.9)  2 9137 (13.4) 9137 (13.4)  3 10,715 (15.7) 10,715 (15.7)  4 14,242 (20.9) 14,242 (20.9)  5 (highest) 20,600 (30.2) 20,600 (30.2) Region of residence 1.000  Urban 29,976 (43.9) 29,976 (43.9)  Rural 38,265 (56.1) 38,265 (56.1) Comorbidity  Hypertension 39,819 (58.4) 39,819 (58.4) 1.000  Diabetes 19,125 (28.0) 19,125 (28.0) 1.000  Dyslipidemia 24,965 (36.6) 24,965 (36.6) 1.000  Ischemic heart disease 7315 (10.7) 6202 (9.1) < 0.001a  Cerebral stroke 13,357 (19.6) 12,027 (17.6) < 0.001a  Depression 10,398 (15.2) 6936 (10.2) < 0.001a SSNHL 576 (0.8) 360 (0.5) < 0.001a a χ2 test; statistical significance set at P < 0.05. View Large Table 2. Crude and Adjusted HRs (95% CIs) of Osteoporosis for SSNHL Characteristic SSNHL Crude P Value Adjusteda P Value Osteoporosis group 1.60 (1.40–1.83) < 0.001b 1.56 (1.37–1.78) < 0.001b Control group 1.00 1.00 Characteristic SSNHL Crude P Value Adjusteda P Value Osteoporosis group 1.60 (1.40–1.83) < 0.001b 1.56 (1.37–1.78) < 0.001b Control group 1.00 1.00 a Adjusted model for age, sex, income, region of residence, hypertension, diabetes, dyslipidemia, ischemic heart disease, cerebral stroke, and depression histories. b Cox proportional hazard regression model; statistical significance set at P < 0.05. View Large Table 2. Crude and Adjusted HRs (95% CIs) of Osteoporosis for SSNHL Characteristic SSNHL Crude P Value Adjusteda P Value Osteoporosis group 1.60 (1.40–1.83) < 0.001b 1.56 (1.37–1.78) < 0.001b Control group 1.00 1.00 Characteristic SSNHL Crude P Value Adjusteda P Value Osteoporosis group 1.60 (1.40–1.83) < 0.001b 1.56 (1.37–1.78) < 0.001b Control group 1.00 1.00 a Adjusted model for age, sex, income, region of residence, hypertension, diabetes, dyslipidemia, ischemic heart disease, cerebral stroke, and depression histories. b Cox proportional hazard regression model; statistical significance set at P < 0.05. View Large In the subgroup analyses performed according to age and sex, all individuals (both men and women) who were aged <60 years had higher HRs for SSNHL in the osteoporosis groups (men aged <60 years: adjusted HR, 2.73; 95% CI, 1.07 to 6.98; P = 0.036; women aged <60 years: adjusted HR, 1.34; 95% CI, 1.09 to 1.64; P = 0.005; Table 3). In the ≥60-year-old subgroups, women with osteoporosis had higher HRs for SSNHL compared with the control groups (women aged 60 to 69 years: adjusted HR, 1.67; 95% CI, 1.34 to 2.08; P < 0.001; women aged ≥70 years: adjusted HR, 1.90; 95% CI, 1.29 to 2.79; P < 0.001). However, men with osteoporosis who were aged ≥60 years did not have a high HR for SSNHL. Table 3. Subgroup Analyses of Crude and Adjusted HRs (95% CI) of Osteoporosis for SSNHL Stratified by Age and Sex Osteoporosis SSNHL Crude P Value Adjusteda P Value Age <60 y  Men (n = 3154) 2.68 (1.05–6.84) 0.040b 2.73 (1.07–6.98) 0.036b  Women (n = 47,248) 1.37 (1.12–1.68) 0.002b 1.34 (1.09–1.64) 0.005b Age 60–69 y  Men (n = 5736) 1.47 (0.76–2.83) 0.251 1.48 (0.77–2.86) 0.242  Women (n = 41,310) 1.71 (1.38–2.12) < 0.001b 1.67 (1.34–2.08) < 0.001b Age ≥70 y  Men (n = 10,494) 2.00 (0.97–4.13) 0.060 1.91 (0.92–3.96) 0.081  Women (n = 28,540) 1.98 (1.35–2.91) 0.001b 1.90 (1.29–2.79) 0.001b Osteoporosis SSNHL Crude P Value Adjusteda P Value Age <60 y  Men (n = 3154) 2.68 (1.05–6.84) 0.040b 2.73 (1.07–6.98) 0.036b  Women (n = 47,248) 1.37 (1.12–1.68) 0.002b 1.34 (1.09–1.64) 0.005b Age 60–69 y  Men (n = 5736) 1.47 (0.76–2.83) 0.251 1.48 (0.77–2.86) 0.242  Women (n = 41,310) 1.71 (1.38–2.12) < 0.001b 1.67 (1.34–2.08) < 0.001b Age ≥70 y  Men (n = 10,494) 2.00 (0.97–4.13) 0.060 1.91 (0.92–3.96) 0.081  Women (n = 28,540) 1.98 (1.35–2.91) 0.001b 1.90 (1.29–2.79) 0.001b a Adjusted model for age, sex, income, region of residence, hypertension, diabetes, dyslipidemia, ischemic heart disease, cerebral stroke, and depression. b Cox proportional hazard regression model; statistical significance set at P < 0.05. View Large Table 3. Subgroup Analyses of Crude and Adjusted HRs (95% CI) of Osteoporosis for SSNHL Stratified by Age and Sex Osteoporosis SSNHL Crude P Value Adjusteda P Value Age <60 y  Men (n = 3154) 2.68 (1.05–6.84) 0.040b 2.73 (1.07–6.98) 0.036b  Women (n = 47,248) 1.37 (1.12–1.68) 0.002b 1.34 (1.09–1.64) 0.005b Age 60–69 y  Men (n = 5736) 1.47 (0.76–2.83) 0.251 1.48 (0.77–2.86) 0.242  Women (n = 41,310) 1.71 (1.38–2.12) < 0.001b 1.67 (1.34–2.08) < 0.001b Age ≥70 y  Men (n = 10,494) 2.00 (0.97–4.13) 0.060 1.91 (0.92–3.96) 0.081  Women (n = 28,540) 1.98 (1.35–2.91) 0.001b 1.90 (1.29–2.79) 0.001b Osteoporosis SSNHL Crude P Value Adjusteda P Value Age <60 y  Men (n = 3154) 2.68 (1.05–6.84) 0.040b 2.73 (1.07–6.98) 0.036b  Women (n = 47,248) 1.37 (1.12–1.68) 0.002b 1.34 (1.09–1.64) 0.005b Age 60–69 y  Men (n = 5736) 1.47 (0.76–2.83) 0.251 1.48 (0.77–2.86) 0.242  Women (n = 41,310) 1.71 (1.38–2.12) < 0.001b 1.67 (1.34–2.08) < 0.001b Age ≥70 y  Men (n = 10,494) 2.00 (0.97–4.13) 0.060 1.91 (0.92–3.96) 0.081  Women (n = 28,540) 1.98 (1.35–2.91) 0.001b 1.90 (1.29–2.79) 0.001b a Adjusted model for age, sex, income, region of residence, hypertension, diabetes, dyslipidemia, ischemic heart disease, cerebral stroke, and depression. b Cox proportional hazard regression model; statistical significance set at P < 0.05. View Large Discussion Osteoporosis increased the risk of SSNHL in patients aged ≥50 years. Osteoporosis was a risk factor for SSNHL independent of age, sex, income, region of residence, hypertension, diabetes, dyslipidemia, ischemic heart disease, cerebral stroke, and depression. In addition to this older population, the osteoporosis group aged ≥50 years also had an elevated risk of SSNHL. When grouped according to sex, the HR for SSNHL in patients with osteoporosis was higher for the women than for the men. To the best of our knowledge, the present study is one of the largest population cohort studies to explore the relationship between osteoporosis and SSNHL using a matched control group and accounting for several confounders. The risk of SSNHL in patients with osteoporosis might be explained by direct, indirect, and confounder effects of osteoporosis on SSNHL, although some of the relevant pathophysiological mechanisms remain unknown. Osteoporotic changes in the otic capsular bones could directly impair auditory function. Patients with bone metabolic diseases, such as Paget disease, have decreased bone mineral density in the otic capsule, and this decrease has been correlated with the degree of SSNHL in a prospective, cross-sectional study (10). Those investigators reported that the main effect of otosclerotic changes on hearing was exerted on the cochlea rather than a retrocochlear lesion. Pathological bone remodeling results in fibrosis and the loss of cochlear vessels, hyalinization of the spiral ligament, and atrophy of the stria vascularis in the lateral wall of the cochlea (13). However, the bone component of the otic capsule is composed of dense and compact lamellar bone and contains few Haversian canals and vessels (8). Thus, demineralization of the otic capsular bone might represent an advanced event in patients with osteoporosis and might, therefore, not exclusively account for the risk of SSNHL in those with osteoporosis. The humoral changes associated with osteoporosis can be anticipated in accordance with osteoporotic bone metabolism. Similar to acute spinal neuropathy in patients with Paget spinal stenosis, secreted toxic cytokines might mediate cochlear dysfunction by inducing hearing cell loss and the loss of auditory neurons (14). In addition, changes in the calcium ionic endolymphatic flow of the cochlea caused by osteoporotic bone metabolism might disturb mechanoelectrical transduction in the cochlea (15). The maintenance of low calcium concentrations in the endolymph of cochlea is very crucial for the homeostasis of endolymph potential and sensory transduction in the cochlear hair cells (15). The abnormally increased bone resorption could result in high calcium concentration in the endolymph, which would disturb the endolymph potential (16–18). Bone remodeling regulators in osteoporosis could influence the inner ear function. For instance, osteoprotegerin knockout resulted in the demyelination and generation of the cochlear nerve and induced apoptosis of spiral ganglion cells, thereby causing SNHL (19). Indirectly, the effect of osteoporosis could also be exerted via bystander effects. Both osteoporosis and SSNHL have multiple etiologies, including endocrine and immunological disorders (20, 21). Systemic changes, including inflammation and endothelial dysfunction, might be associated with osteoporosis and could lead to SSNHL. It has been suggested that osteoporosis elevates the systemic inflammatory response, during which the levels of inflammatory cytokines, such as IL-6, TNF-α, C-reactive protein, and others, are increased (22). These inflammatory responses have been proposed as a causative factor for SSNHL (23). Similarly, osteoporosis was found to be a risk factor for endothelial dysfunction, which resulted in cardiovascular and cerebrovascular diseases. For example, the risk of cerebral infarct (24) and myocardial infarction (25) is greater in patients with osteoporosis, and these endothelial and vascular compromises could induce SSNHL (26, 27). Although we adjusted for several medical comorbidities in the present study, hidden risk factors could have induced both osteoporosis and SSNHL. Because the petrous temporal bone consists of compact bone, changes in the trabecular bone of the skeleton could manifest earlier than those that cause cochlear dysfunction. In accordance with the results of the present study, another population cohort study found an HR of 1.76 for SSNHL in patients with osteoporosis (95% CI, 1.33 to 2.34; P < 0.001) (9). Other studies have also reported an association between osteoporosis and SSNHL (11). However, conclusions regarding the relationship between osteoporosis and hearing loss have been mixed, and the data presented in previous studies have been inconclusive to date. A recent meta-analysis demonstrated that patients with osteoporosis had a 1.20 odds ratio for hearing loss (95% CI, 1.01 to 1.42; P = 0.04) (11). A prospective study found that patients with osteoporosis had higher audiometric thresholds in the 500- to 8000-Hz frequencies (28). Although another study reported finding no statistically significant relationship between osteoporosis and hearing loss (29), that study was a cross-sectional study with a high withdrawal rate, which increased its selection bias (29). The results of the present study have extended the conclusions drawn in previous studies by demonstrating that in osteoporosis, the risk of SSNHL is greater for those individuals aged ≥50 years and the elderly. In the subgroup analysis performed by age, the osteoporosis groups aged ≥50 to 60 years had a greater risk of SSNHL. However, a recent population cohort study reported that the incidence risk rate of SSNHL in osteoporosis was only greater in an older subgroup that included patients aged ≥65 years (OR, 5.30; 95% CI, 1.20 to 23.26) (30). We included a larger number of study groups in our study, making the statistical power of our analysis stronger than that of the previous study. When stratified according to sex, women aged 60 years with osteoporosis had a greater risk of SSNHL in the present study. Similar to our results, previous studies have also reported that the risk of SSNHL in women with osteoporosis is greater than that in the control group (31–33). It was reported that no definite sex preponderance was found in SSNHL (6). However, the incidence of osteoporosis is high in postmenopausal women. Thus, some studies have been performed to explore the relationship between osteoporosis and hearing loss in this population (31). The protective effects exerted by estrogen against osteoporosis might have an additive effect in women with osteoporosis at risk of SSNHL. Estrogen was suggested to influence the ion and fluid balance of the inner ear, and genetic polymorphisms of the estrogen receptor were associated with the development of SSNHL (34). The depletion of estrogen observed in postmenopausal and older women could aggravate the effect of osteoporosis on the development of SSNHL. Because estrogen deficiency initially influences the trabecular bone, the effects on the compact otic capsule might not manifest until the patient is older. A large and representative population was included the present study, which aimed to explore the risk of SSNHL in those with osteoporosis according to age and sex. The fidelity of these data was evaluated in a previous study (35). Numerous confounders were matched and adjusted to investigate their independent effects on SSNHL in those with osteoporosis. Specifically, the availability of medical management was equalized by matching the participants according to income and region of residence. The validated public data available from the Korean NHIS were used to estimate the level of income. In addition, the definitions used for osteoporosis and SSNHL were determined from multiple diagnoses by physicians and the patients’ treatment history. However, some caution should be used when interpreting the present results. The severity and treatment history of osteoporosis could not be assessed. Likewise, the degree of hearing impairment was not considered in those with SSNHL. Although high-frequency hearing has been reported to be more vulnerable to the effect of osteoporosis, in the present study, we did not analyze frequency-specific hearing impairment (10, 31). In conclusion, osteoporosis increased the risk of SSNHL in patients aged ≥50 years. In patients aged ≥60 years, the risk of SSNHL in those with osteoporosis was greater in women. Abbreviations: Abbreviations: HR hazard ratio ICD-10 International Classification of Diseases, 10th Revision NHIS National Health Insurance Service SSNHL sudden sensory neural hearing loss Acknowledgments The report was edited for proper English language, grammar, punctuation, spelling, and overall style by the highly qualified native English-speaking editors at American Journal Experts (99DC-ED7E-0586-60C5-D63P). Financial Support: This work was supported in part by the National Research Foundation (NRF) of Korea (research grant NRF-2015-R1D1A1A01060860 to H.G.C. and research grant 2017R1C1B1007696 to S.Y.K.). Disclosure Summary: The authors have nothing to disclose. References 1. Wright NC , Saag KG , Dawson-Hughes B , Khosla S , Siris ES . 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Increased Risk of Sudden Sensory Neural Hearing Loss in Osteoporosis: A Longitudinal Follow-Up Study

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Endocrine Society
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Copyright © 2018 Endocrine Society
ISSN
0021-972X
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1945-7197
D.O.I.
10.1210/jc.2018-00717
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Abstract

Abstract Context The results of a previous population cohort study suggested an association between osteoporosis and sudden sensory neural hearing loss (SSNHL). Objectives To use a nationwide cohort in the Korean population to investigate the risk of SSNHL in patients with osteoporosis. Design, Setting, and Participants Data entered from 2002 to 2013 were collected from the Korean National Health Insurance Service-National Sample Cohort. A total of 68,241 patients with osteoporosis aged ≥50 years were matched with 68,241 control individuals. The crude (simple) and adjusted hazard ratios (HRs) of SSNHL in those with osteoporosis were analyzed using the Cox proportional hazard model. A subgroup analysis was performed according to age and sex. Results The risk of SSNHL was greater in the osteoporosis group than in the control group (adjusted HR, 1.56; 95% CI, 1.37 to 1.78; P < 0.001). The risk of SSNHL in those with osteoporosis was greater in patients aged <60 years, regardless of sex. Women aged ≥60 years had a higher HR for SSNHL in the presence of osteoporosis (women aged 60 to 69 years: adjusted HR, 1.67; 95% CI, 1.34 to 2.08; P < 0.001; women aged ≥70 years: adjusted HR, 1.90; 95% CI, 1.29 to 2.79; P < 0.001). Conclusions The risk of SSNHL was greater for patients with osteoporosis aged ≥50 years. Middle-age adults, as well as the elderly, are at an increased risk of SSNHL in the presence of osteoporosis. Osteoporosis is a metabolic bone disorder characterized by low bone mineral density and microarchitectural deterioration of the bone, which increases susceptibility to fracturing. In the United States, its prevalence in individuals aged ≥50 years has been estimated at 16.0% in men and 29.9% in women (1). In Korea, of those aged ≥50 years, ~37.3% of women and ~7.5% of men have osteoporosis (2). In those with osteoporosis, bone resorption exceeds bone formation. This imbalance in bone metabolism can be caused by many factors, including age-related metabolic changes in calcium and vitamin D and estrogen deficiency (3). Chronic disorders, such as diabetes mellitus and dyslipidemia, also increase the risk of osteoporosis (4). In addition to fragility and the associated risk of falls and fracture, osteoporosis has been reported as a risk factor for hypertension, coronary heart disease, cerebral stroke, and dyslipidemia (5). Sudden sensory neural hearing loss (SSNHL) is defined as the abrupt onset of sensorineural hearing loss and must be urgently treated. The prevalence of SSNHL increases with age and has shown no sex preference. Its annual incidence has been reported as 27 per 100,000 persons in the United States and 15 per 100,000 persons in Korea (6, 7). Both perturbation of the perilymphatic flow of the cochlea and auditory nerve dysfunction can cause SSNHL. More than 50% of SSNHL cases are idiopathic (6). Many factors, such as vascular and metabolic dysfunction, have been suggested as risk factors for SSNHL (7). The cochlea and internal auditory nerve are encased in hard and compact petrous temporal bone (8). In addition, the calcium ionic flow in the cochlea and stereocilia of the cochlea orchestrate their activities to maintain mechanoelectrical transduction in the cochlea. Therefore, it might be that bone metabolism has a crucial effect on auditory function. In line with this hypothesis, several previous studies have proposed an association between osteoporosis and hearing impairment (9–11). In the present study, we hypothesized that osteoporosis increases the risk of SSNHL independently of confounders, including age, sex, income, region of residence, and medical history. Previously, several studies have suggested a relationship between osteoporosis and hearing impairment, although only a single cohort study reported an association between osteoporosis and SSNHL (9). To verify this association, we searched the PubMed and Embase databases for relevant studies using the keywords “(osteoporosis) AND ([hearing] OR [sudden hearing loss])” and limited the results to human-based studies reported in English before March 2018. The purpose of the present study was to evaluate the association between osteoporosis and SSNHL in the Korean adult population using a national sample cohort. A control group matched and adjusted for age, sex, income, region of residence, and pertinent medical history was used to investigate the risk of SSNHL in the presence of osteoporosis. Additionally, the age- and sex-specific risk of SSNHL in those osteoporosis was evaluated in a subgroup analysis. Materials and Methods Study population and data collection The ethics committee of Hallym University (2014-I148) approved the use of the presented data. The institutional review board exempted the present study from the requirement for written informed consent. The present national cohort study relied on data obtained from the Korean Health Insurance Review and Assessment Service – National Patient Sample. The Korean National Health Insurance Service (NHIS) selects samples directly from a database comprising the entire population to prevent nonsampling errors. Approximately 2% of the samples (1 million) were selected from the entire Korean population (50 million). These selected data were classified at 1476 levels [i.e., age (18 categories), sex (2 categories), and income level (41 categories)] using randomized stratified systematic sampling methods via proportional allocation to represent the entire population. After data selection, the appropriateness of the sample was verified by a statistician who compared the data for the entire Korean population to the sample data. The details related to the methods used to perform these procedures were provided by the National Health Insurance Sharing Service (12). This cohort database included (1) personal information; (2) health insurance claim codes (procedures and prescriptions); (3) diagnostic codes according to the International Classification of Diseases, 10th Revision (ICD-10); (4) death records from the Korean National Statistical Office (according to the Korean Standard Classification of Disease); (5) socioeconomic data (residence and income); and (6) medical examination data for each participant for the period ranging from 2002 to 2013. Because each Korean citizen is recognized by a 13-digit resident registration number from birth to death, exact population statistics can be determined using this database. It is mandatory for all Koreans to enroll in the NHIS. All Korean hospitals and clinics use this 13-digit resident registration number to register individual patients in the medical insurance system. Therefore, the risk of overlapping medical records is minimal, even when a patient has moved from one place to another. Moreover, all medical treatments performed in Korea are, without exception, tracked by the Korean Health Insurance Review and Assessment Service system. In Korea, notice of death to an administrative entity is legally required before a funeral can be held. The cause and date of death are recorded by medical doctors on the death certificate. Participant selection Of 1,125,691 cases with 114,369,638 medical claim codes, we included all participants with a diagnosis of osteoporosis. Patients with osteoporosis were those receiving a diagnosis of osteoporosis from 2002 to 2013 using the ICD-10 codes M80 (osteoporosis with pathological fracture), M81 (osteoporosis without pathological fracture), and M82 (osteoporosis in diseases classified elsewhere). Among the identified patients, we selected participants who had been treated two or more times or had received a diagnosis of osteoporosis because of bone density test results using radiography or computed tomography (claim codes E7001 to E7004 and HC341 to HC345; n = 94,912). SSNHL was considered diagnosed if the medical record had the ICD-10 code H912. Among these patients, we included only those participants who had undergone an audiometry examination (claim codes E6931 to E6937 and F6341 to F6348) and had been treated with steroids. From 2002 through 2013, we identified and included 5244 such SSNHL participants. The participants with osteoporosis were matched 1:1 with participants (control group) in this cohort who had never had osteoporosis diagnosed from 2002 through 2013. The control groups were selected from the mother population (n = 1,030,779). The matches were processed for age, group, sex, income group, region of residence, and medical history (e.g., hypertension, diabetes, and dyslipidemia). To prevent selection bias when selecting matched participants, the control group participants were sorted using a random number order, and they were then selected from top to bottom. It was assumed that the matched control participants were involved at the same time as each matched osteoporosis participant (index date). Therefore, the individuals in the control group who had died before the index date were excluded. In both the osteoporosis and the control groups, the participants with a history of SSNHL before the index date were excluded. In the osteoporosis group, 367 such participants were excluded. The participants with osteoporosis for whom we could not identify enough matching participants were also excluded (n = 11,690). We excluded participants who were aged <50 years because we sought to analyze the effect of osteoporosis (n = 14,614). Finally, 1:1 matching resulted in the inclusion of 68,241 participants with osteoporosis and 68,241 control participants (Fig. 1). These participants were not matched for ischemic heart disease, cerebral stroke, or a history of depression because strict matching would have increased participant removal by the lack of control participants. Figure 1. View largeDownload slide A schematic illustration of the participant selection process used in the present study. Of a total of 1,125,691 participants, 68,241 participants with osteoporosis were matched with 68,241 control participants by age group, sex, income group, region of residence, and medical history. Figure 1. View largeDownload slide A schematic illustration of the participant selection process used in the present study. Of a total of 1,125,691 participants, 68,241 participants with osteoporosis were matched with 68,241 control participants by age group, sex, income group, region of residence, and medical history. Variables The age-matched groups were classified using 5-year intervals as follows: 50 to 54, 55 to 59, 60 to 64, 65 to 69, 70 to 74, 75 to 79, 80 to 84, and ≥85 years, for a total of 8 age groups. The income groups were initially divided into 41 classes (1 health aid class, 20 self-employment health insurance classes, and 20 employment health insurance classes). These groups were recategorized into 5 classes [class 1 (lowest income) to class 5 (highest income)]. The region of residence was divided into 16 areas according to the administrative district. These regions were regrouped into urban (Seoul, Busan, Daegu, Incheon, Gwangju, Daejeon, and Ulsan) and rural (Gyeonggi, Gangwon, Chungcheongbuk, Chungcheongnam, Jeollabuk, Jeollanam, Gyeongsangbuk, Gyeongsangnam, and Jeju) areas. The medical histories of the participants were evaluated using ICD-10 codes. To improve the accuracy of the diagnosis, hypertension (codes I10 and I15), diabetes (codes E10 to E14), and dyslipidemia (code E78) were checked to select participants who had been treated two or more times. Ischemic heart disease (codes I24 and I25) and cerebral stroke (codes I60 to I66) were checked to identify those participants who had been treated one or more times. Depression was defined using the ICD-10 codes F31 (bipolar affective disorder) through F39 (unspecified mood disorder) and was diagnosed by a psychiatrist from 2002 through 2013. Among these patients, we selected participants who had been treated two or more times. Statistical analysis To analyze the hazard ratio (HR) of osteoporosis in SSNHL, a Cox proportional hazard model was used. In this analysis, crude (simple) and adjusted (age, sex, income, region of residence, and history of hypertension, diabetes, dyslipidemia, ischemic heart disease, cerebral stroke, and depression) models were used. A 95% CI was calculated. For the subgroup analyses, we divided the participants according to age (<60, 60 to 69, and ≥70 years) and sex (male and female). Two-tailed analyses were conducted, and P values < 0.05 were considered to indicate statistical significance. The results were analyzed statistically using SPSS, version 22.0 (IBM, Armonk, NY). Results Of the 67,665 and 67,881 participants in the osteoporosis and control groups, 576 (0.8%) and 360 (0.5%) experienced SSNHL, respectively (P < 0.001; Table 1). Age, sex, level of income, region of residence, and medical history of hypertension, diabetes, and dyslipidemia were matched between the osteoporosis and control groups. The prevalence of ischemic heart disease, cerebral stroke, and depression was greater in the osteoporosis group than in the control group (P < 0.001 for each). The osteoporosis group had higher HRs for SSNHL compared with the control group (crude HR, 1.60; 95% CI, 1.40 to 1.83; P < 0.001; Table 2). This risk of SSNHL was also greater in the adjusted model (adjusted HR, 1.56; 95% CI, 1.37 to 1.78; P < 0.001). Table 1. General Characteristics of Participants Characteristic Osteoporosis Group, n (%) Control Group, n (%) P Value Age, y 1.000  50–54 12,753 (18.7) 12,753 (18.7)  55–59 12,448 (18.2) 12,448 (18.2)  60–64 12,463 (18.3) 12,463 (18.3)  65–69 11,060 (16.2) 11,060 (16.2)  70–74 8511 (12.5) 8511 (12.5)  75–79 5767 (8.5) 5767 (8.5)  80–84 3260 (4.8) 3260 (4.8)  ≥85 1979 (2.9) 1979 (2.9) Sex 1.000  Male 9692 (14.2) 9692 (14.2)  Female 58,549 (85.8) 58,549 (85.8) Income 1.000  1 (lowest) 13,547 (19.9) 13,547 (19.9)  2 9137 (13.4) 9137 (13.4)  3 10,715 (15.7) 10,715 (15.7)  4 14,242 (20.9) 14,242 (20.9)  5 (highest) 20,600 (30.2) 20,600 (30.2) Region of residence 1.000  Urban 29,976 (43.9) 29,976 (43.9)  Rural 38,265 (56.1) 38,265 (56.1) Comorbidity  Hypertension 39,819 (58.4) 39,819 (58.4) 1.000  Diabetes 19,125 (28.0) 19,125 (28.0) 1.000  Dyslipidemia 24,965 (36.6) 24,965 (36.6) 1.000  Ischemic heart disease 7315 (10.7) 6202 (9.1) < 0.001a  Cerebral stroke 13,357 (19.6) 12,027 (17.6) < 0.001a  Depression 10,398 (15.2) 6936 (10.2) < 0.001a SSNHL 576 (0.8) 360 (0.5) < 0.001a Characteristic Osteoporosis Group, n (%) Control Group, n (%) P Value Age, y 1.000  50–54 12,753 (18.7) 12,753 (18.7)  55–59 12,448 (18.2) 12,448 (18.2)  60–64 12,463 (18.3) 12,463 (18.3)  65–69 11,060 (16.2) 11,060 (16.2)  70–74 8511 (12.5) 8511 (12.5)  75–79 5767 (8.5) 5767 (8.5)  80–84 3260 (4.8) 3260 (4.8)  ≥85 1979 (2.9) 1979 (2.9) Sex 1.000  Male 9692 (14.2) 9692 (14.2)  Female 58,549 (85.8) 58,549 (85.8) Income 1.000  1 (lowest) 13,547 (19.9) 13,547 (19.9)  2 9137 (13.4) 9137 (13.4)  3 10,715 (15.7) 10,715 (15.7)  4 14,242 (20.9) 14,242 (20.9)  5 (highest) 20,600 (30.2) 20,600 (30.2) Region of residence 1.000  Urban 29,976 (43.9) 29,976 (43.9)  Rural 38,265 (56.1) 38,265 (56.1) Comorbidity  Hypertension 39,819 (58.4) 39,819 (58.4) 1.000  Diabetes 19,125 (28.0) 19,125 (28.0) 1.000  Dyslipidemia 24,965 (36.6) 24,965 (36.6) 1.000  Ischemic heart disease 7315 (10.7) 6202 (9.1) < 0.001a  Cerebral stroke 13,357 (19.6) 12,027 (17.6) < 0.001a  Depression 10,398 (15.2) 6936 (10.2) < 0.001a SSNHL 576 (0.8) 360 (0.5) < 0.001a a χ2 test; statistical significance set at P < 0.05. View Large Table 1. General Characteristics of Participants Characteristic Osteoporosis Group, n (%) Control Group, n (%) P Value Age, y 1.000  50–54 12,753 (18.7) 12,753 (18.7)  55–59 12,448 (18.2) 12,448 (18.2)  60–64 12,463 (18.3) 12,463 (18.3)  65–69 11,060 (16.2) 11,060 (16.2)  70–74 8511 (12.5) 8511 (12.5)  75–79 5767 (8.5) 5767 (8.5)  80–84 3260 (4.8) 3260 (4.8)  ≥85 1979 (2.9) 1979 (2.9) Sex 1.000  Male 9692 (14.2) 9692 (14.2)  Female 58,549 (85.8) 58,549 (85.8) Income 1.000  1 (lowest) 13,547 (19.9) 13,547 (19.9)  2 9137 (13.4) 9137 (13.4)  3 10,715 (15.7) 10,715 (15.7)  4 14,242 (20.9) 14,242 (20.9)  5 (highest) 20,600 (30.2) 20,600 (30.2) Region of residence 1.000  Urban 29,976 (43.9) 29,976 (43.9)  Rural 38,265 (56.1) 38,265 (56.1) Comorbidity  Hypertension 39,819 (58.4) 39,819 (58.4) 1.000  Diabetes 19,125 (28.0) 19,125 (28.0) 1.000  Dyslipidemia 24,965 (36.6) 24,965 (36.6) 1.000  Ischemic heart disease 7315 (10.7) 6202 (9.1) < 0.001a  Cerebral stroke 13,357 (19.6) 12,027 (17.6) < 0.001a  Depression 10,398 (15.2) 6936 (10.2) < 0.001a SSNHL 576 (0.8) 360 (0.5) < 0.001a Characteristic Osteoporosis Group, n (%) Control Group, n (%) P Value Age, y 1.000  50–54 12,753 (18.7) 12,753 (18.7)  55–59 12,448 (18.2) 12,448 (18.2)  60–64 12,463 (18.3) 12,463 (18.3)  65–69 11,060 (16.2) 11,060 (16.2)  70–74 8511 (12.5) 8511 (12.5)  75–79 5767 (8.5) 5767 (8.5)  80–84 3260 (4.8) 3260 (4.8)  ≥85 1979 (2.9) 1979 (2.9) Sex 1.000  Male 9692 (14.2) 9692 (14.2)  Female 58,549 (85.8) 58,549 (85.8) Income 1.000  1 (lowest) 13,547 (19.9) 13,547 (19.9)  2 9137 (13.4) 9137 (13.4)  3 10,715 (15.7) 10,715 (15.7)  4 14,242 (20.9) 14,242 (20.9)  5 (highest) 20,600 (30.2) 20,600 (30.2) Region of residence 1.000  Urban 29,976 (43.9) 29,976 (43.9)  Rural 38,265 (56.1) 38,265 (56.1) Comorbidity  Hypertension 39,819 (58.4) 39,819 (58.4) 1.000  Diabetes 19,125 (28.0) 19,125 (28.0) 1.000  Dyslipidemia 24,965 (36.6) 24,965 (36.6) 1.000  Ischemic heart disease 7315 (10.7) 6202 (9.1) < 0.001a  Cerebral stroke 13,357 (19.6) 12,027 (17.6) < 0.001a  Depression 10,398 (15.2) 6936 (10.2) < 0.001a SSNHL 576 (0.8) 360 (0.5) < 0.001a a χ2 test; statistical significance set at P < 0.05. View Large Table 2. Crude and Adjusted HRs (95% CIs) of Osteoporosis for SSNHL Characteristic SSNHL Crude P Value Adjusteda P Value Osteoporosis group 1.60 (1.40–1.83) < 0.001b 1.56 (1.37–1.78) < 0.001b Control group 1.00 1.00 Characteristic SSNHL Crude P Value Adjusteda P Value Osteoporosis group 1.60 (1.40–1.83) < 0.001b 1.56 (1.37–1.78) < 0.001b Control group 1.00 1.00 a Adjusted model for age, sex, income, region of residence, hypertension, diabetes, dyslipidemia, ischemic heart disease, cerebral stroke, and depression histories. b Cox proportional hazard regression model; statistical significance set at P < 0.05. View Large Table 2. Crude and Adjusted HRs (95% CIs) of Osteoporosis for SSNHL Characteristic SSNHL Crude P Value Adjusteda P Value Osteoporosis group 1.60 (1.40–1.83) < 0.001b 1.56 (1.37–1.78) < 0.001b Control group 1.00 1.00 Characteristic SSNHL Crude P Value Adjusteda P Value Osteoporosis group 1.60 (1.40–1.83) < 0.001b 1.56 (1.37–1.78) < 0.001b Control group 1.00 1.00 a Adjusted model for age, sex, income, region of residence, hypertension, diabetes, dyslipidemia, ischemic heart disease, cerebral stroke, and depression histories. b Cox proportional hazard regression model; statistical significance set at P < 0.05. View Large In the subgroup analyses performed according to age and sex, all individuals (both men and women) who were aged <60 years had higher HRs for SSNHL in the osteoporosis groups (men aged <60 years: adjusted HR, 2.73; 95% CI, 1.07 to 6.98; P = 0.036; women aged <60 years: adjusted HR, 1.34; 95% CI, 1.09 to 1.64; P = 0.005; Table 3). In the ≥60-year-old subgroups, women with osteoporosis had higher HRs for SSNHL compared with the control groups (women aged 60 to 69 years: adjusted HR, 1.67; 95% CI, 1.34 to 2.08; P < 0.001; women aged ≥70 years: adjusted HR, 1.90; 95% CI, 1.29 to 2.79; P < 0.001). However, men with osteoporosis who were aged ≥60 years did not have a high HR for SSNHL. Table 3. Subgroup Analyses of Crude and Adjusted HRs (95% CI) of Osteoporosis for SSNHL Stratified by Age and Sex Osteoporosis SSNHL Crude P Value Adjusteda P Value Age <60 y  Men (n = 3154) 2.68 (1.05–6.84) 0.040b 2.73 (1.07–6.98) 0.036b  Women (n = 47,248) 1.37 (1.12–1.68) 0.002b 1.34 (1.09–1.64) 0.005b Age 60–69 y  Men (n = 5736) 1.47 (0.76–2.83) 0.251 1.48 (0.77–2.86) 0.242  Women (n = 41,310) 1.71 (1.38–2.12) < 0.001b 1.67 (1.34–2.08) < 0.001b Age ≥70 y  Men (n = 10,494) 2.00 (0.97–4.13) 0.060 1.91 (0.92–3.96) 0.081  Women (n = 28,540) 1.98 (1.35–2.91) 0.001b 1.90 (1.29–2.79) 0.001b Osteoporosis SSNHL Crude P Value Adjusteda P Value Age <60 y  Men (n = 3154) 2.68 (1.05–6.84) 0.040b 2.73 (1.07–6.98) 0.036b  Women (n = 47,248) 1.37 (1.12–1.68) 0.002b 1.34 (1.09–1.64) 0.005b Age 60–69 y  Men (n = 5736) 1.47 (0.76–2.83) 0.251 1.48 (0.77–2.86) 0.242  Women (n = 41,310) 1.71 (1.38–2.12) < 0.001b 1.67 (1.34–2.08) < 0.001b Age ≥70 y  Men (n = 10,494) 2.00 (0.97–4.13) 0.060 1.91 (0.92–3.96) 0.081  Women (n = 28,540) 1.98 (1.35–2.91) 0.001b 1.90 (1.29–2.79) 0.001b a Adjusted model for age, sex, income, region of residence, hypertension, diabetes, dyslipidemia, ischemic heart disease, cerebral stroke, and depression. b Cox proportional hazard regression model; statistical significance set at P < 0.05. View Large Table 3. Subgroup Analyses of Crude and Adjusted HRs (95% CI) of Osteoporosis for SSNHL Stratified by Age and Sex Osteoporosis SSNHL Crude P Value Adjusteda P Value Age <60 y  Men (n = 3154) 2.68 (1.05–6.84) 0.040b 2.73 (1.07–6.98) 0.036b  Women (n = 47,248) 1.37 (1.12–1.68) 0.002b 1.34 (1.09–1.64) 0.005b Age 60–69 y  Men (n = 5736) 1.47 (0.76–2.83) 0.251 1.48 (0.77–2.86) 0.242  Women (n = 41,310) 1.71 (1.38–2.12) < 0.001b 1.67 (1.34–2.08) < 0.001b Age ≥70 y  Men (n = 10,494) 2.00 (0.97–4.13) 0.060 1.91 (0.92–3.96) 0.081  Women (n = 28,540) 1.98 (1.35–2.91) 0.001b 1.90 (1.29–2.79) 0.001b Osteoporosis SSNHL Crude P Value Adjusteda P Value Age <60 y  Men (n = 3154) 2.68 (1.05–6.84) 0.040b 2.73 (1.07–6.98) 0.036b  Women (n = 47,248) 1.37 (1.12–1.68) 0.002b 1.34 (1.09–1.64) 0.005b Age 60–69 y  Men (n = 5736) 1.47 (0.76–2.83) 0.251 1.48 (0.77–2.86) 0.242  Women (n = 41,310) 1.71 (1.38–2.12) < 0.001b 1.67 (1.34–2.08) < 0.001b Age ≥70 y  Men (n = 10,494) 2.00 (0.97–4.13) 0.060 1.91 (0.92–3.96) 0.081  Women (n = 28,540) 1.98 (1.35–2.91) 0.001b 1.90 (1.29–2.79) 0.001b a Adjusted model for age, sex, income, region of residence, hypertension, diabetes, dyslipidemia, ischemic heart disease, cerebral stroke, and depression. b Cox proportional hazard regression model; statistical significance set at P < 0.05. View Large Discussion Osteoporosis increased the risk of SSNHL in patients aged ≥50 years. Osteoporosis was a risk factor for SSNHL independent of age, sex, income, region of residence, hypertension, diabetes, dyslipidemia, ischemic heart disease, cerebral stroke, and depression. In addition to this older population, the osteoporosis group aged ≥50 years also had an elevated risk of SSNHL. When grouped according to sex, the HR for SSNHL in patients with osteoporosis was higher for the women than for the men. To the best of our knowledge, the present study is one of the largest population cohort studies to explore the relationship between osteoporosis and SSNHL using a matched control group and accounting for several confounders. The risk of SSNHL in patients with osteoporosis might be explained by direct, indirect, and confounder effects of osteoporosis on SSNHL, although some of the relevant pathophysiological mechanisms remain unknown. Osteoporotic changes in the otic capsular bones could directly impair auditory function. Patients with bone metabolic diseases, such as Paget disease, have decreased bone mineral density in the otic capsule, and this decrease has been correlated with the degree of SSNHL in a prospective, cross-sectional study (10). Those investigators reported that the main effect of otosclerotic changes on hearing was exerted on the cochlea rather than a retrocochlear lesion. Pathological bone remodeling results in fibrosis and the loss of cochlear vessels, hyalinization of the spiral ligament, and atrophy of the stria vascularis in the lateral wall of the cochlea (13). However, the bone component of the otic capsule is composed of dense and compact lamellar bone and contains few Haversian canals and vessels (8). Thus, demineralization of the otic capsular bone might represent an advanced event in patients with osteoporosis and might, therefore, not exclusively account for the risk of SSNHL in those with osteoporosis. The humoral changes associated with osteoporosis can be anticipated in accordance with osteoporotic bone metabolism. Similar to acute spinal neuropathy in patients with Paget spinal stenosis, secreted toxic cytokines might mediate cochlear dysfunction by inducing hearing cell loss and the loss of auditory neurons (14). In addition, changes in the calcium ionic endolymphatic flow of the cochlea caused by osteoporotic bone metabolism might disturb mechanoelectrical transduction in the cochlea (15). The maintenance of low calcium concentrations in the endolymph of cochlea is very crucial for the homeostasis of endolymph potential and sensory transduction in the cochlear hair cells (15). The abnormally increased bone resorption could result in high calcium concentration in the endolymph, which would disturb the endolymph potential (16–18). Bone remodeling regulators in osteoporosis could influence the inner ear function. For instance, osteoprotegerin knockout resulted in the demyelination and generation of the cochlear nerve and induced apoptosis of spiral ganglion cells, thereby causing SNHL (19). Indirectly, the effect of osteoporosis could also be exerted via bystander effects. Both osteoporosis and SSNHL have multiple etiologies, including endocrine and immunological disorders (20, 21). Systemic changes, including inflammation and endothelial dysfunction, might be associated with osteoporosis and could lead to SSNHL. It has been suggested that osteoporosis elevates the systemic inflammatory response, during which the levels of inflammatory cytokines, such as IL-6, TNF-α, C-reactive protein, and others, are increased (22). These inflammatory responses have been proposed as a causative factor for SSNHL (23). Similarly, osteoporosis was found to be a risk factor for endothelial dysfunction, which resulted in cardiovascular and cerebrovascular diseases. For example, the risk of cerebral infarct (24) and myocardial infarction (25) is greater in patients with osteoporosis, and these endothelial and vascular compromises could induce SSNHL (26, 27). Although we adjusted for several medical comorbidities in the present study, hidden risk factors could have induced both osteoporosis and SSNHL. Because the petrous temporal bone consists of compact bone, changes in the trabecular bone of the skeleton could manifest earlier than those that cause cochlear dysfunction. In accordance with the results of the present study, another population cohort study found an HR of 1.76 for SSNHL in patients with osteoporosis (95% CI, 1.33 to 2.34; P < 0.001) (9). Other studies have also reported an association between osteoporosis and SSNHL (11). However, conclusions regarding the relationship between osteoporosis and hearing loss have been mixed, and the data presented in previous studies have been inconclusive to date. A recent meta-analysis demonstrated that patients with osteoporosis had a 1.20 odds ratio for hearing loss (95% CI, 1.01 to 1.42; P = 0.04) (11). A prospective study found that patients with osteoporosis had higher audiometric thresholds in the 500- to 8000-Hz frequencies (28). Although another study reported finding no statistically significant relationship between osteoporosis and hearing loss (29), that study was a cross-sectional study with a high withdrawal rate, which increased its selection bias (29). The results of the present study have extended the conclusions drawn in previous studies by demonstrating that in osteoporosis, the risk of SSNHL is greater for those individuals aged ≥50 years and the elderly. In the subgroup analysis performed by age, the osteoporosis groups aged ≥50 to 60 years had a greater risk of SSNHL. However, a recent population cohort study reported that the incidence risk rate of SSNHL in osteoporosis was only greater in an older subgroup that included patients aged ≥65 years (OR, 5.30; 95% CI, 1.20 to 23.26) (30). We included a larger number of study groups in our study, making the statistical power of our analysis stronger than that of the previous study. When stratified according to sex, women aged 60 years with osteoporosis had a greater risk of SSNHL in the present study. Similar to our results, previous studies have also reported that the risk of SSNHL in women with osteoporosis is greater than that in the control group (31–33). It was reported that no definite sex preponderance was found in SSNHL (6). However, the incidence of osteoporosis is high in postmenopausal women. Thus, some studies have been performed to explore the relationship between osteoporosis and hearing loss in this population (31). The protective effects exerted by estrogen against osteoporosis might have an additive effect in women with osteoporosis at risk of SSNHL. Estrogen was suggested to influence the ion and fluid balance of the inner ear, and genetic polymorphisms of the estrogen receptor were associated with the development of SSNHL (34). The depletion of estrogen observed in postmenopausal and older women could aggravate the effect of osteoporosis on the development of SSNHL. Because estrogen deficiency initially influences the trabecular bone, the effects on the compact otic capsule might not manifest until the patient is older. A large and representative population was included the present study, which aimed to explore the risk of SSNHL in those with osteoporosis according to age and sex. The fidelity of these data was evaluated in a previous study (35). Numerous confounders were matched and adjusted to investigate their independent effects on SSNHL in those with osteoporosis. Specifically, the availability of medical management was equalized by matching the participants according to income and region of residence. The validated public data available from the Korean NHIS were used to estimate the level of income. In addition, the definitions used for osteoporosis and SSNHL were determined from multiple diagnoses by physicians and the patients’ treatment history. However, some caution should be used when interpreting the present results. The severity and treatment history of osteoporosis could not be assessed. Likewise, the degree of hearing impairment was not considered in those with SSNHL. Although high-frequency hearing has been reported to be more vulnerable to the effect of osteoporosis, in the present study, we did not analyze frequency-specific hearing impairment (10, 31). In conclusion, osteoporosis increased the risk of SSNHL in patients aged ≥50 years. In patients aged ≥60 years, the risk of SSNHL in those with osteoporosis was greater in women. Abbreviations: Abbreviations: HR hazard ratio ICD-10 International Classification of Diseases, 10th Revision NHIS National Health Insurance Service SSNHL sudden sensory neural hearing loss Acknowledgments The report was edited for proper English language, grammar, punctuation, spelling, and overall style by the highly qualified native English-speaking editors at American Journal Experts (99DC-ED7E-0586-60C5-D63P). Financial Support: This work was supported in part by the National Research Foundation (NRF) of Korea (research grant NRF-2015-R1D1A1A01060860 to H.G.C. and research grant 2017R1C1B1007696 to S.Y.K.). Disclosure Summary: The authors have nothing to disclose. References 1. Wright NC , Saag KG , Dawson-Hughes B , Khosla S , Siris ES . 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Journal

Journal of Clinical Endocrinology and MetabolismOxford University Press

Published: Aug 1, 2018

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