Increased Acquired Cholesteatoma Risk
in
Patients with Osteoporosis: A
Retrospective
Cohort Study
Tang-Chuan Wang1,2, Che-Chen Lin3,4, Chia-Der Lin1, Hsiung-Kwang Chung1,
Ching-Yuang Wang1, Ming-Hsui Tsai1, Chia-Hung Kao5,6*
Introduction
Advances in healthcare and increases in life expectancy have caused osteoporosis and related
fractures to become crucial health concerns worldwide, particularly among older adults [1].
The World Health Organization has emphasized the importance of osteoporosis.
Osteoporosis-related fractures, which are prevalent in the older population, can lead to complications and
even death. Osteoporosis is caused by reductions in bone mass and destruction of fine structures,
which reduce the mechanical integrity of bone and increase the accumulation of noninvasive
fractures [2].
Bone normally maintains an equilibrium balance of metabolic activity; however, when bone
absorption occurs at a higher rate than bone production, bone volume remains unchanged, but
bone gaps become larger and bone density decreases. Bone loss is progressive and no distinct
symptoms appear at the onset. Osteoporosis is called the "silent disease" and is easily ignored.
However, fractures and lower back pain attributable to osteoporosis are often key factors affecting
the quality of life of older adults.
In addition to bone fracture, lower back pain, and other health-related consequences, previous
studies have reported that osteoclast is associated with middle ear acquired cholesteatoma,
the destructive expansion of a keratinizing squamous epithelium in the middle ear or petrous
apex[3–5]. The mechanisms underlying the molecular and cellular pathogenesis of acquired
middle ear acquired cholesteatoma are not fully understood [6]. Acquired cholesteatoma is not
a malignant disease; however, the pathological process may lead to destruction of the surrounding
bone, including the ossicles.
Little is known regarding the risk factors for cholesteatoma. It is generally accepted that cholesteatoma
may be congenital or acquired, the latter occurring far more frequently. Even the pathogenesis of acquired cholesteatoma has been debated for many years, there are four basic
theories of the pathogenesis of acquired aural cholesteatoma: (1)invagination of the tympanic
membrane (retraction pocket cholesteatoma), (2)basal cell hyperplasia, (3) epithelial ingrowth
through a perforation (the migration theory), and (4) squamous metaplasia of middle ear epithelium
[7]. A study which included 45,980 patients revealed that children with persistent or
refractory middle ear disease who need ventilation tubes were at increased risk of cholesteatoma
besides of well known factors like otitis media, tympanic membrane perforation and
Eustachain tube dysfunction [8]. A few studies have indicated that acquired cholesteatoma is
associated with bone formation and absorption, but most of these studies are case reports, animal
tests, or cytology studies [3–5]. A previous study indicated that acquired cholesteatoma is
osteoporosis [9]. However,
no large-scale epidemiological study has been conducted to investigate this association.
This study examined whether patients with osteoporosis may subsequently develop middle ear
acquired cholesteatoma and whether other risk factors interact with osteoporosis to influence
the development of acquired cholesteatoma.
Materials and Method
Data sources
The National Health Insurance Research Database (NHIRD), which was established in 1996,
comprises data derived from the reimbursement claims of beneficiaries of the National Health
Insurance (NHI) program, which covers more than 99% of the residents in Taiwan. The
National Health Research Institutes (NHRI) maintains this database.
The study cohort was created using the Longitudinal Health Insurance Database (LHID),
which is a subset of the NHIRD. The LHID was established from a randomly sampled set of
one million people insured between 1996 and 2000. To protect the privacy of the insurants in
the LHID, scrambled identification numbers were used to link the database before it was
released for research use. In this study, diseases were classified according to the International
Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). The NHRID
encrypts personal information to protect the privacy of the patients and provides researchers
with anonymous identification numbers associated with relevant claims information, which
includes the patients’ sex, date of birth, registry of medical services, and medication
prescriptions.
Study patients
we identified
patients aged 20 years or over who were newly diagnosed with osteoporosis (ICD-9-CM 733.0)
from 1997 to 2008. The index date was the date of the osteoporosis diagnosis. The comparison
cohort was composed of patients who had no history of osteoporosis and were frequency
matched with the osteoporosis cohort according to sex, age, and index year. Patients with a history
of acquired cholesteatoma (ICD-9 385.3) before the index date were excluded. The followup
period ended when the development of acquired cholesteatoma was observed, when the
patient withdrew from the insurance program, or at the end of 2009. Demographic factors and
acquired cholesteatoma-associated comorbidities were listed as confounding factors. The
examined comorbidities were cancer (ICD-9-CM 140–208 from catastrophic illness registry),
chronic obstructive pulmonary disease (COPD, ICD-9-CM 250), otitis media (ICD-9-CM
381.0−381.4 and 382), hypertension (ICD-9-CM 401–405), diabetes mellitus (DM, ICD-9-CM
250), tympanic membrane perforation (TMP, ICD-9-CM 384) and eustachain tube dysfunction
(ETD, ICD-9-CM 381) occurring before the index date. We also collected the osteoporosis
patient’s bisphosphonate used information from index date to end of follow-up.
Data Availability Statement
All data and related metadata were deposited in an appropriate public repository. The data on
the study population that were obtained from the NHIRD (http://w3.nhri.org.tw/nhird//date_
01.html) are maintained in the NHIRD (http://nhird.nhri.org.tw/). The NHRI is a nonprofit
foundation established by the government.
Ethics Statement
researchers
with anonymous identification numbers associated with relevant claims information, including
sex, date of birth, medical services received, and prescriptions. Patient consent is not required
to access the NHIRD. This study was approved by the Institutional Review Board (IRB) of
China Medical University (CMU-REC-101-012). The IRB specifically waived the consent
requirement.
Statistical analysis
We assessed the distribution of demographic factors and comorbidities of the osteoporosis and
comparison cohorts, and the differences between the cohorts were tested using the chi-square
test and t test. We calculated the acquired cholesteatoma incidence density based on newly
diagnosed acquired cholesteatoma cases and person-years of follow up (from the index date to
the acquired cholesteatoma incident or the end of follow-up) according to demographic status
and comorbidity. The cumulative acquired cholesteatoma incidence curve of the 2 study
cohorts was estimated using the product-limit method and the log-rank test. Cox proportional
hazard regressions were used to estimate the hazard ratios (HRs) and 95% confidences intervals
(CI) for the relative risk of acquired cholesteatoma. All analyses were performed using SAS
statistical software (Version 9.3 for Windows; SAS Institute, Inc., Cary, NC, USA). The cumulative
incidence curve was plotted using R software (R Foundation for Statistical Computing,
Vienna, Austria). Values of P < .05 were considered statistically significant.
Results
We established an osteoporosis cohort comprising 37 124 patients and a comparison cohort
comprising 37 124 patients with similar average ages (63 y) and sex ratios (Table 1). Only 15%
of osteoporosis patients was received the bisphosphonate treatment. Comorbidities were more
prevalent in the osteoporosis cohort than in the comparison cohort (all P values < .0001).
The subsequent acquired cholesteatoma incidence rates for the osteoporosis and comparison
cohorts were 1.12 and 0.83 per 1000 person-years, respectively (Table 2). Fig 1
shows that the
incidence curve for the osteoporosis cohort was significantly higher than for the comparison group (log-rank test P < .0001). After we adjusted for confounding factors, the osteoporosis
cohort exhibited a 1.29-fold increased subsequent risk of acquired cholesteatoma relative to the
comparison cohort (HR = 1.29, 95% CI = 1.09–1.54). The osteoporosis cohort was again associated
with an increased risk of subsequent acquired cholesteatoma compared with the comparison
cohort in patient aged 50–64 years (HR = 1.38, 95% CI = 1.01–1.89) and aged 65– 74 years
(HR = 1.42, 95% CI = 1.02–1.97). A sex-stratified analysis indicated that the risk of subsequent
acquired cholesteatoma was increased relative to that of the comparison cohort among women
(HR = 1.24, 95% CI = 1.03–1.50) and men (HR = 1.73, 95% CI = 1.04–2.86) in the osteoporosis
cohort. Table 2 shows the results of a comorbidity-stratified analysis of subsequent acquired
cholesteatoma risk. Patients who were not diagnosed with otitis media (HR = 1.30, 95%
CI = 1.08–1.56), TMP (HR = 1.29, 95% CI = 1.09–1.54), cancer (HR = 1.31, 95% CI = 1.10–
1.57), hypertension (HR = 1.33, 95% CI = 1.05–1.70) or ETD (HR = 1.31, 95% CI = 1.10–1.56)
in the osteoporosis cohort exhibited a significant increased risk of subsequent acquired cholesteatoma
relative to those in the control cohort. We also observed the cholesteatoma risk was
1.49) or with
COPD (HR = 1.86, 95% CI = 1.09–3.19), and patient without DM (HR = 1.25, 95% CI = 1.04–
1.51) or with DM (HR = 1.67, 95% CI = 1.03–2.71).
Table 3 shows the effects of osteoporosis and comorbidities on the risk of acquired cholesteatoma
development. The results suggested that osteoporosis and comorbidities jointly affected the subsequent development of acquired cholesteatoma, but no interaction between
osteoporosis and comorbidities occurred (P > .05 for all interaction tests).
Discussion
Acquired cholesteatoma can occur in the meninges, central nervous system, skull bones, and,
most commonly, the middle ear and mastoid region. We focused on acquired cholesteatoma of
the middle ear and mastoid region, which may lead to the destruction of middle and inner ear
structures, hearing loss, vestibular dysfunction, and facial paralysis as well as lethal intracranial
complications [10].
The primary strength of this study lies in the large number of patients and use of a national
healthcare database. Taiwan launched the NHI program in 1995 and it is operated by a single
buyer, the government. All insurance claims are scrutinized by medical reimbursement specialists
and undergo peer review. The diagnoses of acquired cholesteatoma and osteoporosis were
based on ICD-9 codes determined by qualified clinical physicians during strict audits in the
reimbursement process. Therefore, the diagnoses of acquired cholesteatoma and osteoporosis
are accurate and reliable even if they were diagnosed by different doctors. Our cohort study indicated that patients with osteoporosis exhibited a 1.31-fold increased
risk of developing acquired cholesteatoma relative to the comparison cohort. The risk of developing
both osteoporosis
and otitis media. Various factors related to inflammation and local pressure influence
osteoclast-mediated bone resorption in pathologic conditions. Protein products released by acquired cholesteatoma, such as interleukins (IL-1α,-1β, and IL-6), tumor necrosis factor α,
interferon β, and parathyroid-hormone-related protein, have been identified [11,12]. Three
factors are involved in the process of bone resorption, namely (1) mechanical factors, which
are related to pressure generated by the expansion of a acquired cholesteatoma as it accumulates
increasing amounts of keratin and purulent debris [13–15]; (2) biochemical factors, which are due to bacterial elements (endotoxins), products of host granulation tissue (collagenase,
acid hydrolases), and substances related to acquired cholesteatoma (growth factors, cytokines)
[16–24]; and (3) cellular factors, which are predominantly induced by osteoclastic activity
[3–5].
Bone morphogenesis and remodeling involve the synthesis of bone matrices by osteoclasts
[25]. Bone resorption under physiological conditions represents a balance of local osteoblast
and osteoclast activity [26]. In 2003, Hamzei indicated that the number of osteoclast precursor
cells is markedly increased in the perimatrix of acquired cholesteatoma tissue [4]. These results
indicated that inflammation related to acquired cholesteatoma induces bone resorption
through the release of the osteoprotegerin ligand from activated T cells, triggering osteoclastogenesis.
In our study, after we adjusted for confounding factors, the osteoporosis cohort exhibited a
1.31-fold increased risk of developing acquired cholesteatoma compared with the comparison
cohort. Moreover, we observed a 6.24-fold increased risk of developing acquired cholesteatoma
in patients with osteoporosis and otitis media. Our results are similar to those reported by previous
studies [4, 11–15]. This is the population-based epidemiologic study with such a large
sample size.Although smoking may be associated with inflammation, we were unable to obtain
information regarding the effect of smoking or drinking on the risk of acquired cholesteatoma
[27].
A recent study demonstrated an association between treatment with bisphosphonates and
the occurrence of cholesteatoma in osteoporosis [28]. We try to collect the history of bisphosphonates
used in osteoporosis patients but observed that only a few osteoporosis patients received bisphosphonates treatment. In fact, bisphosphonates were not paid by our insurance
before osteoporosis fractures happened. I guess the degree of osteoporosis of most of these
patients in our study is mild and without fractures. Therefore, we found a few osteoporosis
patients who received bisphosphonate treatment in the new analyses. However, the data for
individual patient’s BMD (the severity of osteoporosis) is not available in the NHIRD. In addition,
the data for the other anti-osteoporosis drugs such as vitamin D and calcium tablets were
not included in the NHIRD, because the patients might buy these drugs in drugstores and paid
by themselves. Hence, this study could not provide good answer to this question. Thus, more
large-scale epidemiological studies should be conducted to investigate this question.
We concluded that the acquired cholesteatoma risk in patients with osteoporosis is
increased. We recommend that future studies involve monitoring inflammatory mediators and
otitis-media-related values in patients with osteoporosis as well as the incidence of acquired
cholesteatoma. A significantly increased risk of developing acquired cholesteatoma was identified
in patients with osteoporosis and otitis media in this study. Clinicians should pay attention
to both osteoporosis-related injuries and middle ear symptoms in patients with osteoporosis.
Acquired cholesteatoma screening should be included in health assessments of patients with
osteoporosis. The primary treatment for patients with acquired cholesteatoma is surgical excision;
however, certain patients may experience a recurrence after surgical excision. This type of
