Department of Epidemiology and Preventive Medicine, Monash University Medical School, Alfred Hospital, Prahran 3181,
1 MRI Unit, Mayne Health Diagnositc Imaging Group, Epworth Hospital, Richmond 3121 and
2 Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Parkville 3050, Australia
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Abstract |
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Methods. We conducted a cross-sectional study to determine factors influencing knee cartilage volume in 45 males aged (mean±S.D.) 52.5±13.2 yr.
Results. Total and medial tibial volumes were inversely associated with age, body mass index (BMI) and amount of physical activity and positively associated with total bone content. BMI explained the largest amount of the variation in tibial cartilage volume (18.7%). There were similar findings at the lateral tibial cartilage, but for age and total bone content this did not reach statistical significance. There was a positive association with serum testosterone at all tibial cartilage sites, but this only reached statistical significance for medial tibial cartilage, where serum testosterone explained up to 8% of the variation in cartilage volume.
Conclusions. Modifiable risk factors of osteoarthritis also appear to be significant determinants of tibial cartilage volume. Serum testosterone may provide one possible explanation for gender differences in tibial cartilage volume and prevalence of tibiofemoral osteoarthritis. The proposed link between osteoarthritis and knee cartilage volume and the effect of testosterone will need to be confirmed in longitudinal studies.
KEY WORDS: Knee, Cartilage, Risk factors, Men.
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Introduction |
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Recent data have suggested a role for hormonal factors on knee cartilage volume. We have recently shown that women on long-term hormone replacement therapy (HRT) have 10% more knee cartilage than age-matched women not on HRT [5]. Gender differences in knee cartilage volume cannot be explained by differences in body size alone [1, 2] or level of physical activity [2], suggesting a role for hormonal factors. There are no studies relating hormones to knee cartilage volume in men. Marked gender differences in knee cartilage have been shown [1, 68].
A number of factors have been shown to impact on the risk of developing OA. We postulated that these factors might also affect knee cartilage volume. If so, perhaps knee cartilage volume may be used as a potential interim endpoint in studies of OA. We therefore conducted a cross-sectional study to determine what factors, including hormonal factors, affect knee cartilage in male adults.
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Patients and methods |
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Knees were imaged in the sagittal plane on a 1.5-T whole-body magnetic resonance unit (Signa Advantage Echospeed, GE Medical Systems, Milwaukee, WI, USA) using a commercial transmit-receive extremity coil. Knee cartilage volume was measured by two independent observers by means of image processing on an independent work station using the software program Osiris as previously described [1, 2]. The coefficients of variation for total, medial and lateral cartilage volume measures were 2.6, 3.3 and 2.0%, respectively. Medial and lateral tibial plateau areas were determined by creating an isotropic volume from the input images. This was reformatted in the axial plane. The areas were directly measured from these images [2]. Coefficients of variation were 2.3% for medial and 2.4% for lateral tibial plateau areas [2]. MRI scans were examined for features of OA as previously described [10].
Early morning blood samples were taken from all subjects. Serum specimens were stored at -20°C. Total testosterone was measured by radioimmunoassay (DPC Coat-A-Count® Total Testosterone kit). Free testosterone in picomoles (pM) was calculated using the Sodergard equation [11]. The intra- and interassay coefficients of variation were 9.8 and 15.6%, respectively. Sex hormone-binding globulin (SHBG) was measured by immunoradiometric assay (Orion® SHBG kit). The intra- and interassay coefficients of variation were 3.2 and 11.3%, respectively. Dehydroepiandrosterone sulphate (DHEAS) was measured by a DPC Immulite® autoanalyser. The intra- and interassay coefficients of variation were 9.5 and 13%, respectively. Oestradiol was measured by a DPC Immulite® autoanalyser. The intra- and interassay coefficients of variation were 4 and 5%, respectively. Luteinizing hormone (LH) was measured by Abbot AxSym® autoanalyser. The intra- and interassay coefficients of variation were 5.1 and 7.7%, respectively. Total body bone mineral content was measured by dual energy x-ray absorptiometry using a Hologic QDR 1000 W densitometer. The laboratory results were analysed blind to the clinical data.
Statistical analysis
Linear regression was used to examine the effect of age, sex, BMI, physical activity and total bone mineral content on total (medial+lateral) tibial cartilage, medial and lateral tibial cartilage volumes in univariate analyses and in a multivariate model. Cartilage volume is expressed in ml/cm2 to adjust for the significant effect of bone size on cartilage volume, providing an average cartilage thickness over the bone area to enable comparison between individuals. Results are presented as regression coefficients that represent differences in cartilage volume per unit change in the relevant explanatory factor, while other factors are held constant (i.e. controlled for). Tibial, medial and lateral cartilage volumes per cm2 were regressed against various serum hormone levels. Multivariate regression models were then constructed adjusting for known demographic predictors, namely age, BMI, physical activity and total bone mineral content. A P value <0.05 was considered to be statistically significant. Statistical analysis was performed using SAS Version 8.0 (SAS Institute Inc., Cary, NC, USA).
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Results |
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Discussion |
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Age is a well known risk factor for knee OA [12]. There is evidence for a negative association between age and knee cartilage volumes in post-menopausal women, a mixed gender group of 52 subjects with OA and 40 subjects without OA, and in a study of men only [5, 7, 13]. An autopsy study of joint cartilage found similar results [14]. In our study of men, we demonstrated a significant inverse association between age and total tibial cartilage and medial tibial cartilage. At the lateral tibial cartilage there was an inverse, although not statistically significant, association with age. It may be that the effect of age is not as strong at this site in men.
Although elevated BMI is an established risk factor for knee OA, little is known about its relationship to knee cartilage volume [1517]. We found increased BMI was associated with a reduction in tibial cartilage volume at all sites. In post-menopausal women, BMI contributes significantly to the variation in lateral and total tibial cartilage volume [5]. Consistent with our findings relating to cartilage volume, a previous study in a mixed gender group showed that body weight was inversely related to cartilage thickness in the hip [18].
The effect of physical activity on the risk of OA is unclear, although a number of studies suggest that previous and current high levels of physical activity are associated with knee OA [9, 19]. In this study, higher current levels of physical activity were associated with a reduction in tibial cartilage volume. In contrast, in children we have shown a positive association between physical activity and tibial cartilage volume [2]. It may be that there are age-related differences in the effect of physical activity on knee cartilage. Total bone mineral content was associated with total tibial and medial cartilage volume. This has not previously been examined, although a number of studies have suggested an inverse relationship between osteoarthritis and osteoporosis [1517]. However, these studies have mainly been in women rather than men. The Baltimore Longitudinal Study on ageing showed that the adjusted mean bone mineral content and radial width were increased in men with knee OA [20].
In this study we showed a positive association between medial tibial cartilage and serum testosterone levels. A similar, but non-significant, effect was observed for total tibial cartilage and lateral tibial cartilage. Few data are available on the effect of testosterone on joint cartilage or OA, despite its effects on other musculoskeletal tissues being better characterized [21, 22]. Decreasing testosterone level was found to be significantly associated with increasing hand OA scores in 573 women aged 2445 yr participating in the Michigan Bone Health Study [23]. Testosterone receptors have been shown to be present in cartilage in humans [20]. As with the effect of other sex hormones on cartilage, the effect of testosterone may differ according to the developmental age of the organism, and sometimes differs according to gender [2426].
There are a number of potential limitations in using MRI for cartilage volume estimates. The accurate delineation of articular cartilage depends on high contrast relative to adjacent tissues. We used a previously validated fat-suppressed gradient echo sequence [1, 2]. Furthermore, as has previously been recommended [27] in order to improve in-plane resolution we used a matrix of 512x192 pixels, resulting in an in-plane resolution of 0.31x0.83 mm. The reproducibility of our measurements was comparable with previously reported work [28]. In this study we have used tibial cartilage as the measure of joint cartilage at the tibiofemoral joint. We have shown strong correlation between the tibial and femoral cartilage in the medial and lateral tibiofemoral joint compartments [29]. The femoral cartilage articulates the medial and lateral tibiofemoral and the patellofemoral joints; it is difficult to identify the relevant component of femoral cartilage when assessing the respective tibiofemoral joints. In contrast, each of the tibial cartilages only forms part of one joint. Another limitation of our study is that we only included men. Our findings cannot be generalized to women since the associations may be gender specific. Few subjects had knee osteoarthritis. Repeating our analyses excluding these men did not change the magnitude or direction of our findings. There may also be important interactions between sex hormones in their effect on tibial cartilage; however our sample size was too small to examine this, particularly since there is large between-subject variability in cartilage volume [30].
Although we used calculated free testosterone values derived from total testosterone and SHBG, we found similar relationships between total testosterone and tibial cartilage volumes. Despite there being a relatively weak association with free testosterone, no such association existed between cartilage volumes and oestrogen. This suggests that testosterone may have more important effects on tibial cartilage than oestrogen, while the reverse is true for bone where about two-thirds of the bone resorption rate is accounted for by oestrogen [31].
Our data suggest that the modifiable risk factors of OA also appear to be significant determinants of tibial cartilage volume in men. If so, perhaps knee cartilage volume may be used as a potential interim endpoint in studies of OA. However, the proposed link between OA and knee cartilage volume will need to be confirmed in longitudinal studies directly relating these variables.
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Acknowledgments |
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Notes |
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References |
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