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Longitudinal change in patellofemoral cartilage thickness, cartilage T2 relaxation times, and subchondral bone plate area in adolescent vs mature athletes
Accepted Manuscript Title: Longitudinal change in patellofemoral cartilage thickness, cartilage T2 relaxation times, and subchondral bone plate area in adolescent vs mature athletes Authors: Adam G. Culvenor, Wolfgang Wirth, Susanne Maschek, Heide Boeth, Gerd Diederichs, Georg Duda, Felix Eckstein PII: DOI: Reference:
S0720-048X(17)30166-3 http://dx.doi.org/doi:10.1016/j.ejrad.2017.04.018 EURR 7807
To appear in:
European Journal of Radiology
Received date: Revised date: Accepted date:
27-2-2017 21-4-2017 24-4-2017
Please cite this article as: Culvenor Adam G, Wirth Wolfgang, Maschek Susanne, Boeth Heide, Diederichs Gerd, Duda Georg, Eckstein Felix.Longitudinal change in patellofemoral cartilage thickness, cartilage T2 relaxation times, and subchondral bone plate area in adolescent vs mature athletes.European Journal of Radiology http://dx.doi.org/10.1016/j.ejrad.2017.04.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Longitudinal change in patellofemoral cartilage thickness, cartilage T2 relaxation times, and subchondral bone plate area in adolescent vs mature athletes Adam G Culvenor PT PhDa,b, Wolfgang Wirth PhDa, Susanne Mascheka, Heide Boeth PhDc, Gerd Diederichs MDd, Georg Duda PhDc, Felix Eckstein MDa a Institute of Anatomy, Paracelsus Medical University Salzburg & Nuremburg, Strubergasse 21, A5020, Salzburg, Austria b La Trobe Sports & Exercise Medicine Research Centre, School of Allied Health, La Trobe University, Kingsbury Drive, Bundoora 3086, Victoria, Australia c Julius Wolff Institute, Charité-Universitätsmedizin, Charitéplatz 1, 10117 Berlin, Centre for Sports Science and Sports Medicine Berlin, Germany d Department of Radiology, Charité-Universitätsmedizin, Charitéplatz 1, 10117 Berlin, Germany Author contact details: Adam G Culvenor: [email protected] Gerd Diederichs: [email protected] Wolfgang Wirth: [email protected] Georg Duda: [email protected] Susanne Maschek: [email protected] Felix Eckstein: [email protected] Heide Boeth: [email protected] ,805 Address for correspondence: Dr Adam G Culvenor Institute of Anatomy, Paracelsus Medical University, Strubergasse 21, A5020 Salzburg, AUSTRIA Tel: +43 662 2420 80417; Fax: +43 662 44 2002 1249; Email: [email protected] Funding: The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7-NMP-2008-Large-2, grant number 228929) (Nano Diara). Adam Culvenor was supported by postdoctoral funding from a European Union Seventh Framework Programme (FP7PEOPLE-2013-ITN, grant number 607510) (KNEEMO), and National Health and Medical Research Council of Australia (1121173). The sponsors were not involved in the study design, interpretation of data, writing of the manuscript or the decision to submit the manuscript for publication. Conflicts of interest: Wolfgang Wirth and Susanne Maschek have a part time employment with Chondrometrics GmbH and are co-owners of Chondrometrics GmbH, a company providing MRI analysis services to academic researchers and to industry. Felix Eckstein is CEO of Chondrometrics GmbH; he has provided consulting services to Merck Serono, Mariel Therapeutics, Servier, and Bioclinica/Synarc, has prepared educational sessions for Medtronic, and has received research support from Pfizer, Eli Lilly, Merck Serono, GlaxoSmithKline, Centocor R&D, Wyeth, Novartis, Stryker, Abbvie, Kolon, Synarc, Ampio, BICL and Orthotrophix. All of the other authors have no conflict of interest to report. HIGHLIGHTS
First longitudinal study of patellar cartilage thickness/composition during growth Patellofemoral cartilage thickens in late adolescence with no sex differences Patellar cartilage growth accompanied by T2 increases in adolescent women, not men These cartilage changes help interpret findings in subjects after knee trauma
ABSTRACT Objective. Patellofemoral cartilage changes have been evaluated in knee trauma and osteoarthritis; however, little is known about changes in patellar and trochlear cartilage thickness, T2 relaxation-time and subchondral bone plate area (tAB) during growth. Our prospective study aimed to explore 1
longitudinal change in patellofemoral cartilage thickness, T2 and tAB in adolescent athletes, and to compare these data with those of mature (i.e., adult) athletes. Materials and Methods. 20 adolescent (age 16±1 years) and 20 mature (46±5 years) volleyball players were studied over 2-years (10 men and 10 women each group). 1.5T MRI 3D-VIBE and multi-echo spinecho sequences were acquired at baseline and 2-year follow-up. Using manual segmentation and 3D reconstruction, longitudinal changes in patellar and trochlear cartilage thickness, patellar cartilage T2 (mono-exponential decay curve with five echoes [9.7-67.9ms]), and patellar and trochlear tAB were determined. Results. The annual increase in both patellar and trochlear cartilage thickness was 0.8% (95% confidence interval [CI] 0.6, 1.0) and 0.6% (0.3, 0.9), for adolescent males and females respectively; the longitudinal gain in patellar and trochlear tAB was 1.3% (1.1, 1.5) and 0.5% (0.2, 0.8), and 1.6% (1.1, 2.2) and 0.8% (0.3, 0.7) for adolescent males and females, respectively (no significant betweensex differences). Mature athletes showed smaller gains in tAB, and loss of <1% of cartilage thickness annually. While no significant sex-differences existed in adolescent patellar T2 changes, mature males gained significantly greater T2 than mature females (p=0.002–0.013). Conclusions. Patellar and trochlear cartilage thickness and tAB were observed to increase in young athletes in late adolescence, without significant differences between sexes. Mature athletes displayed patellar cartilage loss (and T2 increases in mature males), potentially reflecting degenerative changes.
Abbreviations: ACL: anterior cruciate ligament; KOA: knee osteoarthritis; tAB: subchondral bone plate area; ThCaAB: mean cartilage thickness over the subchondral bone plate area
Keywords: cartilage; thickness; subchondral bone; patella; trochlea; development
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INTRODUCTION Knee injury is a well-established risk factor for accelerated cartilage pathology and longer-term development of knee osteoarthritis (KOA) [1]. As candidate biomarkers for radiographic KOA incidence, typical cartilage parameters evaluated following injury include cartilage morphology (e.g., volume, thickness) and spin-spin relaxation times (T2). Cartilage T2 reflects cartilage composition and has been shown to be sensitive to water and collagen content, and collagen anisotropy [2]. Most reports of posttraumatic cartilage changes published thus far have focused on the tibiofemoral joint. Patellofemoral joint changes are typically under-recognised following knee trauma [1], despite being a potentially important source of knee symptoms [3]. Recently, posttraumatic longitudinal changes in the patellofemoral joint of adolescents and young adults have been highlighted (i.e., after anterior cruciate ligament [ACL] rupture), with patellofemoral cartilage demonstrating significant thinning [4] and prolongation of T2 values [5], and this more so than any other region in the knee. However, an absence of longitudinal reference data on cartilage morphological and compositional development in young athletes limits interpretation of longitudinal changes in patellofemoral cartilage under pathological conditions, typically a traumatic knee injury in physically active adolescents. A single study has thus far generated longitudinal data on patellar cartilage growth, measuring patellar volume over approximately 1.5 years in 74 males and females aged 9-18 years [6]. While peak growth appeared greater among young men than young women, the focus on cartilage volume as a morphometric outcome is limited in that it remains unclear whether the observed gain in cartilage volume was due to an increase in (mean) cartilage thickness or due to growth of bone and subchondral bone plate area. Preliminary cross-sectional studies of patellar cartilage T2 relaxation times and thickness in non-athletic symptomatic 5-22 year old children and adolescents have suggested that cartilage compositional properties may depend on age and sex during growth, and that T2 varies from the bone interface to the cartilage surface [7, 8]. As a result, these studies have concluded that longitudinal evaluations of layer-specific patellofemoral cartilage in adolescents are needed. Such 3
evaluations are particularly important in asymptomatic physically active adolescents as they can serve as reference data for evaluation of longitudinal changes in physically active adolescents with ACL or other injuries. For the tibiofemoral joint, longitudinal changes in cartilage thickness, subchondral bone plate area, and cartilage T2 times over two years have recently been reported in adolescent volleyball athletes and were compared to mature athletes [9, 10]. The distinct properties of patellofemoral cartilage (i.e., patellar cartilage being the thickest cartilage throughout the human body and it being potentially more vulnerable to biochemical and biomechanical changes from physical activity than tibiofemoral cartilage [11]) suggest that its development may differ from other regions in the knee. Therefore, the aims of our prospective study were to determine: i) whether the longitudinal change of patellofemoral cartilage thickness, deep and superficial layer cartilage T2 relaxation-time, and subchondral bone plate area in adolescent athletes differs from that in mature athletes with a similar loading history; and ii) if differences exist in longitudinal cartilage maturation rates between male and female athletes. MATERIALS AND METHODS Participants Study participants were previously described in a report of tibiofemoral cartilage thickness change [9]. 20 elite adolescent volleyball players aged between 15 and 17 years at baseline (baseline age 16.0±0.6 years; 10 male, 10 female) who trained twice daily for ~2h at the Olympiastützpunkt Berlin were studied. For comparison, we additionally examined 20 former elite mature volleyball players aged between 40 and 65 years at baseline (46.3±4.7 years; 10 male, 10 female) who had undergone the same program at the Olympiastützpunkt when they were at the same age, and still actively played volleyball twice weekly at the time of this study. At baseline, the adolescents were in the process of closing their epiphyseal plates; at follow-up, almost all plates were closed [9]. The study protocol was approved by the local ethics committee and all participants (and/or parents) signed informed consent. MR imaging acquisition
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Baseline and 2-year follow-up (mean 24±1 months; range 20-27 months) MR images of the dominant knee (preferred take-off leg) were acquired using the same 1.5T system (Avanto, Siemens Medical Systems, Erlangen, Germany) and a dedicated 8-channel knee coil. A sagittal 3D-VIBE sequence with water excitation (1.5mm slice thickness, 0.31mm in-plane resolution, 14.5ms repetition time, 6.5ms echo time, 20° flip-angle) was used for cartilage quantification. Sagittal multi-echo spin-echo (MESE) images
(repetition time 1500ms, echo
times 9.7/19.4/29.1/38.8/48.5/58.2/67.9ms, slice
thickness/spacing 3.0/3.5mm, in-plane resolution 0.31mm) were used for cartilage T2. Image segmentation and analysis The baseline and follow-up image data sets for each participant were processed in pairs, with blinding to the acquisition time point, all by the same investigator (SM) who has 10 years of continuous experience in cartilage analysis. The subchondral bone plate area (tAB) (i.e., the interface between cartilage and subchondral bone) [12] and the cartilage surface were segmented manually in each image showing the patella and femoral trochlea (Figure 1). The tAB was determined by 3D reconstruction [13] of the bone interface segmentations of the patella and trochlea. The trochlea was separated from the femoral condyles by 3D plane through the trochlear notch in parallel with the femoral shaft and rotated through the posterior ends of both medial and lateral femoral condyles (Figure 1). The mean cartilage thickness over the tAB (ThCaAB) was computed in each cartilage plate independent of the original section orientation, using the bone interface and cartilage surface segmentations [12]. Precision errors for patellofemoral cartilage parameters in subjects with and without OA using similar techniques were found to be 3.4-8.5% [14]. FIGURE ONE HERE Patellar T2 values were computed for each voxel by fitting a mono-exponential decay curve to the measured signal intensities, using a non-linear method as described previously [10]. Briefly, the image with the shortest echo was used for segmenting the patellar bone interface and that with the longest echo for the cartilage surface. As cartilage T2 is known to display spatial variation with tissue depth [15], patellar cartilage was divided into the superficial and deep 50% layers, based on the local distance 5
between the segmented cartilage surface and bone interface. To avoid including T2 values from voxels with poor image quality, we excluded voxels if the coefficient of determination for the curve fitting was below R2=0.66 [10]. Trochlea T2 values were not computed due to flow artefacts from the popliteal artery. Statistical analysis We computed the absolute (and %) change in cartilage morphology and T2 parameters between baseline and follow-up. Because of subtle variations in the follow-up duration between participants, these changes were normalized to a 12-month observation period (i.e., annualized change). Mean annualized changes with corresponding 95%CIs not crossing zero were considered statistically significant. Mann-Whitney U-tests were used to explore whether longitudinal changes in cartilage parameters differed between adolescent vs. mature athletes, or between men and women. All statistical analyses were completed using SPSS V23.0. P-values <0.05 were considered significant. RESULTS Baseline descriptive findings Baseline demographic, patellofemoral cartilage thickness and T2 values, and tAB are presented in Table 1. Men displayed approximately 20-30% greater patellar and trochlear cartilage thickness (with the exception of patellar cartilage in adolescents [3%]) and tAB in both adolescent and mature athletes (Table 1). Adolescents displayed greater patellar and trochlear cartilage thickness than mature athletes, while the mature athletes displayed greater patellar cartilage T2 than adolescents (Table 1). Cartilage was thicker in the patellar than in trochlear cartilage. T2 was greater in the superficial than in the deep patellar cartilage layer across all participant groups (Figure 1). Longitudinal findings In adolescent athletes, the annual increase in patellar and trochlear cartilage thickness was 0.8% (95%CI 0.6, 1.0) and 0.8% (95%CI 0.6, 1.0) in men, and 0.6% (95%CI 0.3, 0.9) and 0.6% (95%CI 0.3, 0.9) in women, respectively (no significant difference between sexes) (Table 2). Male and female mature athletes displayed significant cartilage loss in the patella, but not in the trochlea, with males displaying 6
more than twice the cartilage loss than females (although between-sex differences not statistically significant). While patellar and trochlear subchondral bone plate areas generally increased more during adolescence than maturity, mature men displayed significant subchondral bone plate area growth compared with mature women (p=0.035) (Table 2). A significant longitudinal increase from baseline to 2-year follow-up was observed in both superficial and deep patellar T2 in both the female adolescents and mature males. While no significant sex-specific differences were observed in adolescents, mature males displayed significantly greater increases in patellar T2 compared with mature females (superficial layer: p=0.013, deep layer: p=0.002). TABLE ONE HERE TABLE TWO HERE DISCUSSION In this longitudinal study of patellofemoral cartilage change in active adolescent and mature athletes, we observed significant annual increases in patellar and trochlear cartilage thickness and subchondral bone plate area in young male and female athletes towards the end of adolescence. The growth in patellar cartilage was accompanied by an increase in patellar T2 values in adolescent women, but not in adolescent men. Mature male and female athletes, in contrast, displayed cartilage loss, greater in the patella than trochlea, which was accompanied by an increase in superficial patellar cartilage T2 in mature males, but not in mature females. Until now, longitudinal changes in patellar and trochlear cartilage thickness, T2 and subchondral bone plate area during growth have not been reported. Jones et al. (2003) observed an annual increase in patellar cartilage volume of 286µL (7.1%) and 210µL (6.2%) in male and female children (aged 9-18 years), respectively [6], yet an increase in cartilage volume may be observed with an increase in cartilage thickness or lateral expansion of the subchondral bone plate and overlying cartilage, or both [16]. Although we observed a slightly larger thickness increase in males (22.9µm/year, 0.8%) compared with their female counterparts (17.8µm/year, 0.6%), the previously observed increase in patellar cartilage volume was proportionally much larger than the thickness increases observed in the current 7
study in late adolescence. The larger growth in subchondral bone plate area in adolescent males (13.4mm, 12.5%) and females (15.0mm, 18.1%) in our cohort, and the later age spectrum of our participants (peak cartilage accrual occurs in early adolescence [6]) may explain this difference in cartilage development. Nevertheless, data from the current study clearly affirms that patellar and trochlear cartilage thickness and subchondral bone plate area (and not only volume) increase similarly in both males and females during adolescence. Patellofemoral cartilage appears to undergo similar changes as tibiofemoral cartilage in late adolescence. The 0.6-0.8% increase in patellar and trochlear cartilage thickness observed in the current analysis corresponds with a 0.4-2.2% increase in tibia and femur cartilage thickness increase previously observed in the tibiofemoral joints of the same athletes [9] (no sex-specific differences in either compartment). In contrast, the subchondral bone plate area of the patellar increased annually (1.21.4%) more than twice that of the trochlea (0.4-0.5%), and more than tibiofemoral cartilage (0.2-0.9%) [9]. The larger changes in the patella may relate to the unique properties of the patella, which displays the thickest knee cartilage [17], potentially due to the high pressure per unit of area it experiences [18]. At baseline, men (adolescent and mature) generally displayed 20-30% greater patellar and trochlear cartilage thickness and subchondral bone plate area than women, with these findings extending similar sex-specific data in adolescents [7] and young non-athletic individuals aged ~22 years [17]. Despite continued cartilage thickness growth in the adolescents, baseline cartilage thickness was similar between adolescent and mature athletes, likely indicating that the mature athletes are already in a stage of cartilage thinning. The activity levels at the time of assessment differed between adolescent (volleyball twice per day) and mature athletes (volleyball twice per week), however the loading history at the comparable age was almost identical (i.e., mature athletes were elite volleyball athletes when younger). A greater physical activity level in the older athletes at the time of assessment would likely exacerbate the observed cartilage loss, as high impact activity is associated with greater cartilage strain and hence potential deterioration [11].
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It may not be surprising that T2 values of deep and superficial patellar cartilage were relatively stable in the adolescent athletes, with small changes likely reflecting organizational changes in the collagen matrix. Adolescent males displayed similar (<5% greater) patellar cartilage T2 than adolescent females at baseline, which was also observed in tibiofemoral cartilage T2 in these athletes [10]. The significant (4–7%) increases in patellar cartilage T2 in mature males was accompanied by a significant loss of cartilage thickness, indicating both cartilage morphological and compositional deterioration. Although cartilage thickness loss was also observed in mature women, this occurred at a lower rate than in men, and no significant change in patellar cartilage T2 was observed in these women. The fact that these changes were not closely matched between mature male and females may reflect the 35% greater body mass in mature males, which is a potent risk factor for cartilage loss and incident KOA [19]. While similar to tibiofemoral cartilage from the same athletes (~50msec) [10] and to some previous patellar cartilage T2 data in healthy adults (~42msec) [20], and those with asymptomatic knees with osteoarthritis risk factors (~47msec) [11], our T2 values were higher than in other studies of adolescents and adults [7, 21, 22]. The higher T2 values we observed most likely reflect differences in field strength (T2 relaxation times higher with 1.5T compared with 3T) [23] or the use of more sophisticated fitting methods by previous studies, which result in systemically shorter T2 times [24]. These patellar T2 values from other research groups may be systematically lower due to different computational methods used. Importantly, the observed spatial heterogeneity (and greater superficial than deep T2 values) is in agreement with previous studies that also reported adequate test-re-test precision of layer-specific T2 evaluation [3, 15]. The annualized percent changes in adults were also consistent with previous patellar T2 changes in healthy adults [20]. The small gains we observed in adolescent cartilage thickness contrast the relatively rapid loss of cartilage following ACL injury in young adults, particularly in the trochlea. Over the first year after sustaining an ACL rupture, trochlear cartilage thinned by 1.4% (and patellar cartilage thinned by 0.3%) [25]. Although the cohort of ACL injured knees was slightly older (mean age 26 years), in the context of our results in adolescent knees, the previously observed patellofemoral cartilage thinning is likely 9
to be directly related to the ACL injury. This has important clinical implications, as early posttraumatic patellofemoral cartilage thinning has been linked to worse patient-reported symptoms and function [26], and is likely associated with the development of early-onset patellofemoral OA [27, 28]. Limitations of this study are the modest sample size and that no non-athletic controls were examined to evaluate the specific effect of exercise. The unique study design examining elite volleyball athletes limited the number of available participants, but ensured similar levels of physical activity in men and women. Our results from this highly physically active group also enable comparison to young athletes following a knee trauma as these injuries typically occur in individuals with high physical activity levels. Due to the small sample size, we focused our analysis on longitudinal changes, and used nonparametric statistical tests without adjustment for body size. This also enabled direct comparison to unadjusted tibiofemoral cartilage changes observed in these athletes previously [9, 10]. Greater physical activity levels have been shown to be related to larger patellar cartilage volume accrual in children, but when added to a multivariate model, physical activity explained little (<10%) of the variance in cartilage accrual [6]. It is important to note that the annualized change in cartilage thickness and subchondral bone plate area were much smaller than the standard deviation of the baseline measurements. This was also observed in patellar and trochlear cartilage thickness measures in the first year following ACL injury, and likely reflects the large between-subject variability in cartilage morphology [25]. Finally, all images were acquired on a single 1.5T scanner. Greater MRI field strength provides higher resolution images, reducing the noise and mean values of T2 relaxation times [23], which may partly explain our higher T2 values compared with previous measurements at 3.0T [21, 22]. Cartilage thickness measures taken at 1.5T and 3.0T are very highly correlated (r≥0.96) suggesting that it is unlikely that a higher resolution scanner would have resulted in different conclusions regarding cartilage thickness [29]. CONCLUSIONS In conclusion, patellar and trochlear cartilage thickness and subchondral bone plate area were observed to increase significantly in young athletes towards the end of adolescence, while cartilage 10
composition (T2) was relatively stable, with no significant sex-specific differences. Mature athletes displayed patellar cartilage loss, which, in males, was accompanied by significant patellar compositional changes, potentially reflecting early degenerative changes. These findings on cartilage maturation in adolescent athletes, put in context with the same measures observed in mature adults, cast light on developmental aspects of joint and cartilage morphology during late adolescents, and may help interpret findings in subjects suffering knee trauma (i.e. ACL rupture), an injury typically seen in athletes of this age. AUTHOR CONTRIBUTIONS All authors made substantial contributions to all three sections: (i) the conception and design of the study, data acquisition, analysis and interpretation; (ii) drafting the article or revising it critically; (iii) final approval of the version to be submitted. ROLE OF THE FUNDING SOURCE ACKNOWLEDGEMENTS The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7-NMP-2008-Large-2) under grant agreement No. 228929 (Nano Diara). Adam Culvenor was supported by postdoctoral funding from a European Union Seventh Framework Programme (FP7-PEOPLE-2013-ITN) under grant agreement No. 607510 (KNEEMO), and National Health and Medical Research Council of Australia (1121173). The sponsors were not involved in the study design, interpretation of data, writing of the manuscript or the decision to submit the manuscript for publication. The funding bodies had no involvement in study design, interpretation of data, writing of the manuscript or the decision to submit the manuscript for publication. REFERENCES [1] A.G. Culvenor, J.L. Cook, N.J. Collins, K.M. Crossley, Is patellofemoral joint osteoarthritis an underrecognised outcome of anterior cruciate ligament reconstruction? A narrative literature review, Br J Sports Med. 47 (2013) 66-70.
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magnetic resonance imaging in patellofemoral cartilage composition between patients with patellofemoral pain and healthy controls, Am J Sports Med. 44 (2016) 1172-8. [22] G.B. Joseph, C.E. McCulloch, M.C. Nevitt, U. Heilmeier, L. Nardo, J.A. Lynch, F. Liu, T. Baum, T.M. Link, A reference database of cartilage 3 T MRI T2 values in knees without diagnostic evidence of cartilage degeneration: data from the osteoarthritis intitiative, Osteoarthritis Cartilage. 25 (2015) 897-905. [23] G.E. Gold, E. Han, J. Stainsby, G. Wright, J. Brittain, C. Beaulieu, Musculoskeletal MRI at 3.0T: Relaxation times and image contrast, Am J Roentgenol. 183 (2004) 343-351. [24] J.G. Raya, O. Dietrich, A. Horng, J. Weber, M.F. Reiser, C. Glaser, T2 measurement in articular cartilage: impact of the fitting method on accuracy and precision at low SNR, Magn Reson Med. 63 (2010) 181-93. [25] R.B. Frobell, M.P. Le Graverand, R. Buck, E.M. Roos, H.P. Roos, J. Tamez-Pena, S. Totterman, L.S. Lohmander, The acutely ACL injured knee assessed by MRI: changes in joint fluid, bone marrow lesions, and cartilage during the first year, Osteoarthritis Cartilage. 17 (2009) 161-167. [26] A.G. Culvenor, N.J. Collins, A. Guermazi, J.L. Cook, B. Vicenzino, K.M. Crossley, Early patellofemoral osteoarthritis features 1 year after anterior cruciate ligament reconstruction predict symptoms and quality of life at 3 years, Arthritis Care Res. (2017) doi: 10.1002/acr.22761. [27] A.G. Culvenor, C.C.H. Lai, B.J. Gabbe, M. Makdissi, N.J. Collins, B. Vicenzino, H.G. Morris, K.M. Crossley, Patellofemoral osteoarthritis is prevalent and associated with worse symptoms and function after hamstring tendon autograft ACL reconstruction, Br J Sports Med. 48 (2014) 435-439. [28] A.G. Culvenor, N.J. Collins, A. Guermazi, J.L. Cook, B. Vicenzino, K.M. Khan, N. Beck, J. van Leeuwen, K.M. Crossley, Early knee osteoarthritis is evident one year following anterior cruciate ligament reconstruction: a magentic resonance imaging evaluation, Arthritis Rheum. 67 (2015) 94655.
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[29] F. Eckstein, H.C. Charles, R. J. Buck, V. B. Kraus, A. E. Remmers, M. Hudelmaier, W. Wirth, J. L. Evelhoch, Accuracy and precision of quantiative assessment of cartilage morphology by magnetic reonsance imaging at 3.0T, Arthritis Rheum. 52 (2005) 3132-6. TABLE TITLES Table 1. Adolescent and mature volleyball athletes: baseline demographics and values of patellofemoral cartilage thickness, T2 and subchondral bone plate area in men and women (mean ± standard deviation) Table 2. Male and female adolescent and mature athletes: annualized longitudinal change in patellofemoral cartilage thickness, T2 and subchondral bone plate area
FIGURE LEGENDS Figure 1. Assessment of patellar and trochlear cartilage segmentation and patellar T2 relaxation time: A) spin echo acquisition with the shortest echo time (9.7msec); B) patellar and trochlear subchondral bone area (green contour) and cartilage surface (magenta contour), with the trochlea separated from the femoral condyles by 3D plane through the trochlear notch in parallel with the femoral shaft (red line); C) superficial and deep patellar cartilage layers; and D) patellar cartilage T2 relaxation times.
15
16
17
Figr-1
18
Table 1. Adolescent and mature volleyball athletes: baseline demographics and values of patellofemoral cartilage thickness, T2 and subchondral bone plate area in men and women (mean ± standard deviation) Region
Adolescent Men (n=10)
Mature Women
Men (n=10)
(n=10)
Women (n=10)
Age, years
16±1
16±1
46±3
47±6
Height, cm
193±4
182±4
191±5
176±5
Weight, kg
83±4
70±9
96±13
71±6
Patella
2.96±0.39
2.87±0.24
2.72±0.18
2.25±0.31
Trochlea
2.53±0.29
2.09±0.22
2.32±0.32
1.86±0.14
Patella
10.72±1.29
8.29±1.12
11.01±1.90
9.15±0.57
Trochlea
28.23±2.72
21.47±1.89
25.78±2.29
21.40±1.76
Patella
53.0±1.5
50.7±2.2
54.0±3.7
55.5±2.8
45.2±1.5
43.7±2.1
46.1±3.8
47.6±2.8
Cartilage thickness, mm*
Subchondral bone plate area, cm2*
T2 times, ms§
superficial Patella deep
* Cartilage morphology measures missing in one adolescent woman due to limited image quality at baseline § Patellar T2 values missing in 2 adolescent men and 1 mature man due to missing T2 image acquisition
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Table 2. Male and female adolescent and mature athletes: annualized longitudinal change in patellofemoral cartilage thickness, T2 and subchondral bone plate area Region
Men
Women
p-value*
Mean (95%CI)
Mean (95%
Males vs
CI)
Females
22.9 (16.5,
17.8 (10.3,
0.604
29.3)
25.3)
19.9 (13.2,
12.2 (6.2,
26.6)
18.2)
Patella
1.3 (1.1, 1.6)
1.5 (0.9, 2.1)
0.661
Trochlea
1.1 (0.3, 1.9)
1.1 (0.7, 1.6)
0.905
Patella
-0.3 (-0.6, 0.0)
0.8 (0.4, 1.2)
0.173
Patella deep
0.3 (-0.2, 0.8)
1.3 (0.7, 1.9)
0.515
Patella
-22.8 (-28.5, -
-11.1 (-1.7, -
0.631
17.1)
20.5)
-0.9 (-1.6, 0.3)
-0.1 (-0.6,
Adolescent athletes Cartilage thickness
Patella
change, µm Trochlea
Subchondral bone plate
0.447
area change, mm2
T2 change, ms
superficial
Mature athletes Cartilage thickness change, µm Trochlea
0.579
0.4) Subchondral bone plate
Patella
1.6 (1.2, 1.9)
0.5 (0.2, 0.6)
0.035
Trochlea
1.3 (0.8, 1.9)
0.5 (0.1, 0.9)
0.529
Patella
2.2 (1.5, 2.9)
0.0 (-0.3, 0.3)
0.013
3.4 (2.6, 4.2)
0.1 (-0.4, 0.5)
0.002
area change, mm2
T2 change, ms
superficial Patella deep
* Mann-Whitney U-test to evaluate sex-differences using absolute change cartilage parameters. Evaluation of sex-differences using percentage change resulted in generally the same p-values.
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S0720-048X(17)30166-3 http://dx.doi.org/doi:10.1016/j.ejrad.2017.04.018 EURR 7807
To appear in:
European Journal of Radiology
Received date: Revised date: Accepted date:
27-2-2017 21-4-2017 24-4-2017
Please cite this article as: Culvenor Adam G, Wirth Wolfgang, Maschek Susanne, Boeth Heide, Diederichs Gerd, Duda Georg, Eckstein Felix.Longitudinal change in patellofemoral cartilage thickness, cartilage T2 relaxation times, and subchondral bone plate area in adolescent vs mature athletes.European Journal of Radiology http://dx.doi.org/10.1016/j.ejrad.2017.04.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Longitudinal change in patellofemoral cartilage thickness, cartilage T2 relaxation times, and subchondral bone plate area in adolescent vs mature athletes Adam G Culvenor PT PhDa,b, Wolfgang Wirth PhDa, Susanne Mascheka, Heide Boeth PhDc, Gerd Diederichs MDd, Georg Duda PhDc, Felix Eckstein MDa a Institute of Anatomy, Paracelsus Medical University Salzburg & Nuremburg, Strubergasse 21, A5020, Salzburg, Austria b La Trobe Sports & Exercise Medicine Research Centre, School of Allied Health, La Trobe University, Kingsbury Drive, Bundoora 3086, Victoria, Australia c Julius Wolff Institute, Charité-Universitätsmedizin, Charitéplatz 1, 10117 Berlin, Centre for Sports Science and Sports Medicine Berlin, Germany d Department of Radiology, Charité-Universitätsmedizin, Charitéplatz 1, 10117 Berlin, Germany Author contact details: Adam G Culvenor: [email protected] Gerd Diederichs: [email protected] Wolfgang Wirth: [email protected] Georg Duda: [email protected] Susanne Maschek: [email protected] Felix Eckstein: [email protected] Heide Boeth: [email protected] ,805 Address for correspondence: Dr Adam G Culvenor Institute of Anatomy, Paracelsus Medical University, Strubergasse 21, A5020 Salzburg, AUSTRIA Tel: +43 662 2420 80417; Fax: +43 662 44 2002 1249; Email: [email protected] Funding: The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7-NMP-2008-Large-2, grant number 228929) (Nano Diara). Adam Culvenor was supported by postdoctoral funding from a European Union Seventh Framework Programme (FP7PEOPLE-2013-ITN, grant number 607510) (KNEEMO), and National Health and Medical Research Council of Australia (1121173). The sponsors were not involved in the study design, interpretation of data, writing of the manuscript or the decision to submit the manuscript for publication. Conflicts of interest: Wolfgang Wirth and Susanne Maschek have a part time employment with Chondrometrics GmbH and are co-owners of Chondrometrics GmbH, a company providing MRI analysis services to academic researchers and to industry. Felix Eckstein is CEO of Chondrometrics GmbH; he has provided consulting services to Merck Serono, Mariel Therapeutics, Servier, and Bioclinica/Synarc, has prepared educational sessions for Medtronic, and has received research support from Pfizer, Eli Lilly, Merck Serono, GlaxoSmithKline, Centocor R&D, Wyeth, Novartis, Stryker, Abbvie, Kolon, Synarc, Ampio, BICL and Orthotrophix. All of the other authors have no conflict of interest to report. HIGHLIGHTS
First longitudinal study of patellar cartilage thickness/composition during growth Patellofemoral cartilage thickens in late adolescence with no sex differences Patellar cartilage growth accompanied by T2 increases in adolescent women, not men These cartilage changes help interpret findings in subjects after knee trauma
ABSTRACT Objective. Patellofemoral cartilage changes have been evaluated in knee trauma and osteoarthritis; however, little is known about changes in patellar and trochlear cartilage thickness, T2 relaxation-time and subchondral bone plate area (tAB) during growth. Our prospective study aimed to explore 1
longitudinal change in patellofemoral cartilage thickness, T2 and tAB in adolescent athletes, and to compare these data with those of mature (i.e., adult) athletes. Materials and Methods. 20 adolescent (age 16±1 years) and 20 mature (46±5 years) volleyball players were studied over 2-years (10 men and 10 women each group). 1.5T MRI 3D-VIBE and multi-echo spinecho sequences were acquired at baseline and 2-year follow-up. Using manual segmentation and 3D reconstruction, longitudinal changes in patellar and trochlear cartilage thickness, patellar cartilage T2 (mono-exponential decay curve with five echoes [9.7-67.9ms]), and patellar and trochlear tAB were determined. Results. The annual increase in both patellar and trochlear cartilage thickness was 0.8% (95% confidence interval [CI] 0.6, 1.0) and 0.6% (0.3, 0.9), for adolescent males and females respectively; the longitudinal gain in patellar and trochlear tAB was 1.3% (1.1, 1.5) and 0.5% (0.2, 0.8), and 1.6% (1.1, 2.2) and 0.8% (0.3, 0.7) for adolescent males and females, respectively (no significant betweensex differences). Mature athletes showed smaller gains in tAB, and loss of <1% of cartilage thickness annually. While no significant sex-differences existed in adolescent patellar T2 changes, mature males gained significantly greater T2 than mature females (p=0.002–0.013). Conclusions. Patellar and trochlear cartilage thickness and tAB were observed to increase in young athletes in late adolescence, without significant differences between sexes. Mature athletes displayed patellar cartilage loss (and T2 increases in mature males), potentially reflecting degenerative changes.
Abbreviations: ACL: anterior cruciate ligament; KOA: knee osteoarthritis; tAB: subchondral bone plate area; ThCaAB: mean cartilage thickness over the subchondral bone plate area
Keywords: cartilage; thickness; subchondral bone; patella; trochlea; development
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INTRODUCTION Knee injury is a well-established risk factor for accelerated cartilage pathology and longer-term development of knee osteoarthritis (KOA) [1]. As candidate biomarkers for radiographic KOA incidence, typical cartilage parameters evaluated following injury include cartilage morphology (e.g., volume, thickness) and spin-spin relaxation times (T2). Cartilage T2 reflects cartilage composition and has been shown to be sensitive to water and collagen content, and collagen anisotropy [2]. Most reports of posttraumatic cartilage changes published thus far have focused on the tibiofemoral joint. Patellofemoral joint changes are typically under-recognised following knee trauma [1], despite being a potentially important source of knee symptoms [3]. Recently, posttraumatic longitudinal changes in the patellofemoral joint of adolescents and young adults have been highlighted (i.e., after anterior cruciate ligament [ACL] rupture), with patellofemoral cartilage demonstrating significant thinning [4] and prolongation of T2 values [5], and this more so than any other region in the knee. However, an absence of longitudinal reference data on cartilage morphological and compositional development in young athletes limits interpretation of longitudinal changes in patellofemoral cartilage under pathological conditions, typically a traumatic knee injury in physically active adolescents. A single study has thus far generated longitudinal data on patellar cartilage growth, measuring patellar volume over approximately 1.5 years in 74 males and females aged 9-18 years [6]. While peak growth appeared greater among young men than young women, the focus on cartilage volume as a morphometric outcome is limited in that it remains unclear whether the observed gain in cartilage volume was due to an increase in (mean) cartilage thickness or due to growth of bone and subchondral bone plate area. Preliminary cross-sectional studies of patellar cartilage T2 relaxation times and thickness in non-athletic symptomatic 5-22 year old children and adolescents have suggested that cartilage compositional properties may depend on age and sex during growth, and that T2 varies from the bone interface to the cartilage surface [7, 8]. As a result, these studies have concluded that longitudinal evaluations of layer-specific patellofemoral cartilage in adolescents are needed. Such 3
evaluations are particularly important in asymptomatic physically active adolescents as they can serve as reference data for evaluation of longitudinal changes in physically active adolescents with ACL or other injuries. For the tibiofemoral joint, longitudinal changes in cartilage thickness, subchondral bone plate area, and cartilage T2 times over two years have recently been reported in adolescent volleyball athletes and were compared to mature athletes [9, 10]. The distinct properties of patellofemoral cartilage (i.e., patellar cartilage being the thickest cartilage throughout the human body and it being potentially more vulnerable to biochemical and biomechanical changes from physical activity than tibiofemoral cartilage [11]) suggest that its development may differ from other regions in the knee. Therefore, the aims of our prospective study were to determine: i) whether the longitudinal change of patellofemoral cartilage thickness, deep and superficial layer cartilage T2 relaxation-time, and subchondral bone plate area in adolescent athletes differs from that in mature athletes with a similar loading history; and ii) if differences exist in longitudinal cartilage maturation rates between male and female athletes. MATERIALS AND METHODS Participants Study participants were previously described in a report of tibiofemoral cartilage thickness change [9]. 20 elite adolescent volleyball players aged between 15 and 17 years at baseline (baseline age 16.0±0.6 years; 10 male, 10 female) who trained twice daily for ~2h at the Olympiastützpunkt Berlin were studied. For comparison, we additionally examined 20 former elite mature volleyball players aged between 40 and 65 years at baseline (46.3±4.7 years; 10 male, 10 female) who had undergone the same program at the Olympiastützpunkt when they were at the same age, and still actively played volleyball twice weekly at the time of this study. At baseline, the adolescents were in the process of closing their epiphyseal plates; at follow-up, almost all plates were closed [9]. The study protocol was approved by the local ethics committee and all participants (and/or parents) signed informed consent. MR imaging acquisition
4
Baseline and 2-year follow-up (mean 24±1 months; range 20-27 months) MR images of the dominant knee (preferred take-off leg) were acquired using the same 1.5T system (Avanto, Siemens Medical Systems, Erlangen, Germany) and a dedicated 8-channel knee coil. A sagittal 3D-VIBE sequence with water excitation (1.5mm slice thickness, 0.31mm in-plane resolution, 14.5ms repetition time, 6.5ms echo time, 20° flip-angle) was used for cartilage quantification. Sagittal multi-echo spin-echo (MESE) images
(repetition time 1500ms, echo
times 9.7/19.4/29.1/38.8/48.5/58.2/67.9ms, slice
thickness/spacing 3.0/3.5mm, in-plane resolution 0.31mm) were used for cartilage T2. Image segmentation and analysis The baseline and follow-up image data sets for each participant were processed in pairs, with blinding to the acquisition time point, all by the same investigator (SM) who has 10 years of continuous experience in cartilage analysis. The subchondral bone plate area (tAB) (i.e., the interface between cartilage and subchondral bone) [12] and the cartilage surface were segmented manually in each image showing the patella and femoral trochlea (Figure 1). The tAB was determined by 3D reconstruction [13] of the bone interface segmentations of the patella and trochlea. The trochlea was separated from the femoral condyles by 3D plane through the trochlear notch in parallel with the femoral shaft and rotated through the posterior ends of both medial and lateral femoral condyles (Figure 1). The mean cartilage thickness over the tAB (ThCaAB) was computed in each cartilage plate independent of the original section orientation, using the bone interface and cartilage surface segmentations [12]. Precision errors for patellofemoral cartilage parameters in subjects with and without OA using similar techniques were found to be 3.4-8.5% [14]. FIGURE ONE HERE Patellar T2 values were computed for each voxel by fitting a mono-exponential decay curve to the measured signal intensities, using a non-linear method as described previously [10]. Briefly, the image with the shortest echo was used for segmenting the patellar bone interface and that with the longest echo for the cartilage surface. As cartilage T2 is known to display spatial variation with tissue depth [15], patellar cartilage was divided into the superficial and deep 50% layers, based on the local distance 5
between the segmented cartilage surface and bone interface. To avoid including T2 values from voxels with poor image quality, we excluded voxels if the coefficient of determination for the curve fitting was below R2=0.66 [10]. Trochlea T2 values were not computed due to flow artefacts from the popliteal artery. Statistical analysis We computed the absolute (and %) change in cartilage morphology and T2 parameters between baseline and follow-up. Because of subtle variations in the follow-up duration between participants, these changes were normalized to a 12-month observation period (i.e., annualized change). Mean annualized changes with corresponding 95%CIs not crossing zero were considered statistically significant. Mann-Whitney U-tests were used to explore whether longitudinal changes in cartilage parameters differed between adolescent vs. mature athletes, or between men and women. All statistical analyses were completed using SPSS V23.0. P-values <0.05 were considered significant. RESULTS Baseline descriptive findings Baseline demographic, patellofemoral cartilage thickness and T2 values, and tAB are presented in Table 1. Men displayed approximately 20-30% greater patellar and trochlear cartilage thickness (with the exception of patellar cartilage in adolescents [3%]) and tAB in both adolescent and mature athletes (Table 1). Adolescents displayed greater patellar and trochlear cartilage thickness than mature athletes, while the mature athletes displayed greater patellar cartilage T2 than adolescents (Table 1). Cartilage was thicker in the patellar than in trochlear cartilage. T2 was greater in the superficial than in the deep patellar cartilage layer across all participant groups (Figure 1). Longitudinal findings In adolescent athletes, the annual increase in patellar and trochlear cartilage thickness was 0.8% (95%CI 0.6, 1.0) and 0.8% (95%CI 0.6, 1.0) in men, and 0.6% (95%CI 0.3, 0.9) and 0.6% (95%CI 0.3, 0.9) in women, respectively (no significant difference between sexes) (Table 2). Male and female mature athletes displayed significant cartilage loss in the patella, but not in the trochlea, with males displaying 6
more than twice the cartilage loss than females (although between-sex differences not statistically significant). While patellar and trochlear subchondral bone plate areas generally increased more during adolescence than maturity, mature men displayed significant subchondral bone plate area growth compared with mature women (p=0.035) (Table 2). A significant longitudinal increase from baseline to 2-year follow-up was observed in both superficial and deep patellar T2 in both the female adolescents and mature males. While no significant sex-specific differences were observed in adolescents, mature males displayed significantly greater increases in patellar T2 compared with mature females (superficial layer: p=0.013, deep layer: p=0.002). TABLE ONE HERE TABLE TWO HERE DISCUSSION In this longitudinal study of patellofemoral cartilage change in active adolescent and mature athletes, we observed significant annual increases in patellar and trochlear cartilage thickness and subchondral bone plate area in young male and female athletes towards the end of adolescence. The growth in patellar cartilage was accompanied by an increase in patellar T2 values in adolescent women, but not in adolescent men. Mature male and female athletes, in contrast, displayed cartilage loss, greater in the patella than trochlea, which was accompanied by an increase in superficial patellar cartilage T2 in mature males, but not in mature females. Until now, longitudinal changes in patellar and trochlear cartilage thickness, T2 and subchondral bone plate area during growth have not been reported. Jones et al. (2003) observed an annual increase in patellar cartilage volume of 286µL (7.1%) and 210µL (6.2%) in male and female children (aged 9-18 years), respectively [6], yet an increase in cartilage volume may be observed with an increase in cartilage thickness or lateral expansion of the subchondral bone plate and overlying cartilage, or both [16]. Although we observed a slightly larger thickness increase in males (22.9µm/year, 0.8%) compared with their female counterparts (17.8µm/year, 0.6%), the previously observed increase in patellar cartilage volume was proportionally much larger than the thickness increases observed in the current 7
study in late adolescence. The larger growth in subchondral bone plate area in adolescent males (13.4mm, 12.5%) and females (15.0mm, 18.1%) in our cohort, and the later age spectrum of our participants (peak cartilage accrual occurs in early adolescence [6]) may explain this difference in cartilage development. Nevertheless, data from the current study clearly affirms that patellar and trochlear cartilage thickness and subchondral bone plate area (and not only volume) increase similarly in both males and females during adolescence. Patellofemoral cartilage appears to undergo similar changes as tibiofemoral cartilage in late adolescence. The 0.6-0.8% increase in patellar and trochlear cartilage thickness observed in the current analysis corresponds with a 0.4-2.2% increase in tibia and femur cartilage thickness increase previously observed in the tibiofemoral joints of the same athletes [9] (no sex-specific differences in either compartment). In contrast, the subchondral bone plate area of the patellar increased annually (1.21.4%) more than twice that of the trochlea (0.4-0.5%), and more than tibiofemoral cartilage (0.2-0.9%) [9]. The larger changes in the patella may relate to the unique properties of the patella, which displays the thickest knee cartilage [17], potentially due to the high pressure per unit of area it experiences [18]. At baseline, men (adolescent and mature) generally displayed 20-30% greater patellar and trochlear cartilage thickness and subchondral bone plate area than women, with these findings extending similar sex-specific data in adolescents [7] and young non-athletic individuals aged ~22 years [17]. Despite continued cartilage thickness growth in the adolescents, baseline cartilage thickness was similar between adolescent and mature athletes, likely indicating that the mature athletes are already in a stage of cartilage thinning. The activity levels at the time of assessment differed between adolescent (volleyball twice per day) and mature athletes (volleyball twice per week), however the loading history at the comparable age was almost identical (i.e., mature athletes were elite volleyball athletes when younger). A greater physical activity level in the older athletes at the time of assessment would likely exacerbate the observed cartilage loss, as high impact activity is associated with greater cartilage strain and hence potential deterioration [11].
8
It may not be surprising that T2 values of deep and superficial patellar cartilage were relatively stable in the adolescent athletes, with small changes likely reflecting organizational changes in the collagen matrix. Adolescent males displayed similar (<5% greater) patellar cartilage T2 than adolescent females at baseline, which was also observed in tibiofemoral cartilage T2 in these athletes [10]. The significant (4–7%) increases in patellar cartilage T2 in mature males was accompanied by a significant loss of cartilage thickness, indicating both cartilage morphological and compositional deterioration. Although cartilage thickness loss was also observed in mature women, this occurred at a lower rate than in men, and no significant change in patellar cartilage T2 was observed in these women. The fact that these changes were not closely matched between mature male and females may reflect the 35% greater body mass in mature males, which is a potent risk factor for cartilage loss and incident KOA [19]. While similar to tibiofemoral cartilage from the same athletes (~50msec) [10] and to some previous patellar cartilage T2 data in healthy adults (~42msec) [20], and those with asymptomatic knees with osteoarthritis risk factors (~47msec) [11], our T2 values were higher than in other studies of adolescents and adults [7, 21, 22]. The higher T2 values we observed most likely reflect differences in field strength (T2 relaxation times higher with 1.5T compared with 3T) [23] or the use of more sophisticated fitting methods by previous studies, which result in systemically shorter T2 times [24]. These patellar T2 values from other research groups may be systematically lower due to different computational methods used. Importantly, the observed spatial heterogeneity (and greater superficial than deep T2 values) is in agreement with previous studies that also reported adequate test-re-test precision of layer-specific T2 evaluation [3, 15]. The annualized percent changes in adults were also consistent with previous patellar T2 changes in healthy adults [20]. The small gains we observed in adolescent cartilage thickness contrast the relatively rapid loss of cartilage following ACL injury in young adults, particularly in the trochlea. Over the first year after sustaining an ACL rupture, trochlear cartilage thinned by 1.4% (and patellar cartilage thinned by 0.3%) [25]. Although the cohort of ACL injured knees was slightly older (mean age 26 years), in the context of our results in adolescent knees, the previously observed patellofemoral cartilage thinning is likely 9
to be directly related to the ACL injury. This has important clinical implications, as early posttraumatic patellofemoral cartilage thinning has been linked to worse patient-reported symptoms and function [26], and is likely associated with the development of early-onset patellofemoral OA [27, 28]. Limitations of this study are the modest sample size and that no non-athletic controls were examined to evaluate the specific effect of exercise. The unique study design examining elite volleyball athletes limited the number of available participants, but ensured similar levels of physical activity in men and women. Our results from this highly physically active group also enable comparison to young athletes following a knee trauma as these injuries typically occur in individuals with high physical activity levels. Due to the small sample size, we focused our analysis on longitudinal changes, and used nonparametric statistical tests without adjustment for body size. This also enabled direct comparison to unadjusted tibiofemoral cartilage changes observed in these athletes previously [9, 10]. Greater physical activity levels have been shown to be related to larger patellar cartilage volume accrual in children, but when added to a multivariate model, physical activity explained little (<10%) of the variance in cartilage accrual [6]. It is important to note that the annualized change in cartilage thickness and subchondral bone plate area were much smaller than the standard deviation of the baseline measurements. This was also observed in patellar and trochlear cartilage thickness measures in the first year following ACL injury, and likely reflects the large between-subject variability in cartilage morphology [25]. Finally, all images were acquired on a single 1.5T scanner. Greater MRI field strength provides higher resolution images, reducing the noise and mean values of T2 relaxation times [23], which may partly explain our higher T2 values compared with previous measurements at 3.0T [21, 22]. Cartilage thickness measures taken at 1.5T and 3.0T are very highly correlated (r≥0.96) suggesting that it is unlikely that a higher resolution scanner would have resulted in different conclusions regarding cartilage thickness [29]. CONCLUSIONS In conclusion, patellar and trochlear cartilage thickness and subchondral bone plate area were observed to increase significantly in young athletes towards the end of adolescence, while cartilage 10
composition (T2) was relatively stable, with no significant sex-specific differences. Mature athletes displayed patellar cartilage loss, which, in males, was accompanied by significant patellar compositional changes, potentially reflecting early degenerative changes. These findings on cartilage maturation in adolescent athletes, put in context with the same measures observed in mature adults, cast light on developmental aspects of joint and cartilage morphology during late adolescents, and may help interpret findings in subjects suffering knee trauma (i.e. ACL rupture), an injury typically seen in athletes of this age. AUTHOR CONTRIBUTIONS All authors made substantial contributions to all three sections: (i) the conception and design of the study, data acquisition, analysis and interpretation; (ii) drafting the article or revising it critically; (iii) final approval of the version to be submitted. ROLE OF THE FUNDING SOURCE ACKNOWLEDGEMENTS The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7-NMP-2008-Large-2) under grant agreement No. 228929 (Nano Diara). Adam Culvenor was supported by postdoctoral funding from a European Union Seventh Framework Programme (FP7-PEOPLE-2013-ITN) under grant agreement No. 607510 (KNEEMO), and National Health and Medical Research Council of Australia (1121173). The sponsors were not involved in the study design, interpretation of data, writing of the manuscript or the decision to submit the manuscript for publication. The funding bodies had no involvement in study design, interpretation of data, writing of the manuscript or the decision to submit the manuscript for publication. REFERENCES [1] A.G. Culvenor, J.L. Cook, N.J. Collins, K.M. Crossley, Is patellofemoral joint osteoarthritis an underrecognised outcome of anterior cruciate ligament reconstruction? A narrative literature review, Br J Sports Med. 47 (2013) 66-70.
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[29] F. Eckstein, H.C. Charles, R. J. Buck, V. B. Kraus, A. E. Remmers, M. Hudelmaier, W. Wirth, J. L. Evelhoch, Accuracy and precision of quantiative assessment of cartilage morphology by magnetic reonsance imaging at 3.0T, Arthritis Rheum. 52 (2005) 3132-6. TABLE TITLES Table 1. Adolescent and mature volleyball athletes: baseline demographics and values of patellofemoral cartilage thickness, T2 and subchondral bone plate area in men and women (mean ± standard deviation) Table 2. Male and female adolescent and mature athletes: annualized longitudinal change in patellofemoral cartilage thickness, T2 and subchondral bone plate area
FIGURE LEGENDS Figure 1. Assessment of patellar and trochlear cartilage segmentation and patellar T2 relaxation time: A) spin echo acquisition with the shortest echo time (9.7msec); B) patellar and trochlear subchondral bone area (green contour) and cartilage surface (magenta contour), with the trochlea separated from the femoral condyles by 3D plane through the trochlear notch in parallel with the femoral shaft (red line); C) superficial and deep patellar cartilage layers; and D) patellar cartilage T2 relaxation times.
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16
17
Figr-1
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Table 1. Adolescent and mature volleyball athletes: baseline demographics and values of patellofemoral cartilage thickness, T2 and subchondral bone plate area in men and women (mean ± standard deviation) Region
Adolescent Men (n=10)
Mature Women
Men (n=10)
(n=10)
Women (n=10)
Age, years
16±1
16±1
46±3
47±6
Height, cm
193±4
182±4
191±5
176±5
Weight, kg
83±4
70±9
96±13
71±6
Patella
2.96±0.39
2.87±0.24
2.72±0.18
2.25±0.31
Trochlea
2.53±0.29
2.09±0.22
2.32±0.32
1.86±0.14
Patella
10.72±1.29
8.29±1.12
11.01±1.90
9.15±0.57
Trochlea
28.23±2.72
21.47±1.89
25.78±2.29
21.40±1.76
Patella
53.0±1.5
50.7±2.2
54.0±3.7
55.5±2.8
45.2±1.5
43.7±2.1
46.1±3.8
47.6±2.8
Cartilage thickness, mm*
Subchondral bone plate area, cm2*
T2 times, ms§
superficial Patella deep
* Cartilage morphology measures missing in one adolescent woman due to limited image quality at baseline § Patellar T2 values missing in 2 adolescent men and 1 mature man due to missing T2 image acquisition
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Table 2. Male and female adolescent and mature athletes: annualized longitudinal change in patellofemoral cartilage thickness, T2 and subchondral bone plate area Region
Men
Women
p-value*
Mean (95%CI)
Mean (95%
Males vs
CI)
Females
22.9 (16.5,
17.8 (10.3,
0.604
29.3)
25.3)
19.9 (13.2,
12.2 (6.2,
26.6)
18.2)
Patella
1.3 (1.1, 1.6)
1.5 (0.9, 2.1)
0.661
Trochlea
1.1 (0.3, 1.9)
1.1 (0.7, 1.6)
0.905
Patella
-0.3 (-0.6, 0.0)
0.8 (0.4, 1.2)
0.173
Patella deep
0.3 (-0.2, 0.8)
1.3 (0.7, 1.9)
0.515
Patella
-22.8 (-28.5, -
-11.1 (-1.7, -
0.631
17.1)
20.5)
-0.9 (-1.6, 0.3)
-0.1 (-0.6,
Adolescent athletes Cartilage thickness
Patella
change, µm Trochlea
Subchondral bone plate
0.447
area change, mm2
T2 change, ms
superficial
Mature athletes Cartilage thickness change, µm Trochlea
0.579
0.4) Subchondral bone plate
Patella
1.6 (1.2, 1.9)
0.5 (0.2, 0.6)
0.035
Trochlea
1.3 (0.8, 1.9)
0.5 (0.1, 0.9)
0.529
Patella
2.2 (1.5, 2.9)
0.0 (-0.3, 0.3)
0.013
3.4 (2.6, 4.2)
0.1 (-0.4, 0.5)
0.002
area change, mm2
T2 change, ms
superficial Patella deep
* Mann-Whitney U-test to evaluate sex-differences using absolute change cartilage parameters. Evaluation of sex-differences using percentage change resulted in generally the same p-values.
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