ARTHRITIS & RHEUMATISMVol. 62, No. 8, August 2010, pp 2219–2226DOI 10.1002/art.27510© 2010, American College of Rheumatology

Generalized Bone Loss as a Predictor of Three-YearRadiographic Damage in African American Patients With

Recent-Onset Rheumatoid Arthritis

Jie Zhang,1 David T. Redden,1 Gerald McGwin, Jr.,1 Leigh F. Callahan,2 Edwin A. Smith,3

Graciela S. Alarcon,1 Larry W. Moreland,1 Desiree M. van der Heijde,4 Elizabeth E. Brown,1

Donna K. Arnett,1 Ted R. Mikuls,5 and S. Louis Bridges, Jr.,1 for the Consortium for theLongitudinal Evaluations of African Americans with Early Rheumatoid Arthritis Investigators

Objective. To examine the association betweenbaseline bone mineral density (BMD) and radiographicdamage at 3 years of disease duration in a longitudinalcohort of African Americans with recent-onset rheuma-toid arthritis (RA).

Methods. African American RA patients with adisease duration of <2 years (n � 141) were included inthe study. All patients underwent baseline BMD mea-surements (femoral neck and/or lumbar spine) usingdual x-ray absorptiometry. T scores were calculatedusing normative data from the general population ofAfrican Americans. Patients were categorized as havingosteopenia/osteoporosis (T score less than or equal to�1) or as being healthy. Hand and wrist radiographs,

obtained at baseline and at 3 years of disease duration,were scored using the modified Sharp/van der Heijdemethod. The association between baseline BMD andtotal radiographic score at 3 years of disease wasexamined using multivariable negative binomial regres-sion.

Results. At baseline, the mean age and the meandisease duration were 52.4 years and 14.8 months,respectively; 85.1% of the patients were women. Theaverage total radiographic scores at baseline and at 3years of disease were 2.4 and 5.7, respectively. In thefinal reduced multivariable model, adjusting for age,sex, anti–cyclic citrullinated peptide antibody posi-tivity, and the presence of radiographic damage atbaseline, the total radiographic score at 3 years diseasein patients with osteopenia/osteoporosis of the femoralneck was twice that in patients with normal bonedensity, and the difference was statistically significant(P � 0.0084). No association between lumbar spineosteopenia/osteoporosis and radiographic score wasfound.

Conclusion. Our findings suggest that reducedgeneralized BMD may be a predictor of future radio-graphic damage and support the hypothesis that radio-graphic damage and reduced generalized BMD in RApatients may share a common pathogenic mechanism.

The progression of radiographic damage in rheu-matoid arthritis (RA) is not uniform (1), and despite theadvent of biologic agents, RA continues to cause jointdestruction in a significant proportion of patients (2–6).Initial radiographic damage, antibodies against cycliccitrullinated peptide (anti-CCP), C-reactive protein(CRP) levels, and other markers of inflammation are

Supported by NIH grant N01-AR-02247, General ClinicalResearch Center grants M01-RR-00032 to the University of Alabamaat Birmingham, M01-RR-00039 to Emory University/Grady Hospital,M01-RR-00046 to the University of North Carolina, and M01-RR-01070 to the Medical University of South Carolina, grant N01-AR-6-2278 for the continuation of the Consortium for the LongitudinalEvaluations of African Americans with Early Rheumatoid ArthritisRegistry, and grant UL1-RR-025777 for the Participant & ClinicalInteractions Resources component of the University of Alabama atBirmingham Center for Clinical and Translational Science.

1Jie Zhang, MPH, David T. Redden, PhD, Gerald McGwin,Jr., PhD, MS, Graciela S. Alarcon, MD, MPH, Larry W. Moreland,MD (current address: University of Pittsburgh, Pittsburgh, Pennsylva-nia), Elizabeth E. Brown, PhD, MPH, MSPH, Donna K. Arnett, PhD,S. Louis Bridges, Jr., MD, PhD: University of Alabama at Birming-ham; 2Leigh F. Callahan, PhD: University of North Carolina, ChapelHill; 3Edwin A. Smith, MD: Medical University of South Carolina,Charleston; 4Desiree M. van der Heijde, MD, PhD: Leiden UniversityMedical Center, Leiden, The Netherlands; 5Ted R. Mikuls, MD,MSPH: University of Nebraska Medical Center, Omaha.

Address correspondence and reprint requests to Jie Zhang,MPH, Department of Epidemiology, School of Public Health, Univer-sity of Alabama at Birmingham, 1665 University Boulevard, Birming-ham, AL 35294. E-mail: jszhang@uab.edu.

Submitted for publication October 5, 2009; accepted in re-vised form April 6, 2010.

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currently used to identify patients who are at the greatestrisk of developing progressive joint damage, in an effortto selectively implement early, aggressive treatmentstrategies (7–11).

Recent findings in RA patients of Europeanancestry have suggested that lower bone mineral density(BMD) at various anatomic sites can be used as apredictor of progressive radiographic damage. Signifi-cant associations between reduced BMD in the handand subsequent radiographic damage in patients withearly RA have been reported independently in 3 longi-tudinal studies (12–14). Forslind et al demonstrated thatgeneralized bone loss was a significant predictor ofradiographic progression at 2 years of followup (15). Inaddition to these longitudinal studies, generalized BMDhas been shown to be significantly associated with radio-graphic damage or joint erosions in a number of cross-sectional studies (16–19).

However, it is unknown whether the results ofprevious studies can be extrapolated to African Ameri-can RA patients. Healthy African Americans havehigher BMD (20–22) and a significantly lower risk ofosteoporosis-related fractures than do Caucasians,Asians, and Hispanics (23). African Americans not onlyachieve a higher peak bone mass, but they also differfrom European Americans with respect to skeletal re-sistance to parathyroid hormone, estradiol and testos-terone levels, calcium metabolism, and the rate of boneturnover (24–29).

The objective of this study was to examinewhether generalized BMD of the femoral neck andlumbar spine at baseline correlates with radiographicjoint damage accrued over time in a longitudinal cohortof African American patients with recent-onset RA.

PATIENTS AND METHODS

Our analyses were performed using participants whowere enrolled in the Consortium for the Longitudinal Evalu-ations of African Americans with Early RA (CLEAR) Registryfrom 2001 to 2005. The CLEAR Registry has 5 sites partici-pating in this longitudinal study, including the University ofAlabama at Birmingham (the coordinating site), Emory Uni-versity (Atlanta, GA), the University of North Carolina,Washington University (St. Louis, MO), and the MedicalUniversity of South Carolina (30). The study was approved bythe Institutional Review Board at each participating site, andall participants provided written informed consent.

Briefly, patients were eligible for enrollment into theCLEAR registry if their self-reported race was black orAfrican American, if they had disease that was diagnosedaccording to the American College of Rheumatology (ACR;formerly, the American Rheumatism Association) 1987 classi-

fication criteria for RA (31), and if the disease duration fromsymptom onset was �2 years. At the baseline visit, question-naires were administered to collect information on demo-graphics and medical history (ACR criteria, extraarticularmanifestations, disease duration, current and past use of RAand non-RA medications, and comorbidities). All patientsunderwent a physical examination, during which height andweight were measured. The number of tender and/or swollenjoints was assessed by trained evaluators, the Joint Alignmentand Motion scale (32) was used to assess joint deformity, andthe disability index of the Health Assessment Questionnaire(HAQ) (33) was used to evaluate functional ability. Serumrheumatoid factor (IgM-RF; in IU/ml) (Inova Diagnostics)and anti-CCP antibodies (in units/ml; Axis-Shield Diagnostics)were measured, as previously reported (34). Plasma concen-trations of high-sensitivity CRP (hsCRP; in mg/liter) weredetermined by immunoturbidimetric assay using a Hitachi 917analyzer (Roche Diagnostics), with reagents and calibratorsfrom DiaSorin.

Participants were reevaluated when their disease du-ration (the time elapsed since symptom onset) reached 3 years.Because the CLEAR participants were enrolled at any pointwithin 2 years of disease onset, the disease duration at thebaseline visit varied from 0 to 2 years. As a result, the amountof followup time also varied among study subjects. Betweenthe baseline and 3-year visits, patients were surveyed viatelephone at 6-month intervals to obtain information abouttheir medication use since the last study encounter.

The outcome variable of our study was radiographicdamage at the 3-year followup visit. Radiographs of the handsand wrists were obtained at baseline and at the 3-year visit, andradiographic damage was evaluated using the modified Sharp/van der Heijde score (SHS) (35). Baseline BMD of the femoralneck and lumbar spine was determined at each participatingcenter using dual x-ray absorptiometry. BMD measures werestandardized to Hologic BMD using previously publishedconversion equations (36), and T scores were calculated usingreferent data from the general African American population(for lumbar spine scores, Hologic’s reference database; forfemoral neck scores, the Third National Health and NutritionExamination Survey data). Collection, standardization, andcalculation of T scores were completed as previously described(37). Based on baseline T scores, patients were categorizedinto either an “osteopenia/osteoporosis” group (for patientswith T scores less than or equal to �1) or a “healthy” group(for patients with T scores greater than �1).

Patients in the CLEAR Registry who had an SHS atthe 3-year visit and a baseline BMD assessment of either thefemoral neck or the lumbar spine were included in the analysis(n � 141). The dependent variable was the total SHS at the3-year visit, which was a non-negative integer assuming anoverdispersed Poisson distribution (variance greater thanmean). Hence, linear models were not appropriate, and nega-tive binomial regressions were used in both univariate andmultivariable analyses. The exponentiation of the parameterestimate (EPE) of the negative binomial regression model canbe interpreted in a multiplicative manner. For example, anEPE of 3 for female sex indicates that the total SHS for awoman would be 3 times that for a man, if the 2 subjects werethe same with regard to all other covariates. An EPE of �1indicates that the presence of the characteristic (or of a higher

2220 ZHANG ET AL

value in the case of a continuous variable such as older age) isassociated with greater total 3-year SHS, and an EPE of �1indicates the opposite.

A wide range of baseline characteristics was examinedin univariate analyses, including age, sex, body mass index(BMI), disease duration at baseline, baseline plasma hsCRPlevel, anti-CCP antibody positivity, IgM-RF positivity, pres-ence of radiographic damage (SHS �0), HLA–DRB1 sharedepitope positivity (HLA–DRB1 alleles encoding the sharedepitope were *0101, *0102, *0401, *0404, *0405, *0408, *0413,*1001, and *1402), cumulative oral glucocorticoid use (acomposite of dose, frequency, and duration) prior to the 3-yearvisit (approximately categorized into 3 tertiles: never [n � 47],low [n � 43], and high [n � 44] [data not available on 7patients]), HAQ score, tender and swollen joint counts, thenumber of ACR criteria fulfilled, the number of extraarticularmanifestations, and smoking status (never, past, or currentsmoker).

Age, sex, BMI, cumulative glucocorticoid use, smokingstatus, and variables that had P values that were less than 0.10in univariate analyses were included in an initial multivariablemodel. To produce a final parsimonious model, the initialmodel was then manually reduced by removing variables thathad the greatest P value at each step, if they were notstatistically significant at a significance level of 0.05 and if theremoval of the variables did not produce a 10% or greaterchange in the parameter estimate for femoral neck or lumbarspine osteopenia/osteoporosis (38). Because the BMD of thefemoral neck and the BMD of the lumbar spine were highlycorrelated, 2 separate multivariable models were examined forBMD at the 2 anatomic sites.

All statistical analyses were performed using the SASstatistical package, version 9.1 (SAS Institute).

RESULTS

Baseline patient characteristics are shown in Ta-ble 1. At the baseline visit, the mean � SD age and themean � SD disease duration were 52.4 � 13.0 years and14.8 � 7.3 months, respectively. Women accounted for85.1% of the total study population. The mean � SDvalues for the SHS at the baseline and 3-year visits were2.4 � 5.4 and 5.7 � 11.3, respectively, with an averageannual progression rate of 1.5 units.

At baseline, the average BMD of the lumbarspine and the BMD of the femoral neck were 1.08gm/cm2 and 0.85 gm/cm2, respectively. A total of 38.6%of the subjects had either osteopenia or osteoporosis ofthe lumbar spine, and 44.9% of the subjects had eitherosteopenia or osteoporosis of the femoral neck (T scoreless than or equal to �1). Patients with osteopenia/osteo-porosis at either anatomic site had a higher mean totalSHS at baseline and more progression during the fol-lowup period. The mean total SHS for the femoral neckat the baseline and 3-year visits in patients with osteopenia/osteoporosis was 3.31 and 8.16, respectively, and in

patients who had normal bone density, the mean valueswere 1.76 and 3.91, respectively. For the lumbar spine,the mean total SHS at the baseline and 3-year visits inpatients with osteopenia/osteoporosis was 3.10 and 7.63,respectively, and in patients with normal bone density,the mean values were 2.00 and 4.58, respectively.

Table 2 presents the results of the univariateanalyses and the final reduced multivariable model.Femoral neck osteopenia/osteoporosis at baseline wasassociated with a higher total SHS at the time of the3-year visit (EPE � 2.2, P � 0.0249). In the multivari-able analyses, after controlling for other baseline char-acteristics, femoral neck osteopenia/osteoporosis re-mained significantly associated with a higher total SHS(EPE � 2.1, P � 0.0084). The removal of age andglucocorticoid use from the multivariable model re-sulted in a 17% increase and a 21% reduction, respec-tively, in the parameter estimate for femoral neckosteopenia/osteoporosis, which exceeded the 10% cutoffpoint used in the “change in estimate” strategy toevaluate confounding (38). While these factors were notstatistically significant at the 0.05 alpha level, they werekept in the final multivariable model (Table 2). To testthe robustness of our final model, we built an alternatereduced model retaining only those variables that weresignificant at the 0.05 alpha level, and the results weresimilar. The 3-year total SHS in patients with reducedbone density of the femoral neck were twice those of

Table 1. Baseline characteristics of the 141 African American pa-tients with recent-onset RA*

No. (%) women 120 (85.1)Age, years 52.4 � 13.0Disease duration since symptom onset, months 14.8 � 7.3BMI, kg/m2 31.2 � 6.7Patient’s assessment of pain, by visual analog scale 5.9 � 3.0HAQ score 1.4 � 0.8No. of swollen joints (range 0–38) 5.7 � 7.5No. of tender joints (range 0–42) 10.9 � 11.3No. (%) with rheumatoid nodules† 19 (13.7)No. of ACR criteria fulfilled (range 4–7) 5.0 � 0.8CRP, mg/liter 12.3 � 30.3No. (%) with IgM-RF† 104 (77.6)No. (%) with anti-CCP† 89 (66.9)No. (%) with HLA–DRB1 shared epitope†‡ 69 (50.0)No. (%) with baseline radiographic damage (SHS �0)† 48 (34.5)

* Except where indicated otherwise, values are the mean � SD. RA �rheumatoid arthritis; BMI � body mass index; HAQ � HealthAssessment Questionnaire; ACR � American College of Rheumatol-ogy; CRP � C-reactive protein; IgM-RF � IgM rheumatoid factor;anti-CCP � anti–cyclic citrullinated peptide; SHS � modified Sharp/van der Heijde score.† Data on some patients not available.‡ HLA–DRB1 shared epitope alleles were *0101, *0102, *0401, *0404,*0405, *0408, *0413, *1001, and *1402.

BMD AS A PREDICTOR OF FUTURE RADIOGRAPHIC DAMAGE IN RA PATIENTS 2221

subjects with normal bone density (EPE � 2.1, P �0.0035).

In the univariate analysis, baseline osteopenia/osteoporosis of the lumbar spine was marginally associ-ated with the SHS (EPE � 1.8, P � 0.0897). There wasno final reduced multivariable model for lumbar spineBMD. Lumbar spine osteopenia/osteoporosis was notsignificantly associated with the 3-year total SHS inthe full model and was eliminated during variableelimination.

In order to evaluate the sensitivity of the finalmultivariable model, we excluded 2 patients whose3-year SHS was 5 SD above the mean and who hadosteoporosis at baseline. Reduced bone density of thefemoral neck remained a significant predictor of thetotal SHS (EPE � 2.1, P � 0.0093).

Given that the generalized BMD may be morestrongly related to bony erosions than to joint space

narrowing or to the total SHS, we performed additionalanalyses examining the relationship between femoralneck and hip osteopenia/osteoporosis with erosionscores at 3 years of disease, using the same method asdescribed above. Femoral neck osteopenia/osteoporosiswas significantly associated with the 3-year–disease-duration erosion score in both the univariate analysis(EPE � 2.2, P � 0.0279) and the multivariable analysis(full-model EPE � 2.7, P � 0.0061). A marginallysignificant association was observed for lumbar spineosteopenia/osteoporosis in the univariate analysis(EPE � 2.0, P � 0.0535) and the multivariable analysis(full-model EPE � 1.8, P � 0.0594). These results aresummarized in Table 3.

DISCUSSION

RA patients are at increased risk of developingosteoporosis as compared with subjects who do not have

Table 2. Results of univariate and multivariable models examining baseline characteristics and the3-year SHS among the 141 African Americans with recent-onset RA*

Baseline characteristic

Univariateanalysis

Final reducedmultivariable

model

EPE P EPE P

DemographicsAge 1.02 0.1693 1.02 0.1513Sex (female) 0.60 0.2745Smoking status†

Never 1.50 0.3312Current 1.11 0.8244

Laboratory measuresIgM-RF positivity 2.88 0.0109Anti-CCP positivity 2.38 0.0188 2.80 0.0028CRP 1.01 0.2230

Other RA-related measuresDisease duration 1.02 0.3865No. of ACR criteria fulfilled 1.25 0.2552No. of extraarticular manifestations 1.28 0.2261No. of tender joints 1.00 0.9072No. of swollen joints 1.03 0.2097Pain 1.09 0.1681HAQ score 1.30 0.2440BMI 0.98 0.4165Cumulative oral glucocorticoid use

Low 1.25 0.5994 1.40 0.3667High 0.88 0.7575 0.79 0.4698

Presence of radiographic damage (SHS �0) 9.43 �0.0001 9.60 �0.0001HLA–DRB1‡ 1.01 0.9776

Femoral neck osteopenia/osteoporosis (versus healthy) 2.15 0.0249 2.10 0.0084

* Baseline variables included in the initial multivariable model were age, sex, BMI, smoking status,IgM-RF positivity, anti-CCP positivity, cumulative glucocorticoid use, presence of radiographic damage,and presence of femoral neck osteopenia/osteoporosis. EPE � exponentiation of parameter estimate (seeTable 1 for other definitions).† Reference group was past smokers.‡ HLA–DRB1 shared epitope alleles were *0101, *0102, *0401, *0404, *0405, *0408, *0413, *1001, and*1402.

2222 ZHANG ET AL

RA (39). Increasing evidence suggests a common mech-anism for generalized bone loss and localized radio-graphic joint damage. A number of cross-sectional stud-ies have shown a significant correlation between the 2types of bone manifestations (16–19), and agents target-ing tumor necrosis factor (TNF) have been found to haltboth the generalized bone loss in RA patients and theeffects of RA on localized joint damage (40). Themechanism has been postulated to involve inflammatorycytokines in the regulation of osteoclast differentiationand activation. Research interest has focused on theRANK/RANKL pathway and on TNF� (41,42). Ourfindings of significant associations between reducedBMD (osteopenia/osteoporosis) of the femoral neck andboth the 3-year total SHS and the erosion score inAfrican American patients with recent-onset RA lendsfurther support to this hypothesis.

Our results raise the question of whether bonedensity is already reduced in patients with early RA as

compared with the general population. We obtainedBMD data on a group of African American controls witha similar mean age, age range, and sex distribution (n �161). Using multivariable linear regression to furthercontrol for age and sex, we found a marginally significantdifference for femoral neck BMD (P � 0.0767). Giventhe same age and sex, the bone density of an RA patientwas 0.03 points higher than that of a control subject. Thisfurther suggests that the balance of bone remodeling isalready tilted by the disease.

Our findings also have potentially important clin-ical implications for the treatment of patients withrecent-onset RA, by suggesting that generalized BMDmay be used as a predictor of subsequent radiographicdamage. The identification of patients with early RAwho have a more aggressive disease course is of greatimportance, particularly since prompt initiation ofdisease-modifying treatments has been shown to protectagainst joint damage and RA-related functional and

Table 3. Results of univariate and multivariable models examining baseline characteristics and the 3-year erosion score among the 141 AfricanAmericans with recent-onset RA*

Baseline characteristic

Univariate analysisFemoral neck full

multivariable modelLumbar spine full

multivariable model

EPE P EPE P EPE P

DemographicsAge 1.02 0.0470 1.01 0.4105 1.02 0.1785Sex (female) 0.97 0.9440 2.91 0.0218 2.77 0.0311Smoking status†

Never 1.33 0.5062 0.41 0.0434 0.44 0.0651Current 0.73 0.5284 0.47 0.0936 0.54 0.1658

Laboratory measuresIgM-RF positivity 5.69 0.0002 5.02 0.0051 5.16 0.0054Anti-CCP positivity 4.54 0.0001 2.57 0.0365 2.21 0.0760CRP 1.00 0.7097

Other RA-related measuresDisease duration 1.04 0.1347No. of ACR criteria fulfilled 1.47 0.0698 1.20 0.3250 1.22 0.2920No. of extraarticular manifestations 1.41 0.1360No. of tender joints 1.01 0.6021No. of swollen joints 1.06 0.0352 1.05 0.0404 1.03 0.1384Pain 1.09 0.1744HAQ score 1.35 0.1740BMI 0.97 0.2946 0.97 0.2946 0.96 0.1186Cumulative oral glucocorticoid use

Low 1.55 0.3141 0.97 0.9453 0.71 0.3620High 0.82 0.6548 0.74 0.3986 0.72 0.3679

Presence of erosion (erosion score �0) 6.45 �0.0001 9.61 �0.0001 10.66 �0.0001HLA–DRB1‡ 0.81 0.5607

Femoral neck osteopenia/osteoporosis(versus healthy)

2.17 0.0279 2.71 0.0061

Lumbar spine osteopenia/osteoporosis(versus healthy)

1.99 0.0535 1.81 0.0594

* EPE � exponentiation of parameter estimate (see Table 1 for other definitions).† Reference group was past smokers.‡ HLA–DRB1 shared epitope alleles were DRB1*0101, *0102, *0401, *0404, *0405, *0408, *0413, *1001, and *1402.

BMD AS A PREDICTOR OF FUTURE RADIOGRAPHIC DAMAGE IN RA PATIENTS 2223

work disability (43,44). Denosumab, an investigationalhuman monoclonal antibody against RANKL, has beenshown to reduce localized joint erosions in RA patientsand to increase bone density in postmenopausal women(45,46). Perhaps, given the ability of the new agent totreat both types of bone manifestations, reduced BMDcan be used as a biomarker to predict future jointdamage as well as a biomarker to identify patients whoare likely to benefit most from such new therapy and asan indication to initiate the treatment.

We did not find a significant association betweenbaseline lumbar spine osteopenia/osteoporosis and the3-year SHS. Similar findings of an association betweenradiographic joint damage and BMD in the hip but notthe lumbar spine have been reported previously, inpatients of European ancestry (16–18). One likely ex-planation for the discrepancy is that osteoarthritisand/or other vertebral deformities occur commonly inelderly populations. Osteophyte formation, bone sclero-sis, and disc space narrowing have been found to corre-late positively with lumbar spine BMD, whereas such acorrelation was not observed, or was observed to a lesserdegree, with hip BMD (47). The fact that lumbar spineBMD is often falsely inflated is reflected in the clinicalguidelines of the National Osteoporosis Foundation,which recommends BMD at the hip as the preferred sitefor the diagnosis of osteoporosis (48).

In our study, peak referent BMD from AfricanAmericans was used to derive the T scores. Because theobjective of the study was not to assess fracture risk butto evaluate the association between radiographic dam-age and reduced bone mass, the use of race-specificreferent data allowed us to determine the severity ofbone loss and to measure the amount of reduction fromthe expected peak BMD. We replicated the same mod-els using BMD as a continuous variable. Without adjust-ing for other variables, femoral neck BMD was margin-ally associated with the 3-year total SHS (EPE � 0.21,P � 0.0765), and lumbar spine BMD was not (EPE �0.45, P � 0.3239). Adjusting for the same covariates as inthe final reduced model, femoral neck BMD was againof borderline significance (EPE � 0.14, P � 0.0542).While the association did not reach the 0.05 threshold,the results were consistent with those obtained when thedichotomized measures were used.

There are a number of limitations to our study.First and foremost, the relatively small sample size (n �141) is likely to have resulted in the exclusion of anumber of baseline characteristics from entering themultivariable analyses. To address this issue, the“change in estimate” approach was used in the current

study to evaluate possible confounders and to fit thefinal multivariable model. Perhaps more importantly,because underpowered earlier, underpowered studiestended to show an overinflated effect size (49), themagnitude of the association found in the current studywill need to be evaluated and interpreted with caution.

Another limitation of our study concerns theaccuracy of the patients’ self-reported cumulative oralglucocorticoid use. Patients were asked to provide de-tailed information on the dosage, duration, and type ofglucocorticoid used, and this information was then cat-egorized into tertiles of cumulative glucocorticoid use.While previous research has shown robust agreementbetween quartiles of cumulative glucocorticoid doseobtained from self-reporting and from medical recordreview (50), it is possible that the self-reported informa-tion was inaccurate and that patients were misclassifiedand placed in the wrong group. Misclassification mayhave resulted in uncontrolled confounding and inflationof the magnitude of the association between generalizedBMD and radiographic damage that we observed.

The association between generalized BMD andradiographic damage may be confounded by multiplefactors. In addition to glucocorticoid use, physical inac-tivity due to impaired function, BMI, disease activity,and medications may all influence the relationship.Solomon et al found that the relationship between focalbone erosions and generalized BMD was strongeramong patients with shorter disease duration and lowercumulative oral glucocorticoid use (16), suggesting thatin patients with longer disease duration, the otherfactors exerted greater influence on the relationshipbetween bony erosions and generalized BMD.

Despite the limitations discussed above, ourstudy is the first to examine the relationship betweengeneralized BMD and radiographic damage in AfricanAmerican patients with recent-onset RA. African Amer-icans are underrepresented in RA research, and theknown racial/ethnic differences in the skeletal systemrender it unclear whether previously reported resultsapply to this population.

In summary, the findings from our study suggestthat generalized bone density may be a predictor ofradiographic damage and provide further support forthe hypothesis that the two types of bone manifestationsshare a common mechanism. The elucidation of themechanism responsible for the imbalance in bone re-modeling in future research will not only lead to a betterunderstanding of the pathogenesis of RA, but will alsorepresent one more step toward individualized treat-

2224 ZHANG ET AL

ment and the development of novel therapies that havethe potential to address both types of bone involvement.

ACKNOWLEDGMENTS

We gratefully acknowledge the staff and coordinatorsat the following sites: Stephanie Ledbetter, MS, Selena Luck-ett, RN, CRNC, Laticia Woodruff, RN, MSN, and CandiceMiller at the University of Alabama at Birmingham; JoyceCarlone, RN, RNP, Karla Caylor, BSN, RN, and SharonHenderson, RN, at Emory University; Diane Bresch, RN, atthe University of North Carolina; Trisha Sturgill at the Med-ical University of South Carolina; and Teresa Arb, RN, atWashington University. Members of the Consortium for theLongitudinal Evaluations of African Americans with EarlyRheumatoid Arthritis are George Howard, DrPH (Universityof Alabama at Birmingham), Doyt L. Conn, MD (EmoryUniversity, Atlanta, Georgia), Beth L. Jonas, MD, Richard D.Brasington, Jr., MD (Washington University, St. Louis, Mis-souri).

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising itcritically for important intellectual content, and all authors approvedthe final version to be published. Ms Zhang had full access to all of thedata in the study and takes responsibility for the integrity of the dataand the accuracy of the data analysis.Study conception and design. Zhang, Smith, Alarcon, Moreland,Brown, Bridges.Acquisition of data. Callahan, Smith, Moreland, van der Heijde,Bridges.Analysis and interpretation of data. Zhang, Redden, McGwin, Smith,Alarcon, Moreland, Brown, Arnett, Mikuls, Bridges.

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