RA patients are at increased risk of developing osteoporosis compared with those without RA (39
). Increasing evidence suggests a common mechanism for generalized bone loss and localized radiographic joint damage. A number of cross sectional studies have reported a significant correlation between the two types of bone manifestations(16
) and agents targeting tumor necrosis factor (anti-TNF treatment) has been found to halt generalized bone loss in RA patients in addition to its effect on localized joint damage (40
). The mechanism has been postulated to involve inflammatory cytokines in the regulation of osteoclast differentiation and activation. Research interest has focused on the RANK/RANKL (receptor activator of NF-κβ/RANK ligand) pathway and TNF-α (41
). Our findings of significant associations between reduced BMD (osteopenia/osteoporosis) at femoral neck with 3-year total SvdH score and the erosion score in African American patients with recent-onset RA lends further support to this hypothesis.
Our results raises the question of whether bone density is already reduced in early RA patients compared with general population. We had obtained bone mineral density data on approximately frequency age- and gender-matched African American controls (n=161). Using multivariable linear regression to further control for age and gender, there was a marginally significant difference for femoral neck BMD (p=0.0767). Given the same age and gender, the bone density in RA patient was 0.03 point higher than that in a control. This further suggests that the balance in bone remodeling is already tilted by the disease.
Our findings also have potentially important clinical implications in the treatment of patients with recent-onset RA by suggesting that generalized BMD may be used as a predictor of subsequent radiographic damage. The identification of early RA patients with more a aggressive disease course is of great importance, particularly since prompt initiation of disease modifying treatments have been shown to protect against joint damage and RA-related functional and work disability (43
). Denosumab, an investigational human monoclonal antibody against RANKL, has been shown to reduce localized joint erosions in RA patients and to increase bone density in postmenopausal women (45
). Perhaps, given the ability of the new agent to treat both types of bone manifestations, reduced BMD can be used as more than a biomarker to predict future joint damage, but also as a biomarker to identify patients who are likely to benefit most from such new therapy and as an indication to initiate the treatment.
We did not find a significant association between baseline lumbar spine osteopenia/osteoporosis with 3-year SvdH score. The discrepancy that an association was observed between radiographic joint damage with BMD at the hip but not at the lumbar spine has been reported previously in patients of European ancestry (16
). One likely explanation for the discrepancy is osteoarthritis and/or other vertebral deformities occurring commonly in elderly population. Osteophyte formation, bone sclerosis, and disk space narrowing have been found to correlate positively with lumbar spine BMD whereas such a correlation was either not observed or observed to a lesser degree with hip BMD (47
). The issue that lumbar spine BMD is often falsely inflated is reflected in the clinical guidelines of the National Osteoporosis Foundation (NOF), which recommends hip BMD as the preferred site for the diagnosis of osteoporosis(48
In our study, peak referent BMD from African Americans was used to derive the T-scores. Because the objective of the study was not to assess fracture risk but to evaluate the association between radiographic damage and reduced bone mass, the use of race-specific referent data allowed us to determine the severity of bone loss and to measure the amount of reduction from the expected peak BMD. We replicated the same models using BMD as a continuous variable. Without adjusting for other variables, femoral neck BMD was marginally associated with the 3-year total SvdH score (EPE=0.21, p=0.0765) and lumbar spine BMD was not (EPE=0.45, p=0.3239). Adjusting for the same covariates as in the final reduced model, femoral neck BMD was again borderline significant at p-value 0.0542 (EPE=0.14). While the association did not reach the 0.05 threshold, the results were consistent with those when the dichotomized measures were used.
There are a number of limitations in our study. First and foremost, the relatively small sample size (n=141) is likely to have resulted in the exclusion of a number of baseline characteristics from entering the multivariable analyses. To address this issue, the change-in-estimate approach has been used to evaluate possible confounders and to fit the final multivariable model. Perhaps more importantly, because under-powered early studies tend to report over-inflated effect size (49
), the magnitude of the association found in our study will need to be evaluated and interpreted with caution.
Another limitation of our study concerns the accuracy of the patients’ self-reported cumulative oral glucocorticoid use. Patients were asked to provide detailed information on the dose, duration, and type of glucocorticoid used and were then categorized into tertiles of cumulative glucocorticoid use. While previous research has shown robust agreement between quartiles of cumulative glucocorticoid dose from self-report and medical records review (50
), it is possible that the self-reported information was inaccurate and patients were misclassified into the wrong group regarding this important exposure. Misclassification may result in uncontrolled confounding and inflation of the magnitude of the association between generalized BMD and radiographic damage we found in our study.
The association between generalized BMD and radiographic damage may be confounded by multiple factors. In addition to glucocorticoid use, physical inactivity due to impaired function, body mass index (BMI), disease activity, and medications may all influence the relationship. A study by Solomon et al. (16
) found that the relationship between focal bone erosions and generalized BMD was stronger among patients with shorter disease duration and lower cumulative oral glucocorticoid use, suggesting that in patients with longer disease duration, the other factors exerted greater influence on the relationship between bony erosions and generalized BMD.
Despite the limitations discussed above, our study is the first to examine the relationship between generalized BMD and radiographic damage in African American patients with recent-onset RA. African Americans are under-represented in RA research and the known racial/ethnic differences in the skeletal system render it unclear whether the previously reported results apply in this population.
In summary, the findings from our study suggest that generalized bone density may be a predictor of radiographic damage and provide further support for the hypothesis that the two types of bone manifestations share a common mechanism. The elucidation of such mechanism responsible for the imbalance in bone remodeling in future research will not only lead to a better understanding of the pathogenesis of RA but also one more step toward individualized medicine and development of novel treatment therapies that have the potential of addressing both types of bone involvement.