Abstract
Background:
Osteoporosis and low bone density (LBD) may be associated with higher risk of hearing loss, but findings are inconsistent and longitudinal data are scarce. Bisphosphonates may influence risk, but the relation has not been studied in humans. We longitudinally investigated associations of osteoporosis and LBD, bisphosphonate use, vertebral fracture (VF), hip fracture (HF), and risk of self-reported moderate or worse hearing loss.
Design:
Longitudinal cohort study
Setting:
The Nurses’ Health Study (NHS) (1982-2016) and Nurses’ Health Study II (NHS II) (1995-2017).
Participants:
Participants included 60,821 NHS women, aged 36-61 years at baseline, and 83,078 NHS II women, aged 31-48 years at baseline (total n=143,899).
Measurements:
Information on osteoporosis, LBD, bisphosphonate use, VF, HF and hearing status was obtained from validated biennial questionnaires. In a subcohort (n=3749), objective hearing thresholds were obtained by audiometry. Multivariable-adjusted Cox proportional hazards models were used to examine independent associations between osteoporosis (NHS), osteoporosis/LBD (NHS II), and risk of hearing loss.
Results:
The multivariable-adjusted relative risk (MVRR, 95% CI) of moderate or worse hearing loss was higher among women with osteoporosis or LBD in both cohorts. In NHS, compared with women without osteoporosis, the MVRR was 1.14 (1.09,1.19) among women with osteoporosis; in NHS II, the MVRR was 1.30 (1.21,1.40) among women with osteoporosis/LBD. The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates. VF was associated with higher risk [NHS:1.31 (1.16,1.49); NHS II:1.39 (1.13,1.71)], but HF was not [NHS:1.00 (0.86,1.16);NHS II:1.15 (0.75,1.74)]. Among participants with audiometric measurements, compared with women without osteoporosis/LBD, the mean multivariable-adjusted hearing thresholds were higher (i.e. worse) among those with osteoporosis/LBD who used bisphosphonates.
Conclusion:
Osteoporosis and low bone density may be important contributors to aging-related hearing loss. Among women with osteoporosis, the risk of hearing loss was not influenced by bisphosphonate use.
Keywords: Cohort Study, Aging, Osteoporosis, Fractures, Hearing Loss, Bisphosphonates
Introduction
Hearing loss is the third most common chronic condition in the U.S. and can cause considerable disability.1 Individuals with hearing loss are more likely to have impaired activities of daily living (ADLs),2 reduced quality of life,2 and higher risk of depression3 and cognitive decline.4 The Global Burden Disease Study 2013 reported an estimated 1.23 billion individuals have some form of hearing impairment, accounting for 36.5 years lost to disability (YLDs) globally. Further, over 400 million had hearing loss that was moderate or worse in severity, the vast majority of which was classified as age-related hearing loss.5 Hearing damage is often irreversible, thus identifying potentially modifiable risk factors that may contribute to hearing loss is a pressing public health goal.
Osteoporosis is associated with reduced bone mass and microarchitectural deterioration, leading to compromised bone strength and increased risk of fractures.6 Vertebral fractures (VF) are the most common manifestation of osteoporosis;7 osteoporosis is also strongly related to risk for hip fracture (HF).8 Animal studies suggest pathways involved in bone homeostasis are also important for cochlear sensorineural integrity and hearing.9 Some cross-sectional studies in humans found lower bone density and higher prevalence of osteoporosis among individuals with hearing loss, but findings are inconsistent and longitudinal data are lacking.10,11 Bisphosphonates are the primary therapy for reducing risk of fractures in individuals with osteoporosis and other skeletal conditions characterized by increased osteoclast-mediated bone resorption,12 and potential benefits of bisphosphonates on hearing have been suggested. A study in noise-exposed mice demonstrated regeneration of cochlear synapses after systemic bisphosphonate administration.13 In humans with otosclerosis, treatment with a third-generation bisphosphonate was associated with stabilization or improvement of sensorineural hearing loss.14 The longitudinal association of osteoporosis and hearing loss, and whether bisphosphonate use may influence the risk, is not known. Therefore, we prospectively investigated the association of osteoporosis, bisphosphonate use, and risk of moderate or worse hearing loss in 143,899 participants in the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHS II). We also investigated whether a history of VF or HF, common sites of osteoporotic fractures, were associated with risk of hearing loss.
Methods
Study population
The Conservation of Hearing Study (CHEARS) examines risk factors for hearing loss among participants in the NHS and NHS II, two large ongoing prospective cohort studies. NHS was established in 1976 and enrolled 121,700 female registered nurses ages 30-55 years. NHS II began in 1989 and enrolled 116,430 female registered nurses ages 25-42 years. In this study, NHS participants were followed up to 34 years, from 1982 through 2016; hence, the women were age 36-61 years at baseline and age 70-95 years at the end of follow-up. NHS II participants were followed up to 22 years, from 1995 through 2017; hence, the women were age 31-48 years at baseline and age 53-70 years at the end of follow-up. Participants completed questionnaires at baseline and every two years regarding numerous health outcomes, medications, diet, and lifestyle factors. Both cohorts have >90% follow-up response rates and only 5% of person-time has been lost to follow-up.15 We limited our study to women who provided information on their hearing on the biennial questionnaires. Of the 65,855 women in NHS and 90,059 women in NHS II who answered the questionnaires, we excluded those who reported a hearing problem that began before the baseline for each analysis, did not report a date of onset, or reported cancer other than non-melanoma skin cancer (due to possible exposure to potentially ototoxic chemotherapy). In our primary analyses, 60,821 NHS and 83,078 NHS II women were included in the analytic samples. The study protocol was approved by the Institutional Review Board of Brigham and Women’s Hospital.
Assessment of Exposures
Information on history of osteoporosis or low bone density (LBD) and date of diagnosis was collected by self-report on biennial questionnaires beginning in 1982 (NHS) and 2001 (NHS II). In NHS, women were asked whether they had clinician-diagnosed osteoporosis and date of diagnosis. In NHS II, women were asked about clinician-diagnosed osteoporosis or LBD and date of diagnosis, with osteoporosis and LBD queried separately in some questionnaire cycles and jointly in others. Therefore, in NHS II we examined osteoporosis/LBD as a combined category. Participants were also asked about regular use of bisphosphonates (e.g. Fosamax, Boniva, Actonel) beginning in 1998 (NHS) and 1999 (NHS II) and updated every 2 years. Self-reported diagnosis of osteoporosis and LBD were demonstrated to be valid; medical records for bone density tests were obtained in a random sample and self-reported diagnoses were confirmed in 114/120 (95%) using World Health Organization criteria for osteopenia/osteoporosis.16
Assessment of VF and HF has been described previously.17 In NHS, participants were asked on the 2012 questionnaire about lifetime history of a clinician-diagnosed “vertebral (spine) fracture, X-ray confirmed” and year of diagnosis. Participants were asked again about VF diagnosis in 2014. In NHS II, participants were asked about VF and date of diagnosis in 2013. In NHS, participants who reported a VF in 2002 or afterward were mailed supplemental questionnaires and medical records were requested; VF was confirmed by clinical notes or radiology reports among those for whom sufficient information was available. In NHS, we examined only confirmed VF. In NHS II, few women had confirmed VF, thus we examined self-reported VF in the primary analysis; a sensitivity analysis was conducted examining only confirmed VF.
In NHS, participants reported previous HFs on the 1982 questionnaire and incident fractures were reported on subsequent biennial questionnaires. In NHS II, participants were first asked about HF and date in 2005. Self-reported HF were found to be highly reliable in these registered nurses.18 Thus, we examined self-reported HF in our analyses of HF and risk of hearing loss.
Ascertainment of outcome
The primary outcome, self-reported hearing loss that was moderate or worse in severity, was determined based on responses to questions regarding hearing status, and the date when a change in hearing was first noticed, on biennial questionnaires (https://www.nurseshealthstudy.org/participants/questionnaires). We a priori chose to examine moderate or worse hearing loss as the primary outcome to focus on hearing loss that is likely to be the most clinically meaningful and to minimize misclassification. The use of questionnaires to assess hearing loss in large populations was found to be reasonably reliable in previous studies,19,20 and was effective in detecting significant relations in these cohorts.21,22 In a validation study of self-reported hearing loss compared with audiometric hearing loss, sensitivity of a single question to assess hearing loss among women age <70 was 95% for detecting moderate hearing loss (better ear pure-tone average at 0.5,1,2,4 kHz (PTA0.5,1,2,4) >40 dB) and 100% for detecting “marked” hearing loss (PTA0.5,1,2,4 >60 dB); specificity was 65% and 64%, respectively.20
In secondary analyses among a subcohort in the CHEARS Audiometry Assessment Arm (AAA), we evaluated audiometric thresholds among women with and without osteoporosis/LBD, and with and without bisphosphonate use. Audiometric thresholds are a measure of hearing sensitivity based on the intensity (loudness) of sound. Pure-tone audiometry assesses the threshold of sound intensity reliably detected by each ear, ranging from −10 dB HL (decibels hearing level) to 120 dB HL, at each individual frequency across a range of frequencies (0.5 through 8 kHz). A higher audiometric threshold indicates poorer hearing sensitivity. The methods for the CHEARS AAA are described elsewhere.23,24 Briefly, we assessed pure-tone air conduction hearing thresholds at 19 geographically diverse testing sites, conducted by licensed audiologists using standardized protocols and equipment calibrated data to meet American National Standards Institute standards. We a priori invited participants who reported excellent or good hearing and no history of otologic disease to examine early threshold changes; the mean(SD) worse ear audiometric thresholds were 12.3(8.5) at 0.5 kHz; 11.9(8.6) at 1 kHz; 13.7(9.8) at 2 kHz; 16.9(11.2) at 3 kHz; 21.1(12.9) at 4 kHz; 29.4(15.5) at 6 kHz; and 32.6(18.6) at 8 kHz. Multivariable-adjusted logistic regression models were used to examine differences in mean audiometric thresholds among the 3,749 participants who completed baseline testing. Characteristics of AAA participants did not differ appreciably from the main cohort.24(Supplemental Table 1).
Assessment of Covariates
We considered potential confounders previously suggested to be associated with osteoporosis or hearing loss in these cohorts or previous literature. In our primary analyses, factors included age, race/ethnicity, body mass index, waist circumference, physical activity, Dietary Approaches to Stop Hypertension (DASH) adherence score, alcohol intake, hypertension, diabetes, smoking, thiazide use, menopausal status, and ibuprofen, acetaminophen, and oral hormone use. In additional models, we included furosemide use and intakes of specific nutrients, including dietary and supplemental calcium, magnesium, potassium, sodium, phosphorus, animal protein, sucrose, vitamin C, and vitamin D. Covariate information was obtained from validated biennial questionnaires15 and updated every two years; dietary information was updated every 4 years. Indicator variables were created for missing information for each covariate and included in the multivariable models.
Statistical analysis
The study design was prospective, with information collected before the reported onset of hearing loss. Person-time of follow-up was calculated from the date of return of the baseline questionnaire for that analysis until the date of onset of self-reported hearing loss or end of follow-up. Participants with cancers other than non-melanoma skin cancer were censored when reported during follow-up. Women with no history of osteoporosis or LBD served as the referent group. Person-months of follow-up were allocated according to exposure status at the start of each follow-up period. If a participant reported hearing loss that was mild in severity, that participant did not contribute person-time for that time period but could re-enter the analysis if moderate or worse hearing loss was reported in a subsequent time period. We used Cox proportional hazards regression models to estimate relative risks (RR) and 95% confidence intervals (95% CI) in age- and multivariable-adjusted analyses. We used the Anderson-Gill data structure,25 with a new data record created for each biennial questionnaire, to handle time-varying covariates efficiently. To control as finely as possible for confounding by age, calendar time, and any possible 2-way interactions between these two time scales, we stratified the analysis jointly by age in months at start of follow-up and calendar year of the current questionnaire cycle. The time scale for the analysis was then measured as months since the start of the current questionnaire cycle, which is equivalent to age in months. All P values are 2-tailed and considered statistically significant at P < 0.05. Statistical tests were performed with SAS statistical software, version 9.4 (SAS Institute Inc., Cary, NC).
RESULTS
A total of 60,821 NHS and 83,078 NHS II women were included in the analyses (total n=143,899). The baseline characteristics of participants in the NHS (1982) and NHS II (1995) according to osteoporosis/LBD are presented in Table 1. In both cohorts, women with osteoporosis or LBD were more likely to be older, menopausal, and to use hormone therapy, but there were no other large differences. Among women who used bisphosphonates, the mean (SD) duration of use was 5.8 (3.2) years in NHS and 3.4 (1.9) years in NHS II.
Table 1:
Age-standardized Baseline Characteristics of Women in the Nurses’ Health Study (1982) and Nurses’ Health Study II (1995), According to Osteoporosis or Low Bone Density (LBD)
| Nurses’ Health Study | Nurses’ Health Study II | |||
|---|---|---|---|---|
| Characteristic | No Osteoporosis | Osteoporosis | No Osteoporosis or LBD | Osteoporosis or LBD |
| n=57,472 | n=534 | n=81,078 | n=1,619 | |
| Age, yearsa (baseline) | 46.0 (6.5) | 52.6 (5.7) | 40.2 (4.6) | 43.2 (4.0) |
| Age, yearsa (end of follow-up) | 79.1 (6.1) | 85.8 (5.9) | 62.0 (4.6) | 65.0 (4.0) |
| Mean follow-up, yearsa | 25.3 | 21.5 | 17.9 | 16.9 |
| Race, white, % | 94.5 | 95.7 | 94.1 | 95.0 |
| Body mass index, kg/m2 | 24.2 (4.2) | 24.4 (3.8) | 25.7 (5.8) | 23.9 (5.2) |
| Waist circumference, cmb | 77.3 (10.5) | 79.4 (9.4) | 78 (12.6) | 74.4 (11) |
| Physical activity, METs/weekc | 14.6 (21.1) | 16 (19.8) | 20.8 (26.8) | 23 (30.2) |
| Smoking | ||||
| Never, % | 46.9 | 41.6 | 65.9 | 64.3 |
| Past, % | 30.5 | 32.3 | 23.8 | 22.9 |
| Current, % | 22.4 | 26.0 | 9.9 | 12.2 |
| Hypertension, % | 14.0 | 23.8 | 9.2 | 11.9 |
| Diabetes mellitus, % | 1.3 | 3.8 | 5.1 | 7.1 |
| Regulard ibuprofen use, % | 15.1 | 24.9 | 23.6 | 31.2 |
| Regulard acetaminophen use, % | 12.0 | 18.6 | 13.0 | 19.0 |
| Thiazide use, % | 9.2 | 15.1 | 1.9 | 3.2 |
| DASH dietary score | 23.7 (4.6) | 24.5 (4.7) | 23.7 (4.9) | 23.6 (5.0) |
| Alcohol intake, g % | 6.0 (9.7) | 5.3 (8.3) | 3.5 (6.6) | 3.2 (6.4) |
| Postmenopausal, % | 27.5 | 49.8 | 6.6 | 16.4 |
| Oral hormone therapy use | ||||
| Never user, % | 82.6 | 50.1 | 94.0 | 85.3 |
| <5 years, % | 6.3 | 22.2 | 2.7 | 6.2 |
| ≥5 years, % | 3.6 | 11.5 | 1.2 | 3.8 |
Values are means (SD) for continuous variables, percentages for categorical variables, and are standardized to the age distribution of the study population.
Values of polytomous variables may not sum to 100% due to rounding.
Value is not age-adjusted.
Waist circumference assessed in 1986 (NHS) and 1993 (NHS II).
Metabolic equivalents from recreational and leisure-time activities.
Regular analgesic use defined as 2 or more days per week.
After 1,509,711 person-years of follow-up in NHS and 1,468,175 person-years of follow-up in NHS II, there were 12,460 (NHS) and 4,565 (NHS II) incident cases of moderate or worse hearing loss reported. In multivariable-adjusted analyses, the risk of moderate or worse hearing loss was higher among women with osteoporosis or LBD in both cohorts (Table 2). In NHS, compared with women without osteoporosis, the multivariable-adjusted relative risk (MVRR, 95% CI) of moderate or worse hearing loss was 1.14 (1.09,1.19) among women with osteoporosis; in NHS II, the MVRR was 1.30 (1.21,1.40) among women with osteoporosis/LBD. The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates (Table 3). In NHS, the MVRR among women with osteoporosis who did not use bisphosphonates was 1.13 (1.07,1.20); the MVRR among those who did use bisphosphonates was 1.14(1.06,1.22). In NHS II, the MVRR among women who did not use bisphosphonates was 1.28 (1.17,1.40) and among women who used bisphosphonates was 1.40 (1.15,1.70). In additional analyses further adjusting for furosemide use and intakes of individual nutrients, results were not appreciably changed (data not shown).
Table 2:
Osteoporosis and Risk of Moderate or Worse Hearing Loss Among Women in the Nurses’ Health Study (1982-2016) and Nurses’ Health Study II (1995-2017)
| # Cases | Person-years | Age-adjusted RR (95% CI) | MV-adjusted RRa (95% CI) | |
|---|---|---|---|---|
| NHS | ||||
| Osteoporosis | ||||
| No | 9194 | 1317265 | 1.00 (ref) | 1.00 (ref) |
| Yes | 3266 | 192446 | 1.15 (1.11, 1.20) | 1.14 (1.09, 1.19) |
| NHS II | ||||
| Osteoporosis/LBD | ||||
| No | 3389 | 1248902 | 1.00 (ref) | 1.00 (ref) |
| Yes | 1176 | 219273 | 1.29 (1.20, 1.38) | 1.30 (1.21, 1.40) |
MV-adjusted RR: multivariable-adjusted relative risk adjusted for age, race/ethnicity, body mass index, waist circumference, physical activity, DASH diet score, alcohol intake, thiazide use, history of hypertension, history of diabetes, smoking, ibuprofen use, acetaminophen use, menopausal status, and oral hormone therapy use.
RR: relative risk
NHS: Nurses’ Health Study
NHS II: Nurses’ Health Study II
LBD: low bone density
Table 3:
Osteoporosis, Bisphosphonate Use and Risk of Moderate or Worse Hearing Loss in the Nurses’ Health Study (1998-2016) and Nurses’ Health Study II (1995-2017)
| # Cases | Person-years | Age-adjusted RR (95% CI) | MV-adjusted RRa (95% CI) | |
|---|---|---|---|---|
| NHS I | ||||
| Osteoporosis | ||||
| No | 5286 | 420028 | 1.00 (ref) | 1.00 (ref) |
| Yes, no bisphosphonate use | 1880 | 103332 | 1.15 (1.09, 1.21) | 1.13 (1.07, 1.20) |
| Yes, Bisphosphonate use | 928 | 46961 | 1.13 (1.05, 1.21) | 1.14 (1.06, 1.22) |
| NHS II | ||||
| Osteoporosis/LBD | ||||
| No | 3389 | 1248902 | 1.00 (ref) | 1.00 (ref) |
| Yes, no bisphosphonate use | 736 | 120278 | 1.26 (1.15, 1.38) | 1.28 (1.17, 1.40) |
| Yes, bisphosphonate use | 116 | 17931 | 1.40 (1.16, 1.69) | 1.40 (1.15, 1.70) |
MV-adjusted RR: multivariable-adjusted relative risk adjusted for age, race/ethnicity, body mass index, waist circumference, physical activity, DASH diet score, alcohol intake, thiazide use, history of hypertension, history of diabetes, smoking, ibuprofen use, acetaminophen use, menopausal status, and oral hormone therapy use.
RR: relative risk
NHS: Nurses’ Health Study
NHS II: Nurses’ Health Study II
LBD: low bone density
A history of VF was also associated with higher risk of hearing loss (Table 4). In NHS, compared with women without VF, the MVRR among women with confirmed VF was 1.31 (1.16,1.49). In NHS II, compared with women without VF, the MVRR among women with self-reported VF was 1.39 (1.13, 1.71). There were only 6 cases among women with confirmed VF, and the MVRR was 1.62 (0.72, 3.61). We did not observe a significant association between history of HF and risk of hearing loss; the MVRRs were 1.00 (0.86,1.16) in NHS and 1.15 (0.75,1.74) in NHS II.
Table 4:
Hip and Vertebral Fracture and Risk of Moderate or Worse Hearing Loss Among Women in the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHS II)
| # Cases | Person-years | Age-adjusted RR (95% CI) | MV-adjusted RRa (95% CI) | |
|---|---|---|---|---|
| Hip Fracture b | ||||
| NHS I | ||||
| No | 8383 | 609948 | 1.00 (ref) | 1.00 (ref) |
| Yes | 175 | 11138 | 1.00 (0.86, 1.16) | 1.00 (0.86, 1.16) |
| NHS II | ||||
| No | 4542 | 1463459 | 1.00 | 1.00 |
| Yes | 22 | 4641 | 1.21 (0.80, 1.85) | 1.15 (0.75, 1.74) |
| Vertebral Fracture c | ||||
| NHS I | ||||
| No | 5910 | 412690 | 1.00 | 1.00 |
| Yes | 266 | 12571 | 1.35 (1.20, 1.53) | 1.31 (1.16, 1.49) |
| NHS II | ||||
| No | 4473 | 1452871 | 1.00 (ref) | 1.00 (ref) |
| Yes | 92 | 15304 | 1.53 (1.24, 1.88) | 1.39 (1.13, 1.71) |
MV-adjusted RR: multivariable-adjusted relative risk adjusted for age, race/ethnicity, body mass index, waist circumference, physical activity, DASH diet score, alcohol intake, thiazide use, history of hypertension, history of diabetes, smoking, ibuprofen use, acetaminophen use, menopausal status, and oral hormone therapy use.
NHS I analysis conducted from 1982-2016; NHS II analysis conducted from 1995-2017.
NHS I analysis conducted from 2002-2016; NHS II analysis conducted from 1995-2017. VF in NHS confirmed by medical records.
RR: relative risk
NHS: Nurses’ Health Study
NHS II: Nurses’ Health Study II
In additional analyses among the subcohort of NHS II participants in the CHEARS AAA, we examined the association of osteoporosis/LBD and individual audiometric hearing thresholds (Figure 1)(Supplemental Table 2). Compared with women without osteoporosis/LBD, the mean hearing thresholds were significantly higher (worse) among women with osteoporosis/LBD who used bisphosphonates, particularly at audiometric frequencies of 2 kHz and above. For example, mean worse ear hearing thresholds were 2.19 dB HL higher at 2 kHz, 2.6 dB HL higher at 6 kHz, and 3.66 dB HL higher at 8 kHz than among women without osteoporosis/LBD. There was a suggestion that mean thresholds were also higher at 3 and 4 kHz, but the differences were not statistically significant. The mean thresholds among women with osteoporosis/LBD who did not use bisphosphonates were not significantly different from women who did not have osteoporosis.
Figure 1:
Multivariable-Adjusted Mean Differencesa in Audiometric Thresholdsb (dB HL) Among Women in the NHS II (n=3,749) With and Without Prevalent Osteoporosis/LBD and Bisphosphonate Use (Cross-ectional Analysis)
aMultivariable-adjusted differences between the mean threshold values, measured in decibels hearing level (dB HL), among women with osteoporosis/LBD compared with women without osteoporosis/LBD (referent group). Mean differences are adjusted for age, race/ethnicity, body mass index, waist circumference, physical activity, DASH diet score, alcohol intake, thiazide use, history of hypertension, history of diabetes, smoking, ibuprofen use, acetaminophen use, menopausal status, and oral hormone use.
bPure-tone audiometric thresholds indicate hearing sensitivity for calibrated pure tones. Audiometric hearing thresholds were measured at individual frequencies (0.5 through 8 kilohertz, kHz) in each ear.
*p<0.03, indicating statistically significant differences between the mean threshold values among women with osteoporosis/LBD and BP use compared with women without osteoporosis/LBD (referent group).
dB HL: decibels hearing level
kHz: kilohertz
OP: Osteoporosis
LBD: Low bone density
Bisphos: Bisphosphonate
No OP/LBD: Women without osteoporosis or low bone density
Bisphos--Yes: Women with osteoporosis/LBD who used bisphosphonates
Bisphos--No: Women with osteoporosis/LBD who did not use bisphosphonates
DISCUSSION
In this large nationwide longitudinal study of nearly 144,000 women with up to 34 years of follow-up, we found that osteoporosis or LBD was independently associated with higher risk of incident moderate or worse hearing loss. The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates. We also found that risk of hearing loss was higher among women with a history of VF, but not HF. To our knowledge, this is the first large longitudinal study to evaluate the relations of bone density, bisphosphonate use, fractures and risk of hearing loss.
It is estimated that ~25% of US women aged ≥65 have osteoporosis,26 characterized by reduced bone density and qualitative changes in bone microarchitecture that lead to skeletal fragility and higher risk of fractures.27 Osteoporosis results in an estimated 1.5 million fractures per year in the US, most of which occur in postmenopausal women.28 Osteoporosis has been suggested as a potential risk factor for hearing loss, but the underlying mechanisms are unclear. Bone mass at peripheral sites is correlated with bone mass at central sites, such as hip and spine, with correlation coefficients between 0.6 and 0.7.29 Plausibly, systemic bone demineralization could involve the temporal bone, the otic capsule and the middle ear ossicles.30–32 Evidence suggests pathways involved in bone homeostasis may influence cochlear sensorineural integrity; demineralization of the otic capsule and the cochlea have been associated with neuronal degeneration and sensorineural hearing loss.33 Hearing loss has been demonstrated in other pathologic bone disorders, such as otosclerosis and Paget’s disease, with pathologic changes in bone density and bone quality that overlap with those associated with osteoporosis.34,35 In individuals with Paget’s disease, cochlear demineralization was associated with both sensorineural and conductive hearing loss.35 Among individuals with otosclerosis, high-resolution computer tomography (CT) demonstrated lower bone density at specific loci on the cochlear capsule.36 Notably, in both Paget’s disease and otosclerosis, abnormal bone remodeling in the otic capsule juxtaposed to the cochlea’s lateral wall may lead to alterations in ion and fluid homeostasis in the perilymphatic space of the cochlea.37 Potentially, imbalances in bone formation and resorption in osteoporosis may lead to alterations in ionic metabolism that result in hearing loss. Further, a simulation study indicated that osteoporosis of the ossicles could increase high frequency displacement of the umbo and stapes footplate, suggesting ossicular osteoporosis could contribute to hearing loss.38
Most previous studies of bone density and hearing loss have been cross-sectional, relatively small, and findings have been inconsistent. While some studies found poorer hearing among individuals with lower bone density,11 others have not.10,39 A cross-sectional study among ~2,000 participants (1,082 women) in The Health, Aging and Body Composition Study (Health ABC) found lower total hip BMD was associated with higher odds of hearing loss among black men [n=310; OR: 1.36 (1.05, 1.75)], but not white men [n=660; OR: 0.86 (0.72, 1.03)]; no associations between bone density and hearing loss in women were observed.40 One cross-sectional study in the Korea Health and Nutrition Examination Survey (KHANES) found no association between femoral neck or lumbar spine bone density measurements and hearing loss,39 but another found higher odds of hearing loss among those with lower femoral neck BMD and no association with femoral shaft or lumbar spine BMD.41
Increased bone resorption coupled with decreased bone formation causes reductions in bone mass quantity and bone quality leading to compromised bone strength and increased risk of fractures. As a complement to our analyses of osteoporosis, we also examined whether VF or HF, the most common osteoporosis-related fractures, was associated with risk of hearing loss. Our findings of up to a 40% higher risk among women with VF, but not HF, were intriguing and merit further study. Despite shared risk factors between these fracture types, substantial heterogeneity in risk factors exists.7 The discordant findings between these skeletal sites may reflect differences in composition and metabolism of bones in the spine and hip and could provide insight into the pathophysiological changes in the ear that may lead to hearing loss. The temporal bone differs from both the hip and vertebrae in that it is a flat bone with a layered structure with a cancellous bone layer sandwiched between two layers of dense cortical bone. Differential influences of mechanical, hormonal and other factors on osteoporosis-related changes at different bone sites have been demonstrated.42,43
Our study did not observe that systemic bisphosphonates influenced the risk of hearing loss among women with osteoporosis. Bisphosphonates are the primary therapy for managing osteoporosis or other skeletal conditions characterized by increased osteoclast-mediated bone resorption. Some research suggests a beneficial influence of bisphosphonates on slowing or stabilizing progression of hearing loss among patients with otosclerosis, but the findings were not conclusive. A double-blind clinical trial found a non-significant trend toward stabilization or improvement in air conduction thresholds at 1 kHz and 4 kHz after treatment with etidronate.14 A small study of patients with otosclerosis and progressive hearing loss prior to treatment was suggestive of stabilization of hearing thresholds and word recognition scores after zoledronate treatment, but there was no control group for comparison.44 A promising study in noise-exposed mice found zoledronate reversed noise-induced damage to primary afferent auditory synapses and subsequent recovery of peripheral auditory function. Specifically, regeneration of inner hair cell synapses and recovery of Auditory Brainstem Response wave I amplitudes were observed.13 Studies in animals and humans have shown survival of spiral ganglion neuronal cell bodies for months or years after noise-induced peripheral synaptic and neuronal injury, suggesting a therapeutic window for synaptic recovery.45 Possibly, a potential influence of bisphosphonates on the relation of osteoporosis and hearing loss in humans may depend on the type, dose and timing of bisphosphonate administration. Additional studies that evaluate these factors could be informative.
In our cross-sectional analysis of osteoporosis/LBD and audiometric hearing thresholds, the mean thresholds among women with osteoporosis/LBD who used bisphosphonates were significantly worse than those among women without osteoporosis/LBD. We did not observe a significant association among women who did not use bisphosphates. Although the cross-sectional findings suggest poorer audiometric thresholds among those who used bisphosphonates, the longitudinal findings demonstrate no significant difference in the risk of hearing loss among those with osteoporosis who did and did not use bisphosphonates (the 95% confidence intervals overlap). Possibly, the women who were treated with bisphosphonates had more substantially reduced bone density, indicating that more severe osteoporosis was associated with poorer audiometric thresholds. The influence of bisphosphonate use on the bony and membranous labyrinth as well as middle ear merits further investigation.
Study strengths include the large sample size, longitudinal design, and use of well-validated covariate information. Our findings among two large and distinct cohorts of women were consistent. We also complemented our findings with those from a subcohort of women with longitudinal audiometric assessments. Limitations of our study include hearing assessment based on self-report. Hearing decline is often subtle, thus there is imprecision in date of onset. Pure-tone audiometry is the standard approach for hearing evaluation, but does not capture many aspects of hearing experience in real-world environments.46 Hearing assessments based on self-report have been found to be reasonably reliable.19 We a priori chose to examine moderate or worse hearing loss to minimize potential misclassification. The sensitivity of a single question to detect moderate or severe hearing loss among women of similar age to our population was high (95% and 100%, respectively).20 The potential low specificity of a single question could mean the magnitudes of the associations may be even larger. This is an observational study, thus residual confounding could have influenced the results; nevertheless, the analyses were carefully adjusted for potentially confounding variables, many of which were demonstrated to be well-reported in this cohort. The study population included predominantly white female health care professionals, which enhanced validity of the health information collected and reduced variability in educational achievement and socioeconomic status, but research in non-white women and additional populations is warranted.
CONCLUSION
In this large nationwide longitudinal study of women with decades of follow-up, osteoporosis and LBD were associated with increased risk of incident moderate or worse hearing loss. The magnitude of the elevated risk was similar among women who did and did not use bisphosphonates. The risk of hearing loss was higher among women with a history of vertebral fracture, but not of hip fracture. Osteoporosis and low bone density may be important contributors to aging-related hearing loss.
Supplementary Material
Supplemental Materials:
Supplemental Table 1: Characteristics of Women in the Nurses’ Health Study II CHEARS Audiometry Assessment Arm (n=3,749)
Supplemental Table 2: Mean Multivariable-Adjusteda Differences in Audiometric Hearing Thresholds Among Women in the NHS II AAA (n=3749) (Cross-sectional Analysis)
Key Points.
In a large longitudinal study of women, osteoporosis was associated with higher risk of moderate or worse hearing loss.
In women with osteoporosis, the risk of hearing loss was not influenced by bisphosphonates.
Why does this Paper Matter?
Osteoporosis may be an important contributor to aging-related hearing loss.
Acknowledgements
We would like to thank Elaine Coughlin-Gifford for her programming help on this project. We would also like to thank the CHEARS Audiology Assessment Arm Site Directors and study sites whose efforts made this project possible: Albert Einstein College of Medicine (Drs. Laura Tocci, Elizabeth Dinces); Callier Center for Communication Disorders (Dr. Kenneth Pugh); Cleveland Hearing & Speech Center (Drs. Michelle Burnett, Laura Brady, Bridgid Whitford); Columbia University Medical Center (Drs. Jaclyn Spitzer, Jessica Galatioto, Anil Lalwani) Henry Ford Hospital (Drs. Jessica Messer, Virginia Ramachandran, Jaclyn Sommerville); Indiana University at Indianapolis (Dr. Rich Miyamoto); LIJ Hearing and Speech Center (Drs. Andrea Vambutas, Leslie Wexler); Massachusetts Eye and Ear Infirmary (Dr. Chris Halpin); Southern New England Ear Nose and Throat (Dr. Ken Yanagisawa); Phelps Memorial Hospital Center (Drs. Judith Christopher, Jessica LaCorte); San Diego Hearing Center (Dr. Blanche Blackington); St. Louis University Medical Center (Dr. David Harris); Stanford Hospital and Clinics (Drs. Gerald Popelka, Matthew Fitzgerald); University of California, Irvine (Dr. Alicia Tratkman); University of Cincinnati (Dr. Stephanie Lockhart); University of Michigan (Drs. Bruce Edwards, Paul Kileny); University of Pennsylvania (Drs. Jennifer Rotz, Michael Ruckenstein); University of Pittsburgh Medical Center (Drs. Catherine Palmer, Lori Zitelli); University of Rochester (Dr. Mark Orlando); Yale University (Dr. Eli Michaelides).
Sponsor’s Role
This research was supported by grants DC010811, AR075117, UM1 CA186107 and UO1 CA176726 from the National Institutes of Health.
Footnotes
Conflicts of Interest
Dr. S. Curhan serves as a consultant to Decibel Therapeutics. Dr. G. Curhan serves as a consultant to Decibel Therapeutics, AstraZeneca, Shire, Allena Pharmaceuticals, RenalGuard, OrfanBiotech, OM1, and Merck. He receives royalties from UpToDate for being an author and Section Editor. The other authors declare no conflicts of interest. All authors had access to the data and participated in the preparation of the manuscript.
References
- 1.Summary health statistics for US adults: National Health Interview Survey. 2012. at http://www.cdc.gov/nchs/data/series/sr_10/sr10_260.pdf.) [PubMed]
- 2.Dalton DS, Cruickshanks KJ, Klein BE, Klein R, Wiley TL, Nondahl DM. The impact of hearing loss on quality of life in older adults. Gerontologist 2003;43:661–8. [DOI] [PubMed] [Google Scholar]
- 3.Kiely KM, Anstey KJ, Luszcz MA. Dual sensory loss and depressive symptoms: the importance of hearing, daily functioning, and activity engagement. Front Hum Neurosci 2013;7:837. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Lin FR, Yaffe K, Xia J, et al. Hearing loss and cognitive decline in older adults. JAMA Intern Med 2013;173:293–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Global Burden of Disease Study C. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2015;386:743–800. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Nih Consensus Development Panel on Osteoporosis Prevention D, Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785–95. [DOI] [PubMed] [Google Scholar]
- 7.Ensrud KE. Epidemiology of fracture risk with advancing age. J Gerontol A Biol Sci Med Sci 2013;68:1236–42. [DOI] [PubMed] [Google Scholar]
- 8.Kelsey JL, Samelson EJ. Variation in risk factors for fractures at different sites. Curr Osteoporos Rep 2009;7:127–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Kao SY, Kempfle JS, Jensen JB, et al. Loss of osteoprotegerin expression in the inner ear causes degeneration of the cochlear nerve and sensorineural hearing loss. Neurobiol Dis 2013;56:25–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Lee SY, Hong HS, Yang SC, Kim KS, Kim HJ. Is There a Relationship Between Bone Quality and Hearing Level? Otol Neurotol 2018;39:e752–e6. [DOI] [PubMed] [Google Scholar]
- 11.Kshithi K, Vijendra Shenoy S, Panduranga Kamath M, et al. Audiological profiling in postmenopausal women with osteoporosis. Am J Otolaryngol 2018;39:271–6. [DOI] [PubMed] [Google Scholar]
- 12.Lewiecki EM. Bisphosphonates for the treatment of osteoporosis: insights for clinicians. Ther Adv Chronic Dis 2010;1:115–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Seist R, Tong M, Landegger LD, et al. Regeneration of Cochlear Synapses by Systemic Administration of a Bisphosphonate. Front Mol Neurosci 2020;13:87. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Kennedy DW, Hoffer ME, Holliday M. The effects of etidronate disodium on progressive hearing loss from otosclerosis. Otolaryngol Head Neck Surg 1993;109:461–7. [DOI] [PubMed] [Google Scholar]
- 15.Bao Y, Bertoia ML, Lenart EB, et al. Origin, Methods, and Evolution of the Three Nurses’ Health Studies. Am J Public Health 2016;106:1573–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Prochaska M, Taylor E, Vaidya A, Curhan G. Low Bone Density and Bisphosphonate Use and the Risk of Kidney Stones. Clin J Am Soc Nephrol 2017;12:1284–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Paik JM, Rosen HN, Gordon CM, Curhan GC. Diuretic Use and Risk of Vertebral Fracture in Women. Am J Med 2016;129:1299–306. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Huang T, Tworoger SS, Redline S, Curhan GC, Paik JM. Obstructive Sleep Apnea and Risk for Incident Vertebral and Hip Fracture in Women. J Bone Miner Res 2020;35:2143–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Ferrite S, Santana VS, Marshall SW. Validity of self-reported hearing loss in adults: performance of three single questions. Revista de saude publica 2011;45:824–30. [DOI] [PubMed] [Google Scholar]
- 20.Sindhusake D, Mitchell P, Smith W, et al. Validation of self-reported hearing loss. The Blue Mountains Hearing Study. Int J Epidemiol 2001;30:1371–8. [DOI] [PubMed] [Google Scholar]
- 21.Curhan SG, Shargorodsky J, Eavey R, Curhan GC. Analgesic use and the risk of hearing loss in women. Am J Epidemiol 2012;176:544–54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Curhan SG, Wang M, Eavey RD, Stampfer MJ, Curhan GC. Adherence to Healthful Dietary Patterns Is Associated with Lower Risk of Hearing Loss in Women. J Nutr 2018;148:944–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Curhan SG HC, Wang M, Eavey RD, Curhan GC. Tinnitus and 3-Year Change in Audiometric Hearing Thresholds 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Curhan SG, Halpin C, Wang M, Eavey RD, Curhan GC. Prospective Study of Dietary Patterns and Hearing Threshold Decline. Am J Epidemiol 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Therneau TM. Extending the Cox model. 2nd ed. New York: Springer Verlag; 1997. [Google Scholar]
- 26.Osteoporosis. 2019. (Accessed 11-24-2020, at https://www.cdc.gov/nchs/fastats/osteoporosis.htm.)
- 27.Black DM, Rosen CJ. Clinical Practice. Postmenopausal Osteoporosis. N Engl J Med 2016;374:254–62. [DOI] [PubMed] [Google Scholar]
- 28.Black DM, Rosen CJ. Postmenopausal Osteoporosis. N Engl J Med 2016;374:2096–7. [DOI] [PubMed] [Google Scholar]
- 29.Miller PD, Zapalowski C, Kulak CA, Bilezikian JP. Bone densitometry: the best way to detect osteoporosis and to monitor therapy. J Clin Endocrinol Metab 1999;84:1867–71. [DOI] [PubMed] [Google Scholar]
- 30.Kim JY, Lee SB, Lee CH, Kim HM. Hearing loss in postmenopausal women with low bone mineral density. Auris Nasus Larynx 2016;43:155–60. [DOI] [PubMed] [Google Scholar]
- 31.Yeh MC, Weng SF, Shen YC, et al. Increased Risk of Sudden Sensorineural Hearing Loss in Patients With Osteoporosis: A Population-based, Propensity Score-matched, Longitudinal Follow-Up Study. J Clin Endocrinol Metab 2015;100:2413–9. [DOI] [PubMed] [Google Scholar]
- 32.Kahveci OK, Demirdal US, Yucedag F, Cerci U. Patients with osteoporosis have higher incidence of sensorineural hearing loss. Clin Otolaryngol 2014;39:145–9. [DOI] [PubMed] [Google Scholar]
- 33.Kao SY, Katsumi S, Han D, et al. Postnatal expression and possible function of RANK and RANKL in the murine inner ear. Bone 2020;145:115837. [DOI] [PubMed] [Google Scholar]
- 34.Huizing EH, de Groot JA. Densitometry of the cochlear capsule and correlation between bone density loss and bone conduction hearing loss in otosclerosis. Acta Otolaryngol 1987;103:464–8. [PubMed] [Google Scholar]
- 35.Monsell EM, Cody DD, Bone HG, Divine GW. Hearing loss as a complication of Paget’s disease of bone. J Bone Miner Res 1999;14 Suppl 2:92–5. [DOI] [PubMed] [Google Scholar]
- 36.Shin YJ, Fraysse B, Deguine O, Cognard C, Charlet JP, Sevely A. Sensorineural hearing loss and otosclerosis: a clinical and radiologic survey of 437 cases. Acta Otolaryngol 2001;121:200–4. [DOI] [PubMed] [Google Scholar]
- 37.Wangemann P Supporting sensory transduction: cochlear fluid homeostasis and the endocochlear potential. J Physiol 2006;576:11–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Zhou L, Shen N, Feng M, Liu H, Duan M, Huang X. Study of age-related changes in Middle ear transfer function. Comput Methods Biomech Biomed Engin 2019;22:1093–102. [DOI] [PubMed] [Google Scholar]
- 39.Jung DJ, Cho HH, Lee KY. Association of Bone Mineral Density With Hearing Impairment in Postmenopausal Women in Korea. Clin Exp Otorhinolaryngol 2016;9:319–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Helzner EP, Cauley JA, Pratt SR, et al. Hearing sensitivity and bone mineral density in older adults: the Health, Aging and Body Composition Study. Osteoporos Int 2005;16:1675–82. [DOI] [PubMed] [Google Scholar]
- 41.Yoo JI, Park KS, Seo SH, Park HW. Osteoporosis and hearing loss: findings from the Korea National Health and Nutrition Examination Survey 2009-2011. Braz J Otorhinolaryngol 2020;86:332–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Seref-Ferlengez Z, Kennedy OD, Schaffler MB. Bone microdamage, remodeling and bone fragility: how much damage is too much damage? Bonekey Rep 2015;4:644. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Viswanathan M, Reddy S, Berkman N, et al. Screening to Prevent Osteoporotic Fractures: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 2018;319:2532–51. [DOI] [PubMed] [Google Scholar]
- 44.Jan TA, Remenschneider AK, Halpin C, Seton M, McKenna MJ, Quesnel AM. Third-generation bisphosphonates for cochlear otosclerosis stabilizes sensorineural hearing loss in long-term follow-up. Laryngoscope Investig Otolaryngol 2017;2:262–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Liberman MC, Kujawa SG. Cochlear synaptopathy in acquired sensorineural hearing loss: Manifestations and mechanisms. Hear Res 2017;349:138–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Jacobson GP. Hearing Difficulties in the Absence of Hearing Loss. J Am Acad Audiol 2018;29:456. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Materials:
Supplemental Table 1: Characteristics of Women in the Nurses’ Health Study II CHEARS Audiometry Assessment Arm (n=3,749)
Supplemental Table 2: Mean Multivariable-Adjusteda Differences in Audiometric Hearing Thresholds Among Women in the NHS II AAA (n=3749) (Cross-sectional Analysis)