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The Laryngoscope C 2012 The American Laryngological, V Rhinological and Otological Society, Inc. Association Between Bone Mineral Density and Hearing Loss in Osteogenesis Imperfecta Freya K. R. Swinnen, MS; Els M. R. De Leenheer, MD, PhD; Stefan Goemaere, MD; Cor W. R. J. Cremers, MD, PhD; Paul J. Coucke, PhD; Ingeborg J. M. Dhooge, MD, PhD Objectives/Hypothesis: Osteogenesis imperfecta (OI) is a heritable connective tissue disorder, predominantly characterized by bone fragility. In half of the patients, progressive hearing loss develops, which is associated with abnormal bony changes involving the middle ear ossicles and stapes footplate. In the present study, we investigated whether the development of hearing loss in OI may be related to the overall aberrant bone quality. Study Design: Observational study. Methods: Following audiologic evaluation, 56 adult OI patients were classified as presenting normal hearing or conductive/mixed or pure sensorineural hearing loss. Areal bone mineral density (BMD) (aBMD) was measured using lumbar spine (LS) and whole body (WB) dual X-ray absorptiometry. By means of peripheral computed tomography, volumetric BMD (vBMD) and morphometric bone parameters were determined at distal and proximal radius, providing separate results for trabecular and cortical bone. The obtained bone parameters were compared between normal-hearing OI patients and those with either conductive/mixed or pure sensorineural hearing loss. Results: Z scores demonstrated decreased LS aBMD, WB aBMD, and trabecular vBMD in OI adults compared to the healthy population. Patients with conductive/mixed hearing loss had lower trabecular vBMD compared to those with normal hearing or pure sensorineural loss at both whole-group and between-relatives comparisons. Conclusions: It is hypothesized that OI patients with lower BMD might be more susceptible to accumulating microfractures, which may interfere with the bone remodeling inhibition pathways in the temporal bone and, therefore, contribute to stapes footplate fixation and a conductive hearing loss component. Key Words: Osteogenesis imperfecta, bone mineral density, hearing loss, type I collagen. Level of Evidence: 2c. Laryngoscope, 122:401–408, 2012 INTRODUCTION Osteogenesis Imperfecta (OI) is an uncommon, hereditary connective tissue disorder that may involve the musculoskeletal system, skin, sclerae, ear, and cardiovascular system. OI is characterized by a large phenotypic as well as genotypic heterogeneity. The most widely used classification of OI was introduced by Sillence et al.,1 who, on the basis of clinical and radiographic features, distinguished four major types covering a mild (type I), a lethal (type II), a severe (type III), and a moderate (type IV) phenotype. More recently, several attempts have been made to further differentiate this classification by adding types V, VI, VII, and VIII.2 Still, addition of these uncommon OI types is not supFrom the Department of Otorhinolaryngology (F.K.R.S., E.M.R.D.L., Unit for Osteoporosis and Metabolic Bone Diseases (S.G.), and Center for Medical Genetics (P.J.C.), Ghent University Hospital, Ghent, Belgium; and FC Donders Institute for Neurosciences (C.W.R.J.C.), Radboud University Nijmegen Medical Centre, Department of Otorhinolaryngology, Nijmegen, The Netherlands.. Editor’s Note: This Manuscript was accepted for publication October 3, 2011. Freya K. R. Swinnen, MS, holds a PhD fellowship of the Research Foundation Flanders (FWO Vlaanderen), Belgium. The authors have no other funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Freya K. R. Swinnen, MS, Department of Otorhinolaryngology (1P1), Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. E-mail: [email protected] I.J.M.D.), DOI: 10.1002/lary.22408 Laryngoscope 122: February 2012 ported by all clinicians, because, unlike the initial classification, their differentiation is based on moleculargenetic rather than clinical grounds.3 The clinical expression may partially be predicted on the basis of the underlying OI genotype. In 90% of cases, the genotype is characterized by an autosomaldominant mutation in the COL1A1 or COL1A2 gene, encoding for two a1(I) and one a2(I) chains of type I collagen, the principal component of the organic matrix of bone. Mutations in COL1A1 or COL1A2 may hinder the type I collagen synthesis in an either quantitative or qualitative way. A mutation causing a quantitative defect results into the underproduction of a normal type I collagen molecule, whereas a qualitative impairment refers to the formation and incorporation of structural abnormal type I collagen.4 The clinical severity of the disease is partially determined by the whether the nature of the type I collagen defect is quantitative or qualitative, which of the chains is affected, and at which position within the triple helical portion of the chain the mutation occurs.3,4 Although a direct relationship between the collagen gene mutations and the clinical phenotype remains largely unclear, the collagen defect causes brittle bones, the hallmark feature of OI, of which the severity may be assessed clinically. From a mechanical viewpoint, two types of bone may be distinguished. Trabecular bone is prominent in the vertebral bodies and at the end of long Swinnen et al.: BMD and Hearing Loss in OI 401 bones, whereas cortical bone tissue is mainly found in the shafts of the long bones. Bone fragility in OI is determined by decreased bone quantity and altered bone quality. The amount of bone is commonly evaluated by means of dual X-ray absorptiometry (DXA) or peripheral quantitative computed tomography (CT) (pQCT), which measure bone mineral content and bone mineral density (BMD), at well-defined sites of the human body. Both methods have demonstrated a reduced BMD in OI adults and children.3,5,6 In the OI population, three-dimensional pQCT measurements of volumetric BMD (vBMD) have been suggested to be preferable to two-dimensional DXAmeasurements of areal BMD (aBMD).6 PQCT allows separate measurements of trabecular and cortical compartments and offers insight into geometrical properties of bone. Fracture rate in OI patients often decreases after puberty, when the skeleton has attained its adult size. However, BMD often remains below normal values in adult life, particularly for trabecular bone.5,6 At the beginning of adulthood, when an improvement in the skeletal condition is often experienced, another problem may arise. Approximately half of the OI patients develop a hearing loss. The hearing impairment usually appears as a conductive hearing loss in the second to fourth decade of life and most often progresses to a mixed hearing loss thereafter.7,8 A minority of patients develop a pure sensorineural hearing loss (SNHL).8 The conductive hearing loss component is often caused by otosclerosis-like lesions, inducing a thickened and fixed stapes footplate. However, in comparison with classic otosclerosis, the conductive hearing impairment in OI is generally characterized by an earlier onset and more often progresses to a mixed hearing loss, which is associated with a more extensive degree of pericochlear demineralization on CT.9 In addition, OIrelated conductive hearing loss may be due to ossicular discontinuity, in particular fractured or atrophic stapes crura replaced by fibrous threads, whether or not it is in combination with oval window obliteration.7 The SNHL component has been suggested to result from several pathologic conditions with regard to the inner ear structures, such as encroachment of abnormal bone on the cochlea, hemorrhage into the labyrinth, and atrophy of the stria vascularis or the cochlear hair cells.10 Like many phenotypic features of OI, the hearing loss characteristics are heterogeneous, and even relatives with an identical underlying COL1A1 or COL1A2 mutation may radically differ in hearing ability or hearing loss type.11 This variability remains largely unclear. Because the underlying pathology causing hearing impairment in OI is apparently tied up with bony changes in the ossicular chain and the cochlear capsule, a possible association between hearing performance and generalized bone disease was investigated. MATERIALS AND METHODS Subjects Patients were recruited at the departments of Otorhinolaryngology, Medical Genetics, Orthopedics & Fysiotherapy, and Endocrinology & Rheumatology of the Ghent University Hospi- Laryngoscope 122: February 2012 402 tal (UZ Ghent) and by means of an advertisement in the periodical of the Belgian patients’ association for OI (Zelfhulp Osteogenesis Imperfecta). Approval of the study was provided by the local ethical committee, and, prior to participation, all patients signed the informed consent form in accordance with the Declaration of Helsinki. In all patients the diagnosis of OI was clinically confirmed. The OI type according to the Sillence classification (I–IV) was assessed by a geneticist. History To preclude causes for hearing loss other than OI, medical and otologic history were documented. Patients were asked for noise exposition, ear surgery, head injury, and drugs intake, in addition to fracture history, mobility and sports activities, physical complaints, bisphosphonate (BP) treatment, and family history of OI. Audiologic Examination After micro-otoscopy to evaluate the intactness of the eardrum and ventilation of the middle ear, bilateral tympanograms were obtained using an 85-dB SPL 226-Hz probe tone, and ipsiand contralateral stapedius reflex thresholds were measured using 0.5, 1.0, 2.0 kHz and broadband noise stimuli (TympStar; Grason Stadler Inc., Eden Prairie, MN). Pure-tone audiometry was performed in a double-walled sound-attenuated room, applying the modified Hughson-Westlake method to bilaterally determine air conduction (AC) thresholds expressed in decibel hearing level (dB HL) at octave frequencies 0.25 to 8.0 kHz and at half-octave frequencies 3.0 and 6.0 kHz, as well as bone conduction (BC) thresholds at octave frequencies 0.25 to 4.0 kHz and half-octave frequency 3.0 kHz (AC 40 Clinical Audiometer; Interacoustics, Assens, Denmark). At frequencies from 0.25 to 4.0 kHz, the air-bone gap (ABG) was calculated by subtracting the BC from the AC thresholds. Hearing loss was classified as follows: 1) conductive: BC thresholds < 15 dB HL and ABG 15 dB averaged over 0.5, 1.0, and 2.0 kHz; 2) pure sensorineural: AC thresholds 15 dB HL and ABG < 15 dB averaged over 0.5, 1.0, and 2.0 kHz; 3) high-frequency sensorineural: AC thresholds > 30 dB averaged over 4.0, 6.0, and 8.0 kHz; and 4) mixed: BC thresholds 15 dB HL and ABG 15 dB HL averaged over 0.5, 1.0, and 2.0 kHz. Hearing loss was substantiated by comparison with the 95th percentile value for sex- and age-related hearing thresholds.12 Bone Densitometry Anthropometric parameters, height and weight, were measured to the nearest 0.1 cm using a wall-mounted Harpenden stadiometer (Holtain, Crymych, UK) and the nearest 0.1 kg on a calibrated balance scale in light, indoor clothing without shoes, respectively. Body mass index was calculated as the ratio of weight (kilograms) to the squared height (square meters). By means of DXA at lumbar spine (LS) (L1–L4) and whole body (WB) level, the aBMD (grams per square centimeter) was calculated, being the ratio of the bone mineral content (grams) to the scanned bone area (square centimeters) (Hologic QDR4500A device, software version 11.2.1; Hologic, Bedford, MA). LS DXA predominantly reflects trabecular aBMD, whereas WB DXA provides an estimation of cortical bone aBMD. Three-dimensional, volumetric bone parameters were determined by pQCT at the proximal radius (66% of radius length from distal [R-66]) of the dominant forearm, mainly made up of cortical bone, and at the distal radius (4% of radius length from distal [R-4]) of the nondominant forearm, predominantly consisting of trabecular bone tissue (XCT2000 scanner, Swinnen et al.: BMD and Hearing Loss in OI software version 5.4; Stratec, Pforzheim, Germany). The R-66 pQCT bone density parameter of interest was cortical bone vBMD (Cort vBMD) (milligrams per cubic millimeter). Additional parameters at this site were the bone geometry parameters cortical thickness (millimeters), periosteal circumference (millimeters), and endosteal circumference (millimeters). From R-4 pQCT, trabecular bone vBMD (Trab vBMD) (milligrams per cubic millimeter) was included for further analyses. Comparisons with age- and sex-matched reference data enabled the conversion of absolute values into z scores (number of standard deviations from the mean) for LS aBMD, WB aBMD, and R-4 Trab vBMD. Genetic Analysis Molecular-genetic screening and analysis of mutations in COL1A1 and COL1A2 were performed at the Center for Medical Genetics from the UZ Ghent in accordance with previously described procedures.13 Nonsense and frameshift mutations in COL1A1 or COL1A2 resulting in a premature stop codon were classified as mutations leading to a quantitative type I collagen defect. Missense mutations in either of these genes were interpreted as qualitative mutations, as they induce the formation of structural abnormal type I collagen. To verify whether a splicesite mutation led to a quantitative or qualitative defect, a skin biopsy was obtained in the proband to perform cDNA analysis and a COL1A1 null allele test, of which the procedures were analogous to those described by Symoens et al.14 and Nuytinck et al.15 A positive COL1A1 null allele test and/or a decreased migration of type I (pro)collagen on biochemistry pointed toward a quantitative defect of type I collagen synthesis, whereas splice site mutations associated with a negative COL1A1 null allele test and/or abnormal biochemical migration patterns of type I (pro)collagen were considered qualitative mutations. Statistical Analysis All data were entered into SPSS for statistical analysis (SPSS Inc., Chicago, IL). A v2 and Fisher exact test were performed to check associations between categorical variables. Continuous variables were evaluated for normal distribution by the Kolmogorov-Smirnov test. To determine whether z scores differed from 0, we used the one-sample t test. The Student t test was applied for comparison of bone parameters between two groups. Pearson correlation coefficient (r) was calculated to determine associations between continuous variables. Analyses of covariance (ANCOVA) were performed to investigate differences in BMD and geometry parameters as a function of hearing, employing the Bonferroni adjustment for post hoc multiple comparisons. When the normal distribution was not achieved by the outcome variable, we used Mann-Whitney and Kruskal-Wallis tests and Spearman rank correlation coefficient (rs). For betweenrelatives comparisons of bone parameters, paired t tests were applied. A 5% significance level was used throughout all analyses. RESULTS Demographics, Clinical OI Type, and Genotype Fifty-six adult OI patients (22 male, 34 female) with a mean age of 43 years (standard deviation: 13.7; range, 18–80 years) participated in the study. None of them had been treated with BP intravenously, with oral BP before the age of 24 years, or with oral BP for a period longer than 4 years. Postmenopausal women (n ¼ 6) were completely free of hormonal drug administration. Fifty-two of 56 participants showed a positive family history for OI and originated from 25 different Laryngoscope 122: February 2012 families from which one to four affected relatives participated in this study. In four participating patients, there was evidence of an isolated form of OI, which was confirmed genetically. All patients had been clinically diagnosed as OI type I (n ¼ 49) or IV (n ¼ 7). Based on the results from genetic tests, it was possible to differentiate between patients with quantitatively (n ¼ 45) and qualitatively (n ¼ 11) impaired type I collagen synthesis. All the patients with quantitative defects and four of those with qualitative defects had mutations located in COL1A1. Only seven patients had a mutation in COL1A2, all of which induced a qualitative type I collagen defect. Hearing Thirty-seven of 56 participants (66%) were diagnosed with hearing loss, which was bilateral in 31 patients. Forty-four of the total number of 112 ears (39%) demonstrated normal hearing thresholds. The hearing-impaired ears reflected a conductive, mixed, flat sensorineural, or high-frequency sensorineural loss or they had previously undergone stapes surgery. The proportionality of these different types is illustrated in Figure 1. For further analysis, a classification into three groups with respect to hearing was introduced. The first group consisted of ears with normal hearing (NL H). The second group comprised the ears with conductive and mixed hearing loss (C/M HL), as well as the ears that underwent stapes surgery. Finally, the last group was characterized by pure SNHL, whether or not it was limited to the highest frequencies. In all patients with bilateral hearing loss, the same type of hearing loss was found in both ears. Consequently, each patient could exhaustively be assigned to the group of NL H, C/M HL, or SNHL. Six patients had unilateral hearing loss, which was a C/M HL in five patients and an SNHL in one patient, and were classified according to their hearing-impaired ear. In summary, 19 patients had NL H (34%), whereas 29 and eight patients demonstrated C/M HL (52%) and pure SNHL (14%), respectively. The occurrence and type of hearing loss as a function of clinical OI type and genotype are presented in Table I and Table II, respectively. Fisher exact test could not demonstrate significant associations between the occurrence or type of hearing loss and the OI type, the mutated gene, or the type I collagen defect. Finally, hearing loss occurred in patients with a positive family history of OI, as well as in patients with isolated OI. Two of four patients with isolated OI showed C/M HL. In the 17 families with two or more participating relatives, we noticed intrafamilial variability with regard to hearing loss. Associations Between Hearing Loss and Bone Parameters Osteosynthetic material biased BMD measurements in one patient at DXA LS and in five patients at DXA WB. Consequently, their results were excluded from the analysis. In addition, pQCT measurements were not Swinnen et al.: BMD and Hearing Loss in OI 403 Fig. 1. Normal hearing and different types of hearing loss in 112 ears from 56 osteogenesis imperfecta patients. Because a similar underlying pathologic process was suspected, ears that had undergone stapes surgery and those with conductive or mixed hearing loss (C/M HL) could be bundled. Ears with sensorineural hearing loss (SNHL), whether or not limited to the highest frequencies, were considered to form one group. performed in five patients because forearms had been fractured in the past 2 years. Mean values for age and anthropometrics for the patients belonging to the groups of NL H, C/M HL, and SNHL, separately, as well as for the whole group may be consulted in Table III. Results for total fracture number, BMD, and geometry parameters in the groups of patients with NL H, C/M HL, and SNHL, as well as for the whole group of patients, are presented in Table IV. In the patient population taken as a whole, z scores were significantly below 0 for LS aBMD (P < .001), WB aBMD (P < .001), and R-4 Trab vBMD (P < .001). However, when considering the subgroups based on hearing, z scores remained significantly below 0 in the groups with NL H and C/M HL but not in the patients with SNHL, which formed the smallest group. To determine differences in BMD and bone geometry between the groups, a one-way ANCOVA was conducted on each bone parameter with appropriate adjustments. The latter are displayed as covariates in Table IV and were based on significant correlations of bone parameters with anthropometrics and age and on differences in bone parameters according to sex or type I collagen defect. Comparison of LS and WB aBMD converted into z scores with appropriate adjustments revealed significantly higher LS and WB aBMD z scores in the patients with SNHL, compared to those with NL TABLE I. Prevalence and Types of Hearing Loss as a Function of Clinical Osteogenesis Imperfecta Type in 56 Osteogenesis Imperfecta Adults. OI Type I Normal hearing No. of Subjects 16 COL1A1 No. of Subjects Qualitative COL1A1 % No. of Subjects COL1A2 % No. of Subjects % % % Normal hearing 14 25 1 2 4 8 29 3 5 Conductive/mixed 26 46 2 4 1 2 5 9 1 2 2 4 45 Sensorineural hearing loss 8 14 404 Quantitative No. of Subjects 25 Laryngoscope 122: February 2012 TABLE II. Prevalence and Types of Hearing Loss as a Function of Quantitative or Qualitative Type I Collagen Defect in the COL1A1 or COL1A2 Gene in 56 Adult Osteogenesis Imperfecta Patients. OI Type IV Conductive/mixed hearing loss OI ¼ osteogenesis imperfecta. H (P < .01 and P < .05, respectively) or C/M HL (P < .05 for both parameters). At R-4, differences between groups were observed for Trab vBMD and Trab z score. The patients with C/M HL reflected lower values than the groups with NL H (P < .05 for both parameters) and SNHL (P < .05 for both parameters). At R-66, no differences between hearing groups could be demonstrated for Cort vBMD or for parameters of bone geometry. No association was found in the group of patients with C/M HL or in the patients with SNHL between the average AC thresholds, BC thresholds, or average ABGs (0.5, 1.0, 2.0 kHz) and the bone parameters obtained by DXA and pQCT. Intrafamilial paired comparisons between relatives with NL H and C/M HL were executed in eight unrelated families, of which both patients with NL H and C/ M HL participated in the study. Between-relative comparisons for DXA and pQCT z scores are graphically presented in Figure 2. Paired comparisons of BMD parameters yielded lower values in patients with C/M HL compared to their NL H relatives. However, differences were only significant for DXA LS aBMD (P < .05), LS z score (P < .05), WB z score (P < .05), and R-4 Trab z score (P < .05). 4 7 — hearing loss Sensorineural hearing loss Swinnen et al.: BMD and Hearing Loss in OI TABLE III. Age and Anthropometrics in Osteogenesis Imperfecta Patients With Normal Hearing, Conductive/Mixed Hearing Loss, Sensorineural Hearing Loss, and in the Whole Group. NL H C/M HL No. F/M 13/6 15/14 Age, yr 35.4 6 8.5 47.2 6 13.8 SNHL 6/2 159.3 6 8.8 34/22 43.6 6 13.7 Height, cm 159.6 6 9.3 Weight, kg 64.0 6 9.5 65.3 6 11.0 75.8 6 15.4 66.4 6 11.7 BMI, kg/m 25.2 6 4.0 24.6 6 3.8 29.8 6 5.4 25.6 6 4.4 Radius length, cm 25.4 6 1.4 26.2 6 2.0 25.4 6 1.6 25.8 6 1.8 2 162.9 6 9.9 49.8 6 15.7 Whole Group 161.3 6 9.5 Data are presented as mean 6 standard deviation. NL H ¼ normal hearing; C/M HL ¼ conductive/mixed hearing loss; SNHL ¼ sensorineural hearing loss; No. F/M ¼ female-to-male ratio; BMI ¼ body mass index. DISCUSSION Hearing Loss Sixty-six percent of our patients demonstrated hearing loss, of which the severity varied from mild to profound and which was bilateral in most cases. Consistent with other studies, mixed hearing loss emerged as the predominant hearing loss type in the adult OI population.7,8,16 After correction for the physiologically normal age- and sex-related decline in hearing thresholds, we diagnosed a pure SNHL in a minority of the adult OI patients, which was in accordance with other studies.7,8 Although it has often been claimed to occur most often in OI type I, hearing impairment has been reported in patients with clinical OI types III and IV as well.1,8 Both our OI type I and type IV population demonstrated hearing loss; however, pure SNHL was not diagnosed in our type IV patients. Despite the limited number of type IV patients in the present study, a similar observation was made by Pillion and Shapiro,16 and in the study by Kuurila et al.8 less than 4% of type IV patients exhibited pure SNHL. Finally, in the population under study, the occurrence and type of hearing loss seemed to be independent of the mutated gene or the effect of the mutation on type I collagen synthesis, which was in accordance with the results of a large Finnish population study.8 Associations Between Hearing Loss and BMD Compared to the healthy population, our OI patients had reduced BMD. This was demonstrated by reduced z scores for aBMD and Trab vBMD, and is in accordance with results of other studies focusing on BMD in adult and pediatric OI patients.3,5,6 Furthermore, we encountered variations in BMD as a function of occurrence and type of hearing loss. Hearing loss presenting as a conductive hearing loss that progresses to a mixed hearing loss is associated with a lower trabecular BMD at both between-groups and between-relatives comparisons. Conversely, a pure SNHL appears to develop in the OI patients with more Laryngoscope 122: February 2012 appropriate BMD compared to patients with normal hearing or C/M HL. However, the relationship between higher BMD and the development of pure SNHL in OI relied on a small number of patients. Before interpreting these findings, we have to admit that bone metabolism in the normal temporal bone differs from the rest of the skeleton in three major aspects. First, the ossicles and cochlear capsule attain adult dimensions and configuration at mid-fetal age, and calcification process is complete at age 1 year, after which growth, modeling, and remodeling are virtually absent. In the long bones, growth and modeling continue until the age of 24 years. Second, the ossicles and bony cochlear capsule are almost completely made up of cortical bone. The different patterns in BMD according to the occurrence and type of hearing loss predominantly account for measurements at sites consisting of mainly trabecular bone. Unfortunately, because of the partial volume effect, the R-66 pQCT parameter Cort vBMD has been reported to be an unreliable parameter when cortical thickness is decreased, as is often the case in OI.17 A third characteristic unique to the temporal bone is the endochondral layer of the otic capsule being the sole region in the human body in which primary trabeculae persist throughout life. A conceivable explanation for the development of otosclerosis-like lesions in the temporal bones of the OI patients with low BMD seeks supports from the hypothesis that otosclerosis is related to the disruption of the normal inhibition of bone remodeling in the temporal bone following the accumulation of intraosseous microfractures and fatigue microdamage.18 Recently, researchers have discovered that the inhibition of bone remodeling in the normal temporal bone may most likely be attributed to the action of the antiresorptive cytokine osteoprotegerin (OPG), which is expressed in extreme amounts in the inner ear and diffuses centrifugally to the perilabyrinthine bone and the middle ear through an extensive network of osteocytic lacunar canaliculi in the bone of the otic capsule.19 Because of the bone remodeling inhibition, microfractures and fatigue microdamage are likely to accumulate in the temporal bones. These Swinnen et al.: BMD and Hearing Loss in OI 405 Laryngoscope 122: February 2012 406 Swinnen et al.: BMD and Hearing Loss in OI 1.26 6 1.10* n ¼ 27 134 6 40 1.27 6 1.20* n ¼ 18 157 6 56 39.1 6 4.6 25.6 6 4.1 37.8 6 5.3 24.4 6 5.1 Periosteal circumference, mm Endosteal circumference, mm 25.5 6 3.9 38.7 6 3.9 2.10 6 0.17 1,152 6 44 n¼6 0.70 6 1.28 174 6 42 n¼6 0.47 6 1.38 1.024 6 0.112 n¼7 0.93 6 2.01 0.860 6 0.213 n¼7 17 (3–25) n¼8 SNHL 25.2 6 4.4 35.6 6 4.7 2.14 6 0.39 1,164 6 47 n ¼ 51 1.61 6 1.16* 147 6 48 n ¼ 51 1.17 6 1.17* 0.991 6 0.083 n ¼ 51 2.09 6 1.38* 0.789 6 0.134 n ¼ 55 15 (7–25) n ¼ 56 Whole Group ‡ NS NS NS NS C/M HL < NL H‡; C/M HL < SNHL‡ C/M HL < NL H ; C/M HL < SNHL ‡ NLH < SNHL‡; C/M HL < SNHL‡ NS NLH < SNHL†; C/M HL < SNHL‡ NS NS Between-Groups Differences Sex, age, radius length collagen defect Sex, age, type I collagen defect Sex, weight, type I Sex, weight, type I collagen defect Covariates Total fracture number is presented as median (interquartile range), as the normal distribution was not achieved. All other data are presented as mean 6 standard deviation. *The z score was significantly different below 0 at one-sample t test (P < .001). † P < .01 at one-way analysis of covariance. ‡ P < .05 at one-way analysis of covariance. NL H ¼ normal hearing; C/M HL ¼ conductive/mixed hearing loss; SNHL ¼ sensorineural hearing loss ; n ¼ number of subjects; NS ¼ not significant; DXA ¼ dual X-ray absorptiometry; aBMD ¼ areal bone mineral density; Type I collagen defect ¼ either quantitatively or qualitatively impaired type I collagen synthesis; R-4 ¼ radius measurement site at 4% from distal; pQCT ¼ peripheral computed tomography; vBMD ¼ volumetric bone mineral density; R-66 ¼ radius measurement site at 66% from distal. 2.15 6 0.47 2.12 6 0.32 1,159 6 47 0.987 6 0.072 0.986 6 0.092 1,176 6 48 n ¼ 29 n ¼ 19 n ¼ 27 2.21 6 1.21* 2.35 6 1.20* n ¼ 18 0.774 6 0.117 0.786 6 0.123 1.93 6 0.90* n ¼ 29 n ¼ 19 1.43 6 1.32* 15 (6–23) n ¼ 29 15 (10–23) n ¼ 19 C/M HL Cortical thickness, mm Cortical bone vBMD, mg/mm3 R-66 pQCT Trabecular bone z score vBMD, mg/mm 3 Trabecular bone R-4 pQCT z Score aBMD, g/cm 2 DXA whole body z Score aBMD, g/cm 2 DXA lumbar spine Total fracture no. Fractures NL H TABLE IV. Total Fracture Number and Bone Densitometry Results in Osteogenesis Imperfecta Patients With Normal Hearing, Conductive/Mixed Hearing Loss, Sensorineural Hearing Loss, and in the Whole Group. Fig. 2. Intrafamilial variability in hearing and bone density. Mean between-relative differences in z scores for (A) areal bone mineral density (aBMD) at lumbar spine (LS) dual X-ray absorptiometry (DXA), (B) whole body (WB) DXA, and (C) trabecular volumetric BMD (vBMD) at 4% of radius length from distal (R-4) peripheral quantitative computed tomography are displayed in eight families (x axis) of whom at least one relative had normal hearing (NL H) and one demonstrated conductive/mixed hearing loss (C/M HL). Two NL H data points in (B) and one C/ M HL data point in (C) are missing because of osteosynthetic material and forearm fractures, respectively. lesions are physiologically normal responses to mechanical load and strains during daily activities and are constantly removed in other bones by bone remodeling. Frisch et al.18 have suggested that accumulating microfractures and fatigue microdamage in the temporal bones may disrupt the OPG signaling pathways and could offer a pathogenetic factor in otosclerosis, in which abnormal bone remodeling occurs. Indeed, Proops et al.20 have demonstrated increases in the numbers of microfractures in temporal bones with increasing age, as well as a higher prevalence in otosclerosis. However, it was not reported whether these microfractures particularly occur at the lateral capsular wall, the site of predilection for otosclerosis. Because OI is associated with a higher overall bone fragility and a much faster accumulation of fatigue damage in cortical bone,2 the accumulation of temporal bone microfractures in the ossicles and the stapes footplate, acting on the OPG canalicular network, and consequently, resulting into bone loss and otosclerosis-like foci, sounds like a very plausible hypothesis for the development of conductive hearing loss in OI. Still, because the middle ear ossicles are also relatively metabolically inactive and dominantly constituted of cortical bone, the association between lower trabecular BMD and development of middle ear pathology in OI remains ambiguous. The present findings need to be confirmed in large OI populations. Moreover, longitudinal follow-up of BMD and bone geometry parameters in patients with OI from a young age onwards is recommended, because bone parameters are relatively dynamic and influenced by growth, drugs, hormonal changes, and physical activity. In addition, the effects of BP and other drugs on hearing ability in OI should be investigated. Administration of BP is the current therapy of preference for increasing bone mass and BMD in OI children and adults with high fracture rates and low BMD z scores by inhibition of the augmented osteoclastic bone resorption activity. If the development of OI-related conductive hearing loss is associated with reduced BMD and higher bone turnover rate, BP administration may have an inhibitory effect on Laryngoscope 122: February 2012 the development and progression of conductive hearing loss. Finally, histomorphometric analyses of temporal bone structures and in vivo quantitative densitometric imaging methods directly applied at the level of the temporal bones in OI patients developing different types of hearing loss will hopefully offer more insight into the underlying pathophysiology of OI-related hearing loss. CONCLUSIONS OI adults with C/M HL, which are most likely due to otosclerosis-like lesions and fixation of the stapes footplate, were found to reflect a lower trabecular BMD compared to OI patients with normal hearing or pure SNHL. Whether this relationship implies that a low trabecular BMD involves a higher susceptibility to thinning of the middle ear ossicles and accumulation of microfractures interfering with the temporal bone remodeling inhibition pathways deserves attention in future research. Longitudinal follow-up studies evaluating BMD and hearing performance from a young age onwards, as well as the effects of BP administration in OI on hearing, should be encouraged. Acknowledgment The authors would like to thank all the participating patients. Furthermore, they would like to express their gratitude to the employees from the Unit for Osteoporosis and Metabolic Diseases for their assistance in bone densitometry. BIBLIOGRAPHY 1. Sillence DO, Senn A, Danks DM. Genetic heterogeneity in osteogenesis imperfecta. J Med Genet 1979;16:101–116. 2. Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet 2004;363: 1377–1385. 3. Rauch F, Lalic L, Roughley P, Glorieux FH. Relationship between genotype and skeletal phenotype in children and adolescents with osteogenesis imperfecta. J Bone Miner Res 2010;25:1367–1374. 4. Byers PH, Wallis GA, Willing MC. Osteogenesis imperfecta: translation of mutation to phenotype. J Med Genet 1991;28:433–442. 5. Gatti D, Colapietro F, Fracassi E, et al. The volumetric bone density and cortical thickness in adult patients affected by osteogenesis imperfecta. J Clin Densitom 2003;6:173–177. Swinnen et al.: BMD and Hearing Loss in OI 407 6. Rauch F, Land C, Cornibert S, Schoenau E, Glorieux FH. High and low density in the same bone: a study on children and adolescents with mild osteogenesis imperfecta. Bone 2005;37:634–641. 7. Pedersen U. Hearing loss in patients with osteogenesis imperfecta. A clinical and audiological study of 201 patients. Scand Audiol 1984;13: 67–74. 8. Kuurila K, Kaitila I, Johansson R, Grenman R. Hearing loss in Finnish adults with osteogenesis imperfecta: a nationwide survey. Ann Otol Rhinol Laryngol 2002;111:939–946. 9. Tabor EK, Curtin HD, Hirsch BE, May M. Osteogenesis imperfecta tarda: appearance of the temporal bones at CT. Radiology 1990;175:181–183. 10. Shapiro JR, Pikus A, Weiss G, Rowe DW. Hearing and middle ear function in osteogenesis imperfecta. JAMA 1982;247:2120–2126. 11. Hartikka H, Kuurila K, Korkko J, et al. Lack of correlation between the type of COL1A1 or COL1A2 mutation and hearing loss in osteogenesis imperfecta patients. Hum Mutat 2004;24:147–154. 12. ISO-7029. Acoustics - Statistical Distribution of Hearing Thresholds as a Function of Age. Geneva, Switzerland: International Organization for Standardization; 2000. 13. Swinnen FK, De Leenheer EM, Coucke PJ, Cremers CW, Dhooge IJ. Audiometric, surgical, and genetic findings in 15 ears of patients with osteogenesis imperfecta. Laryngoscope 2009;119:1171–1179. Laryngoscope 122: February 2012 408 14. Symoens S, Nuytinck L, Legius E, Malfait F, Coucke PJ, De PA. Met>Val substitution in a highly conserved region of the pro-alpha1(I) collagen C-propeptide domain causes alternative splicing and a mild EDS/OI phenotype. J Med Genet 2004;41:e96. 15. Nuytinck L, Coppin C, De PA. A four base pair insertion polymorphism in the 30 untranslated region of the COL1A1 gene is highly informative for null-allele testing in patients with osteogenesis imperfecta type I. Matrix Biol 1998;16:349–352. 16. Pillion JP, Shapiro J. Audiological findings in osteogenesis imperfecta. J Am Acad Audiol 2008;19:595–601. 17. Rauch F, Tutlewski B, Schonau E. The bone behind a low areal bone mineral density: peripheral quantitative computed tomographic analysis in a woman with osteogenesis imperfecta. J Musculoskelet Neuronal Interact 2002;2:306–308. 18. Frisch T, Bretlau P, Sorensen MS. Intravital microlesions in the human otic capsule. Detection, classification and pathogenetic significance revisited. ORL J Otorhinolaryngol Relat Spec 2008;70:195–201. 19. Zehnder AF, Kristiansen AG, Adams JC, Merchant SN, McKenna MJ. Osteoprotegerin in the inner ear may inhibit bone remodeling in the otic capsule. Laryngoscope 2005;115:172–177. 20. Proops DW, Hawke WM, Berger G. Microfractures of the otic capsule. The possible role of masticatory stress. J Laryngol Otol 1986;100:749–758. Swinnen et al.: BMD and Hearing Loss in OI