We found that higher aBMD and vBMD were associated with prevalent RHOA in this cohort of elderly men, and that these differences in BMD measurements were greater in subjects with severe versus moderate RHOA. While aBMD was higher at all measurement sites (total hip, femoral neck, trochanter and lumbar spine) in RHOA groups compared to the controls, a greater percentage difference in vBMD was seen at sites which were composed of predominantly cortical bone. In addition, osteophytic, or osteophyte-predominant, RHOA was associated with a higher vBMD in cortical-predominant sites, while the atrophic RHOA phenotype was not.
These aBMD and vBMD results support previous reports of an association between increased BMD and large joint radiographic OA in subject groups with RHOA compared to those without RHOA. These BMD differences were found both at the site of the OA and distal to it. Nevitt et al (4
) reported a nearly 10% increase in aBMD at the hip in elderly Caucasian women with RHOA, and similarly, Burger et al (3
) reported a higher (3 - 8% increase) in femoral neck aBMD in male subjects with RHOA. A positive association was reported between femoral neck aBMD and hip OA in monozygotic and dizygotic twins, as well (21
). Our vBMD findings differ from a study by Arokoski et al. (11
) that evaluated the association of vBMD measured by MRI and hip OA. The investigators studied 57 men and reported no association between aBMD by DXA or MRI and hip OA, but did find a positive association between BMC and hip OA. Differences in sample size, the technique of vBMD measurement and case definition may account for the different findings between the two studies.
A positive association of osteoarthritis of other large joints, such as the knee, and BMD has also been reported. Female subjects in the Framingham cohort with higher BMD were at greater risk of developing incident knee OA over an 8 year follow-up period than women with low BMD (20
). Similarly, systemic BMD has been reported to be higher in subjects who develop incident knee OA (7
). The present results confirm these reported associations between radiographic OA in a large joint and higher BMD at the site of OA.
We also found aBMD and vBMD to be higher in RHOA subjects compared to controls at the lumbar spine, a site that is anatomically distant from the hip joint. These results are similar to several published reports of lumbar spine aBMD and large joint OA (4
), and suggest that a skeletal phenotype with high BMD may alter loading across large joints and accelerate joint degeneration. However, adjusting for the BMI and physical activity, which should be associated with a possible skeletal phenotype effect, did not change our results.
We also found a significant association between the osteophytic phenotype and both aBMD and vBMD; of note, our DXA and QCT regions of interest were distal to the region of the femoral head where femoral or acetabular osteophytes would be located. Our findings are consistent with other reports (4
) and underscore the potentially different pathophysiology between these two OA phenotypes. One possible explanation for the differences may be explained by the contrasting actions of the wnt pathway on cartilage and bone. The wnt system is a large family of extracellular cysteine-rich glycoproteins, which help regulate embryogenic formation, and in adult cartilage and bone repair. There is evidence from animal studies that wnt signaling has different effects on cartilage compared to bone (24
). Higher serum levels of the wnt antagonist Dickoff-1 (Dkk-1) have been found to be protective against the progression of RHOA in older women (26
) and secreted frizzle-related protein 3 (sFRP-3), another wnt antagonist, may be protective against cartilage injury (26
). These results are intriguing, and the role of wnt signaling in cartilage and bone in relation to the osteophytic and atrophic phenotypes requires further study.
In our study, we used QCT to measure vBMD and examine its association with RHOA. Most published reports on the association of BMD and OA have utilized DXA and reported on aBMD. The development of OA is often characterized by an increase in osteophyte formation at the joint margins and cortical bone modeling resulting in increased cortical thickness on the medial side of the femoral neck; this increased cortical thickness can, in turn, change the size and shape of the bone. These bone changes can lead to inaccuracies in a 2-dimensional measurement of BMD by DXA. In contrast, BMC measures may be less affected by changes in bone size and shape, and may be a more accurate 2-dimensional assessment of bone status in patients with and without OA. This difference may explain why subjects with OA are sometimes found to have increases in BMC but not BMD compared to subjects without OA (28
The lumbar spine QCT vBMD measurement is not affected by inaccuracies of DXA scans such as the inclusion of osteophytes, sclerosis or adjacent aortic calcification (29
). QCT allows the measurement of the cortical and trabecular compartments both together and separately. This distinction is especially relevant as trabecular bone has been reported to be more sensitive to changes in stress loading and subsequent remodeling than cortical bone compartment (30
). QCT may be a more sensitive method to assess pathophysiologic changes in bone as disease evolves. For example, studies of the effect of glucocorticoid use on bone have used QCT to demonstrate a rapid loss in trabecular vBMD followed by a slower loss of cortical vBMD (32
Our aBMD and vBMD findings support a potential role for both trabecular and cortical bone changes in the pathogenesis of OA. Our finding that aBMD was higher in the femoral neck of the hip with prevalent RHOA is consistent with previous reports (3
), and suggests that local trabecular thickening of the principal compressive region (33
) may contribute to higher femoral neck aBMD. Histomorphometric studies support the hypothesis that trabecular bone remodelling in the femoral neck contributes in part to the buttressing the proximal femur against increased hip joint loading (34
We reported that the vBMD in the cortical compartment in the hip was significantly increased compared to controls, and the trabecular compartment vBMD was not. However these results must be interpreted with caution as the proportional change in cortical bone volume was only 3.3% between severe RHOA and mild RHOA, while it was 5.8% in the trabecular compartment. Since the sequence in which trabecular bone changes and cartilage loss occurs is unclear (35
), further investigation is needed to clarify the role of trabecular and cortical changes associated with different phases of RHOA. The relative location and changes in cortical and trabecular vBMD suggest that the pathogenic changes seen in RHOA may be associated with a redistribution of load across the proximal femur.
Our study has several strengths including a well-characterized cohort of elderly men with comprehensive radiographic hip OA and bone mineral density assessments. However there are also a number of weaknesses. The software program’s threshold for measurement of cortical bone volume of 350mg/cm3 may not be optima as the study by Poole et. al (38
) clearly demonstrates that our threshold may over-estimate the cortical bone volume in the hip. However, we used the same threshold for the cases of RHOA and controls, and we detected a significant difference. Therefore, the direction of the association is probably valid but the magnitude of the difference may be different with different software analyses programs. Future studies are needed to confirm and elucidate this association will use different thresholds for cortical bone for a more accurate assessment of the two bone compartments.
Another weakness was that this study was cross-sectional, and associations could only be made with prevalent RHOA. The QCT measurements were done 4.6 years prior to the pelvic radiograph and DXA scans obtained at Visit 2. To insure that no incident RHOA cases were included, QCT scout films of all cases from the baseline visit were reviewed to confirm the presence of RHOA in all cases. While CT is a sensitive measurement of bone features, the scout films were not taken specifically for the assessment of the subject’s hip OA status, and could have been a source of potential bias through inadvertent inclusion of incident RHOA cases. Lastly, this was a cohort of largely Caucasian (91%) older men, and the results are therefore not generalizable to other populations.
In summary, both areal BMD and volumetric BMD of the hip are associated with prevalent hip OA in elderly men. Furthermore, vBMD at the hip was increased only in the cortical compartment, suggesting that there may be different roles for trabecular and cortical bone remodeling in different stages of the pathogenesis of RHOA. Additional longitudinal studies with QCT scans of the hip would be needed to explore this hypothesis.