Association between knee cartilage volume and bone mineral density in older adults without osteoarthritis

F. Cicuttini, A. Wluka, S. Davis1, B. J. G. Strauss2, S. Yeung3 and P. R. Ebeling3

Department of Epidemiology and Preventive Medicine, Monash University Medical School, Alfred Hospital, Prahran 3181, 1 Jean Hailes Foundation, Clayton, Victoria, 2 Department of Medicine, Monash Medical Center, 3 Departments of Diabetes and Endocrinology, and Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville 3050, Australia.

Correspondence to: F. Cicuttini, Department of Epidemiology and Preventive Medicine, Monash University, Alfred Hospital, Prahran, Victoria, 3181, Australia. E-mail: flavia.cicuttini{at}med.monash.edu.au


    Abstract
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 Abstract
 Introduction
 Methods
 Statistics
 Results
 Discussion
 References
 
Objectives. Studies have suggested an inverse association between osteoarthritis (OA) and osteoporosis, based on the presence of osteophytes rather than joint space narrowing (JSN), an indirect measure of joint cartilage. We conducted a cross-sectional study to determine the relationship between knee cartilage volume, a direct measure of joint cartilage, and bone mineral density (BMD) in an adult population.

Methods. 86 adults aged 55.1±10.4 years (50% females) had total BMD and bone mineral content (BMC) measured using dual X-ray absorptiometry. Site-specific BMD was performed on men in the study. Tibial and patella cartilage volumes were determined by processing images acquired in the sagittal plane using T1-weighted fat saturation magnetic resonance on an independent work station.

Results. Tibial knee cartilage volume was positively associated with total body BMD in both men and women after adjusting for age, BMI, tibial bone area and physical activity. In men, tibial cartilage volume was positively associated with proximal femur BMD, but not lumbar spine BMD. No relationship was seen between patellar cartilage volume and BMD at any region.

Conclusions. We have shown a positive association between tibial cartilage volume and total BMD in men and women, but no such association with patellar cartilage volume. The mechanism for this is unclear but may represent a common environmental or genetic component. This study also highlights the need to examine the osteophyte and joint cartilage separately when investigating factors affecting the joint in health and disease since each feature is likely to reflect different aspects of the pathogenic process in OA.

KEY WORDS: Knee cartilage, Bone mineral content, Bone mineral density.


    Introduction
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 Abstract
 Introduction
 Methods
 Statistics
 Results
 Discussion
 References
 
Osteoarthritis (OA) and osteoporosis are two of the most common diseases of ageing. A number of studies have suggested that there is an inverse association between these two diseases [15]. Cross-sectional studies using bone densitometry and radiographs have shown that the prevalence of radiographic knee and hip OA, especially when defined in terms of osteophytes, increases with increasing bone mineral density (BMD) [15]. A recent prospective study has given further support for this by demonstrating that a higher BMD increases the risk of incident radiographic knee OA in older women [6]. However, other studies indicate that despite a higher than average bone mass, women with larger joint OA do not have the reduced risk of fracture which a higher bone mass should confer [7, 8].

Recently, a cohort study of white women showed that baseline BMD at the lumbar spine and hip was significantly higher in women who subsequently developed incident knee osteophytes, supporting previous cross-sectional studies [9]. In addition this study suggested that high BMD was associated with the development of osteophytes, but not joint space narrowing. This suggests that high bone density may have a different relationship to the development of osteophytes than cartilage loss because different pathogenic mechanisms may be involved.

The relationship between BMD and articular cartilage has been difficult to establish, largely due to the difficulties in accurately assessing cartilage. Radiology of the knee provides us with an indirect assessment of joint cartilage and is subject to potential measurement problems [10, 11]. Recently, magnetic resonance imaging (MRI) has been shown to be a simple, safe and non-invasive technique for measuring knee cartilage volume [12, 13] in vivo. Knee cartilage volume as measured by MRI has being shown to be valid, when compared with direct anatomical dissection and measurement of cartilage [12, 13], and reproducible [12, 13], with a coefficient of variation of 2% [14]. We have also shown that cartilage volume correlates strongly with radiographic grade of OA [15] and change in knee cartilage volume correlates with change in knee symptoms [16]. We conducted a cross-sectional study to determine the relationship between volume of knee cartilage in normal men and women and total body BMD. In men, we also determined the relationship between knee cartilage volume and BMD at the spine and proximal femur.


    Methods
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 Abstract
 Introduction
 Methods
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 Discussion
 References
 
Normal subjects were recruited through advertising in newspapers, through sporting clubs, and through the hospital staff association. Subjects were excluded if any form of arthritis other than OA present, including evidence of chondrocalcinosis on plain films or evidence of focal cartilage lesion on MRI to suggest a post-traumatic aetiology. Subjects were excluded if they had a contraindication to MRI, hemiparesis of either lower limb or planned total knee replacement.

Subjects completed a questionnaire that included demographic data, past medical and surgical history, current physical activity [17] and smoking history. Weight was measured to the nearest 0.1 kg using a single pair of electronic scales with shoes, socks and bulky clothing removed. Height was measured to the nearest 0.1 cm using a stadiometer with shoes and socks removed. Body mass index (BMI) [weight/height2 (kg/m2)] was calculated. Total body bone mineral density (TB-BMD) was measured in all subjects using dual X-ray absorptiometry (DXA; Hologic QDR 1000 W). The coefficient of variation for total body BMD was 1.2–1.3% [18]. In the men, BMD was also measured at the following sites: lumbar spine, total hip, femoral neck, Ward's triangle, trochanteric and inter-trochanteric. The in-vitro and in-vivo coefficients of variation were 0.38% and 1% at the lumbar spine and 0.38% and 1.7% at the femoral neck, respectively [19].

Each subject had an MRI performed on their dominant knee, defined as the lower limb from which they stepped off when walking. Knee cartilage volume was determined as previously described [14]. Knees were imaged in the sagittal plane on a 1.5 T whole body magnetic resonance unit (Signa Advantage HiSpeed GE Medical Systems Milwaukee, WI) using a commercial transmit–receive extremity coil. The following sequence and parameters were used: a T1-weighted fat-suppressed 3D gradient recall acquisition in the steady state, flip angle 55°, repetition time 58 ms, echo time 12 ms, field of view 16 cm, 60 partitions, 512 x 196 matrix, one acquisition time 11 min 56 s. Sagittal images were obtained at a partition thickness of 1.5 mm and an in-plane resolution of 0.31 x 0.08 mm (512 x 512 pixels). The image data were transferred to a workstation. The volumes of the individual cartilage plates (medial and lateral tibial and patella) were isolated from the total volume by manually drawing disarticulation contours around the cartilage boundaries on each section. These data were resampled by bilinear and cubic interpolation (area of 312 x 312 µm and 1.5 mm thickness, continuous sections) for the final 3D rendering. The volume of the particular cartilage plate was determined by summing the pertinent voxels within the resultant binary volume. A trained observer read each MRI. The coefficients of variation for medial and lateral tibial cartilage volume and the patella cartilage were 2.6, 3.3 and 2.0% respectively. Total tibial cartilage volume is the sum of the medial and lateral tibial plate. The patella bone volume was measured in an analogous way to the tibial cartilage. The coefficient of variation for patella bone volume was 2.2%. The tibial plateaux area was determined by creating an isotropic volume from the three input images closest to the knee joint which were reformatted in the axial plane. The area was directly measured from these images. The CV for the tibial plateau area was 2.3% [14, 15].

Ethics approval was obtained from the Alfred Hospital Ethics Committee.


    Statistics
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Descriptive statistics for characteristics of the subjects were tabulated. Independent t-tests were used for comparison of means. The {chi}2 test was used to compare nominal characteristics between the groups. The outcome variables, tibial cartilage and patella volume, were initially assessed for normality before being regressed against various measures of BMD and composition. Multivariate regression models were then constructed adjusting for known demographic predictors including age, gender, BMI, bone size (either tibial bone area or patella bone volume) and current level of physical activity. A P value< 0.05 was considered to be statistically significant. All analyses were performed using the SPSS statistical package (version 10.0.5, SPSS, Cary, NC) with a P value less than 0.05 considered to be statistically significant.


    Results
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Baseline characteristics of the population are presented in Table 1. Five subjects had OA according to ACR criteria (two females, three males). The men were slightly older than the women, weighed more, although their BMI was similar, and were more physically active. The men had significantly larger tibial and patella cartilage volumes, tibial bone area, patella bone volume, total bone density and content.


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TABLE 1. Characteristics of participants [mean (S.D.)]

 
Tibial knee cartilage volume was associated with TB-BMD and bone mineral content (BMC) after adjusting for confounders (age, gender, tibial bone size and level of physical activity) (Table 2). This finding was consistent when men and women were examined separately. This relationship persisted, with similar magnitude, when the subjects with OA were excluded from the analyses (data not shown). No such relationship was shown between patella cartilage volume and TB-BMD after adjusting for the same confounders (Table 2).


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TABLE 2. Relationship between tibial and patella knee cartilage volume and TB-BMD in normal men and women

 
In the men, data were also available on site-specific BMD (Table 3). Tibial knee cartilage volume was associated with hip (total, femoral neck, trochanteric, inter-trochanteric and Ward's triangle) BMD. No such association existed between knee cartilage volume and lumbar spine BMD. Following adjustment for age, BMI, tibial bone size and physical activity, the strength of association was increased. After adjusting for these, total body and hip BMD accounted for 13 and 16% of variation in tibial knee cartilage volume. After excluding the subjects with OA, there were no differences in this association.


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TABLE 3. Relationship between tibial knee cartilage volumea and site specific measures of bone mineral density (BMD) in men

 
Since using BMD may lead to spuriously higher values in larger subjects who have larger bones and this may not be entirely corrected by adjusting for BMI, we repeated the analyses using femoral neck and lumbar spine BMD at the third lumbar vertebra corrected for bone volume at each site. There was a significant association between tibial bone cartilage volume and femoral neck BMD corrected for bone volume after adjusting for age, BMI, tibial bone size and physical activity (regression coefficient 0.46, P = 0.02). There was no significant association between tibial bone cartilage volume and lumbar spine BMD at the third lumbar vertebra corrected for bone volume after adjusting for age, BMI, tibial bone size and physical activity (regression coefficient 0.05, P = 0.40). No positive association was seen between patellar cartilage volume and BMD in any region (data not shown).


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Statistics
 Results
 Discussion
 References
 
In this study, tibial knee cartilage volume was positively associated with total body BMD in both men and women after adjusting for age, BMI, tibial bone area and level of physical activity. Tibial cartilage volume was also positively associated with hip (total, femoral neck, trochanteric, inter-trochanteric and Ward's triangle) BMD in men. However, there was no association between knee cartilage volume and lumbar spine BMD in men. Following adjustment for age, BMI, tibial bone size and physical activity the strength of association was increased, with total body and hip BMD accounting for 13 and 16% of variation in tibial knee cartilage volume, respectively. By contrast, no relationship was seen between patellar cartilage volume and BMD in any region in men or women.

No previous study has examined the relationship between knee cartilage volume and bone mineral density and content in a healthy population. Previous studies have been based on radiological assessment of joints and BMD. Most such studies have shown a positive association between radiographic OA, based on the presence of osteophytes, and BMD [15]. However, no study has demonstrated a relationship between BMD and joint space narrowing, an indirect measure of articular cartilage. In our study, we have used tibial cartilage volume to directly measure articular cartilage, which has recently been shown to correlate with joint space narrowing but not osteophytes [15]. In contrast to previous studies which have essentially shown a positive relationship between BMD and osteophytes, our study has shown a positive relationship between tibial cartilage volume and both BMD and BMC. This is further supported by the observation that despite the previously described inverse association between OA and osteoporosis, there is no evidence that those with OA are less likely to fracture [7, 8] or that treatment of osteoporosis had adverse effects of risk of OA [20]. In contradistinction, studies are now under way to determine whether risedronate, a bisphosphonate that reduces bone turnover, can also reduce the progression of knee OA.

When we examined the relationship between tibial cartilage volume and BMD at specific sites in men, we found an association at all hip BMD sites (total hip, femoral neck, Ward's triangle, trochanteric, and inter-trochanteric). However, no association was found with lumbar spine BMD. Site specificity has previously been observed at other sites such as the radius, where BMD was not associated with knee OA in either gender [1, 3, 21]. The association between hip BMD and tibial cartilage volume could relate to the presence of osteophytes. However, this is unlikely to be the case. The prevalence of hip OA is likely to be lower than that of knee OA, which was 5.8%. The relationship also held for femoral BMD as well as trochanteric BMD, inter-trochanteric BMD and Ward's triangle BMD where femoral osteophytes are less likely to influence the results. The prevalence of lumbar osteophytes is likely to be more than the prevalence of knee osteophytes. However, we did not find a relationship between lumbar BMD and cartilage volume.

In contrast to the findings with tibial cartilage, our study showed no association between patella cartilage volume and BMD in either men or women. No previous study examined associations between the patellofemoral joint and bone mineral density. There is some evidence that risk factors for patellofemoral OA are different from those important to the development of tibiofemoral OA [22]. It may be that factors influencing the development and maintenance of patella cartilage even in healthy subjects differ from those important for tibial cartilage.

Our study included both healthy men and women. However, site-specific BMD measurements were only performed on men. Nevertheless, the main findings in relation to total body BMD and total body BMC were the same for both groups. Using BMD may lead to spuriously higher values in larger subjects who have larger bones and this may not be entirely corrected by adjusting for BMI. However, we observed a similar association between cartilage volume and volumetric femoral neck and lumbar spine BMD. Our subjects were generally healthy, with few having knee OA. Repeating our analyses excluding these subjects did not change the magnitude or direction of our findings. It may be that the relationship between OA and osteoporosis differs between normal subjects and those with disease. Our numbers are too small to separately examine the subgroup with radiological OA. However, our measure of cartilage volume directly visualized the articular cartilage and is a more sensitive method than radiography for assessing articular cartilage. We have recently shown that tibial cartilage volume correlates with joint space narrowing rather than osteophytes [15] and that those who have grade 1 joint space narrowing have already lost up to 11–13% of their tibial cartilage [23]. This suggests that the definition of OA and those pre-disease may not be as clear-cut as previously thought.

Further work is needed to clarify the role of the osteophyte in the pathogenesis of OA. OA is believed to be a disease that results from changes in the articular cartilage and osteophytosis may play a peripheral role in the pathogenesis of OA, developing after the initial changes in cartilage [24]. Osteophytes are part of the proliferative bone response, and arise from enchondral ossification and bony metaplasia of new cartilage that forms at the bone margins [24]. The potential over-reliance on the osteophyte in scoring of OA at the knee for epidemiological studies may in part be the result of the weaker performance of radiological joint space narrowing as a measurement tool at the knee. By contrast, assessment of minimum joint space narrowing is the optimum method for assessing OA at the hip [25]. This may reflect differences in measurement performance of the joint space at these two sites. In support of this, we have recently shown that change in cartilage volume over 2 yr correlated with change in symptoms over that time [16]. We have also recently shown that those with grade 1 joint space narrowing have already lost up to 11–13% of their tibial cartilage while grade 1 osteophytosis was associated with substantial increases in lateral and medial tibial bone surface area (adjusted mean difference 10–16%) [23]. In contrast, osteophytosis was not associated with a significant change in cartilage volume and joint space narrowing was not associated with a significant change in tibial bone area. It may be that a better understanding of the epidemiology of articular cartilage in health and disease will be possible using newer measures such as cartilage volume.

The association between tibial cartilage volume and BMD observed in this study may be explained by shared common genetic determinants or, alternatively, environmental determinants. Regarding potential environmental determinants, there is some evidence for knee cartilage volume to be positively associated with physical activity, both in children [26] and adults [27]. In this study, physical activity correlated with both BMD and cartilage volume. The positive associations between tibial cartilage and TB-BMD remained even after adjusting for physical activity. This suggests that it is a confounder and, at best, is not the explanation for the common environmental effect. However, we only measured current level of physical activity and it may be that the lifelong level of activity is also important. We also showed no association between patella cartilage volume and BMD at any site. This further suggests that it is unlikely that physical activity alone can explain the association between tibial cartilage and hip and total body BMD since the available evidence suggests a positive effect of exercise on both tibial and patella cartilage [26]. It is possible that our results can be explained by confounding due to body size. However, in this study we adjusted for gender, BMI and bone size in order to take into account differences in bone and body size. Furthermore, the direction and magnitude of the relationship between tibial and patella knee cartilage volume and total BMD and total BMC were essentially unchanged when men and women were examined separately (data not shown).

An alternative explanation for the relationship between tibial cartilage volume and BMD is that it is due to a common genetic mechanism. This is likely given that osteoblasts and chondrocytes are of mesodermal origin and originate from a common progenitor cell called an osteochondroprogenitor [28]. Many genes control chondrocyte differentiation, but only a handful have been yet identified that control osteoblast differentiation. These are RUNX2 (CFBA1) and SP7 (Osterix), while the LRP5 (low density lipoprotein receptor-related protein 5) signalling pathway controls osteoblast proliferation [29]. Further work using the twin model and family studies will be needed to determine the relative importance of genetic and environmental factors on cartilage volume and bone mass.

Our study has shown a positive association between tibial cartilage volume, but not patellar cartilage, and TB-BMD in healthy men and women. In the men, we showed that the relationship between tibial cartilage volume predominated at the hip, but not at the lumbar spine. In contrast to the studies showing a positive relationship between osteophytes and BMD, no previous study has demonstrated a relationship between BMD and joint space narrowing, an indirect measure of articular cartilage volume. This study also highlights the need to examine the osteophyte and joint cartilage separately when investigating factors affecting the joint in health and disease since each feature is likely to reflect different aspects of the pathogenic process in OA.

The authors have declared no conflicts of interest.


    Acknowledgments
 
Thanks to Ms Judy Hankin and Ms Vikki White for coordinating the recruitment of participants for this study. This study was funded by the Shepherd Foundation. Special thanks to the study participants who made this study possible.


    References
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 Abstract
 Introduction
 Methods
 Statistics
 Results
 Discussion
 References
 

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Submitted 9 September 2003; revised version accepted 6 February 2004.



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