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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Objective

To determine if metacarpal bone mineral density (mBMD) gain occurs in patients with rheumatoid arthritis (RA). If mBMD loss is driven by inflammation, we expect to find mBMD gain in patients who are in remission.

Methods

mBMD was measured by digital x-ray radiogrammetry in consecutive radiographs of 145 patients with RA with either continuous high disease activity (HDA; Disease Activity Score [DAS] >2.4), low disease activity (LDA; 1.6 ≥ DAS ≤ 2.4), or continuous clinical remission (CR; DAS <1.6) during a 1-year observation period. The association of mBMD changes with disease activity was investigated with multinomial regression analysis. Next, clinical variables associated with mBMD gain were identified.

Results

Mean change in mBMD in CR patients was −0.03%, compared to −3.13% and −2.03% in HDA and LDA patients, respectively (overall, P < 0.001). Of the patients in CR, 32% had mBMD loss (less than or equal to −4.6 mg/cm2/year), compared to 62% and 66% of the patients with HDA or LDA, respectively, whereas 26% of the patients in CR had mBMD gain (≥4.6 mg/cm2/year), compared to 2% of the patients with HDA and 5% of the patients with LDA. Patients in CR had a higher chance of having mBMD gain, compared with LDA and HDA (relative risk [RR] 14.9, 95% confidence interval [95% CI] 3.0–18.7 and RR 4.7, 95% CI 1.2–6.3, respectively). CR, hormone replacement therapy, and lower age were significant independent predictors of mBMD gain.

Conclusion

In RA, mBMD gain occurs primarily in patients in continuous (≥1 year) CR and rarely in patients with continuous HDA or LDA. This suggests that mBMD loss is driven by inflammation.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Bone damage in rheumatoid arthritis (RA) is present in erosions as well as in accelerated bone mineral density (BMD) loss at the spine and hips (generalized bone loss) and at the hand (local bone loss) (1, 2). Hand BMD loss in RA is reported to precede radiographic joint damage (3–5) and has been observed in early stages of RA and in undifferentiated arthritis that later progressed to RA (6, 7).

BMD loss in RA is primarily thought to be the effect of increased osteoclast activity (8) and to a lesser extent the effect of impairment of bone formation by osteoblasts (9). With high disease activity, levels of inflammatory mediators such as tumor necrosis factor α (TNFα), interleukin-1 (IL-1), IL-6, and IL-17 are high (10–18). These mediators induce expression of RANKL and macrophage colony-stimulating factor, both of which are important for the differentiation and activation of osteoclasts. Also, the increased level of TNFα could induce Dkk-1, a Wnt antagonist, to inhibit the differentiation of osteoblast formation (19). Therefore, high disease activity could contribute to bone loss through 2 pathways. Moreover, BMD decreases more rapidly in active disease than in inactive disease (20, 21). This implies that the extent of BMD loss might be different for patients with different levels of disease activity. Given the fact that bone is a dynamic tissue, the balance between osteoclast and osteoblast activity may be restored and BMD loss may be (re)gained when disease activity is sufficiently suppressed. In RA, this would mean that patients need to be in prolonged remission. In remission, levels of inflammatory mediators are low (11, 13, 17), and thus osteoclast activation and osteoblast inhibition will be decreased, possibly resulting in bone gain.

Therefore, the aim of this study was to investigate the differences in hand BMD changes, measured with digital x-ray radiogrammetry (DXR) at the metacarpal joints, between patients with high and low disease activity and patients in clinical remission during a 1-year period. It was hypothesized that inflammation drives BMD loss and that therefore patients in remission might show an increase in BMD.

Significance & Innovations

  • To our knowledge, this is the first study to demonstrate that bone mineral density gain is possible, but almost exclusively in patients where clinical remission was achieved.

  • These results strongly suggest that damage to bone occurs early in the disease course, is inflammation driven, and supports the hypothesis that damage may be reversible if inflammation is adequately suppressed.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Patients.

For the current analysis, all of the patients participating in the BeSt (Behandelstrategieën voor Reumatoide Artritis) trial with either standard analog radiographs of both hands or digital radiographs of both hands at 2 consecutive time points over 1-year followup were selected. From these, patients with continuous (at all time points during that year of followup) clinical remission (Disease Activity Score [DAS] <1.6), low disease activity (DAS ≥1.6 but ≤2.4), or high disease activity (DAS >2.4) were selected. The result is a subpopulation of 145 of the original 508 patients participating in the BeSt trial. The DAS used in this study is the original DAS, with a 44 swollen and 53 tender joint count.

The BeSt trial is a multicenter randomized clinical trial comparing 4 different treatment strategies in patients who had never taken disease-modifying anti-rheumatic drugs who fulfilled the revised inclusion criteria for RA as defined by the American College of Rheumatology in 1987 (1). Patients were randomized to 1 of 4 treatment strategies: 1) sequential monotherapy, 2) step-up therapy, 3) initial combination therapy with tapered high dose of prednisone, or 4) initial combination therapy including infliximab. Treatment adjustments were steered by 3-monthly calculations of the DAS. Patients in group 1 started with methotrexate (MTX). If the DAS remained >2.4, treatment was changed to sulfasalazine (SSZ), next to leflunomide, next to MTX + infliximab, next to gold, and other steps. Patients in group 2 also started with MTX, followed by, if the DAS remained >2.4, MTX + SSZ, next MTX + SSZ + hydroxychloroquine (HCQ), then MTX + SSZ + HCQ + prednisone and MTX + infliximab, and other steps. Patients in group 3 started with MTX + SSZ + prednisone (tapered from 60 to 7.5 mg/day), then, with persistent DAS >2.4, MTX + cyclosporin A + prednisone 7.5 mg/day and then MTX + infliximab, and other steps. Patients in group 4 started with MTX + infliximab, changed to SSZ if the DAS remained >2.4, next leflunomide, and other steps. Full details on the BeSt study design and treatment protocol were previously published (22–24).

Hand BMD measurements.

DXR was used (25) to measure metacarpal BMD (mBMD). Conventional radiographs made in the individual centers participating in the BeSt study were first digitalized on a high-resolution Vidar scanner at 570 dots per inch and 12 bits before mBMD was measured. Image acquisition parameters, film type, tube voltage, exposure level, and foil sensitivity were the standard for hand images used at the respective participating sites at the time. Mean surrogate mBMD was calculated from cortical thickness at the center of metacarpal joints 2, 3, and 4 through an automated analysis of a standard projection digital radiograph of the hands (Figure 1) using DXR online technology (Sectra). Mean mBMD of both hands was used for the analysis in order to avoid bias of the dominant and nondominant hands. mBMD loss was defined as a change in mBMD less than or equal to −4.6 mg/cm2/year, mBMD gain was defined as a change in mBMD ≥4.6 mg/cm2/year, and a stable mBMD was defined as a change of −4.6 > mBMD < 4.6 mg/cm2/year, according to the smallest detectable difference (26).

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Figure 1. Regions of interest, i.e., cortical thickness at the center of metacarpal joints 2, 3, and 4, for the digital x-ray radiogrammetry measurements.

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Baseline and followup.

Patients were divided into 3 groups based on the level of continuous disease activity over the 1-year followup period: continuous high disease activity (DAS >2.4), continuous low disease activity (1.6 ≤ DAS ≤ 2.4), and continuous clinical remission (DAS <1.6). “Baseline” in this analysis denotes the start of the 1-year followup period in which mBMD was measured, not inclusion in the trial. Patients with continuous high disease activity were predominantly found in the first year after inclusion, while patients in continuous clinical remission were particularly found in the third and fourth years after inclusion. As a result, some patients were treated with antirheumatic medication before the start of the followup period (baseline) and others were not. For each individual, all demographic and clinical variables were adjusted to their specific baseline and followup values.

Demographic and clinical variables.

The following baseline variables were collected in all patients: age; sex; body mass index (BMI); DAS; functional ability as measured by the Health Assessment Questionnaire; presence of IgM rheumatoid factor (RF) and anti–cyclic citrullinated peptide antibodies (anti-CCP); symptom duration; race; current smoking and alcohol use; postmenopause status; osteoporosis in first-degree relatives; use of bisphosphonates, calcium, vitamin D, and hormone replacement therapy (HRT); and use of antirheumatic medication.

Radiographic joint damage was assessed according to the Sharp/van der Heijde (SHS) method (27). Radiographs were scored in random order by 2 independent readers who were blinded for patient identity and treatment allocation. The interobserver correlation coefficient was 0.93 and the intraobserver coefficients were 0.93 and 0.94. The mean score from the readers was used for the analysis.

Statistical analysis.

Baseline characteristics were compared between the 3 defined groups. Differences were tested using the chi-square test for categorical data and either one-way analysis of variance or the Kruskal-Wallis test for continuous data, depending on the distribution of the tested variable. In case of an overall significant difference, a post hoc analysis was performed. A multinomial regression analysis was performed to identify variables showing an association with changes in mBMD. The variables entered were age, sex, BMI, symptom duration, DAS, swollen joint count, Ritchie Articular Index, visual analog scale global health and erythrocyte sedimentation rate at baseline, RF and anti-CCP status, erosions at baseline, change in SHS, previous and current treatment, and antiresorptive therapy. The DAS was entered as a continuous variable (weighed mean of the DAS) and next as a categorical variable. Variables showing an association with changes in mBMD were entered as possible predictors in a multivariate multinomial regression analysis. With a backward selection procedure, using a P value of 0.10 as the removal criterion, associations with mBMD were identified. Several obtained odds ratios (ORs) were corrected into relative risks (RRs) with the formula of Zhang and Yu (28) in order to interpret the magnitude of the associations more appropriately.

Lastly, the association between mBMD and the SHS score was investigated with a Kruskal-Wallis one-way analysis of variance, with P values corrected for multiple comparisons by the step-down Bonferroni-Holmes adjustment. Also, Spearman's correlations were calculated to determine how changes in total SHS within the disease activity groups were correlated to changes in mBMD. All tests were 2-tailed and P values less than 0.05 were considered to be statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Patient characteristics for each defined patient group are shown in Table 1. The selected patients (n = 145) were on average 56 years old, most patients were women (68%) and postmenopausal (68%), 50% and 54% of the patients were RF and anti-CCP positive, respectively, and 47% had erosions. These patients did not differ in baseline characteristics from the other patients in the BeSt cohort (n = 363) with the exception of anti-CCP and RF (patients with BMD measurements were more often negative).

Table 1. Baseline (i.e., start of 1-year followup) characteristics of the 3 different disease activity groups*
 Continuous clinical remission (DAS <1.6) (n = 57)Continuous low disease activity (1.6 ≤ DAS ≥2.4) (n = 38)Continuous high disease activity (DAS <2.4) (n = 50)P
  • *

    DAS = Disease Activity Score; BMI = body mass index; RA = rheumatoid arthritis; IQR = interquartile range; anti-CCP = anti–cyclic citrullinated peptide antibodies; RF = rheumatoid factor; HAQ = Health Assessment Questionnaire; SHS = Sharp/van der Heijde score; JSN = joint space narrowing; BMD = bone mineral density; MTX = methotrexate; SSZ = sulfasalazine; DMARDs = disease-modifying antirheumatic drugs; IFX = infliximab; HRT = hormone replacement therapy.

  • There are missing data for this variable.

Demographic    
 Women, no. (%)29 (51)29 (76)40 (80)0.002
 Postmenopause status, no. (%)22 (76)16 (55)27 (68)0.002
 Age, mean ± SD years60 ± 1453 ± 1553 ± 150.014
 BMI, mean ± SD kg/m225.7 ± 3.026.0 ± 2.826.8 ± 4.80.305
 White race, no. (%)55 (97)34 (90)47 (94)0.380
 Current smoker, no. (%)13 (24)12 (33)21 (45)0.080
 Current alcohol use, no. (%)33 (60)15 (42)10 (21)0.000
 Familial osteoporosis, no. (%)11 (19)6 (16)11 (22)0.738
RA activity    
 Symptom duration, median (IQR) years2.8 (1.5–3.5)1.6 (1.3–2.4)0.6 (0.3–1.1)0.000
 Time from inclusion in the trial,  mean ± SD years2.0 ± 1.11.2 ± 0.50.1 ± 0.30.000
 Anti-CCP, no. (%)24 (42)19 (50)29 (58)0.260
 RF, no. (%)29 (51)19 (50)30 (60)0.552
 DAS, median (IQR)0.9 (0.6–1.2)2.1 (1.7–2.4)4.6 (4.1–5.1)0.000
 HAQ, median (IQR)0.0 (0.0–0.3)0.4 (0.1–0.6)1.4 (1.0–2.0)0.000
 Total SHS, median (IQR)3.0 (0.5–7.8)2.0 (0.3–12.0)2.5 (0.0–5.4)0.414
  Mean ± SD6.5 ± 9.07.2 ± 9.64.9 ± 9.6
 SHS JSN score, median (IQR)1.5 (0.0–5.0)1.0 (0.0–4.5)0.3 (0.0–2.9)0.317
  Mean ± SD3.5 ± 4.83.5 ± 5.42.8 ± 6.6 
 SHS erosion score, median (IQR)0.5 (0.0–2.8)1.0 (0.0–6.5)0.5 (0.0–2.5)0.432
  Mean ± SD3.0 ± 5.33.7 ± 5.22.1 ± 3.5 
 Erosive disease, no. (%)24 (42)21 (57)23 (47)0.379
 Metacarpal BMD, mean ± SD gm/cm20.59 ± 0.090.57 ± 0.080.58 ± 0.070.488
RA and osteoporotic treatment in the year of  followup    
 RA treatment groups, no. (%)   0.079
  Sequential monotherapy14 (25)3 (8)16 (32) 
  Step up from mono- to combination therapy9 (16)11 (29)14 (28) 
  Initial combination therapy with prednisone15 (26)12 (32)11 (22) 
  Initial combination therapy with infliximab19 (33)12 (32)9 (18) 
 RA treatment history, %    
  No treatment00900.000
  MTX401120.000
  SSZ7800.142
  Other DMARDs2340.777
  Combination therapy (MTX, SSZ, prednisone)263280.014
  Other DMARD combination therapy23260.000
  Combination therapy, IFX + MTX333240.000
 RA active treatment, no. (%)    
  No treatment26 (46)0 (0)0 (0)0.000
  MTX monotherapy10 (18)6 (16)29 (58)0.000
  Other DMARD monotherapy2 (4)3 (8)1 (2)0.371
  Combination therapy (MTX, SSZ, prednisone)10 (18)12 (32)9 (18)0.203
  Other DMARD combination therapy0 (0)7 (18)1 (2)0.000
  Combination therapy, IFX + MTX9 (16)10 (26)10 (20)0.454
 Osteoporotic treatment, no. (%)    
  Bisphosphonates10 (18)5 (13)7 (14)0.810
  Calcium supplements17 (30)11 (29)12 (24)0.779
  Vitamin D supplements6 (11)6 (16)5 (10)0.661
  HRT5 (9)6 (16)10 (20)0.266

Since the patients in each disease activity category were mostly found in different years of followup in the BeSt cohort, there were differences in previous as well as in current antirheumatic treatment. Further, patients in continuous clinical remission were also older, more often men, and the women more often postmenopausal, and more patients in continuous clinical remission reported use of alcohol than patients with high or low disease activity. Use of calcium, vitamin D, bisphosphonates, and HRT was similar in the 3 groups.

BMD change.

Overall mean ± SD mBMD at baseline was 0.58 ± 0.08 gm/cm2. After 1 year, mean ± SD absolute change in mBMD was −0.002 ± 0.01 gm/cm2 for patients in continuous clinical remission, −0.019 ± 0.01 gm/cm2 for patients with continuous low disease activity, and −0.018 ± 0.02 gm/cm2 for patients with continuous high disease activity. These values correspond to an mBMD loss of −0.034%, −2.03%, and −3.13% in patients in continuous clinical remission and continuous low and high disease activity, respectively (overall, P < 0.001; patients in remission had less mBMD loss than the other patients). Accelerated mBMD loss, defined as mBMD loss more than 4.6 mg/cm2/year (26), was found in 32% of the patients in continuous clinical remission, 66% of the patients with continuous low disease activity, and 62% of the patients with continuous high disease activity. mBMD gain was observed in 26% of the patients in continuous clinical remission, compared to 5% of the patients with continuous low disease activity and 2% of the patients with continuous high disease activity (P < 0.001; patients in remission had more often mBMD gain than the other patients). Percentages of patients with stable mBMD were similar in both groups (Figure 2).

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Figure 2. Dynamics of metacarpal bone mineral density (mBMD) in patients with 1) continuous high disease activity (Disease Activity Score [DAS] >2.4), 2) continuous low disease activity (1.6 ≤ DAS ≤ 2.4), and 3) continuous clinical remission (DAS <1.6) during 1-year followup.

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Association between BMD and disease activity.

With univariate multinomial analysis, variables associated with changes in mBMD were identified (Table 2). These were entered in the multivariate multinomial analysis together with other possible confounders. Previous and current use of prednisone or infliximab was not significantly associated with mBMD changes, nor was use of bisphosphonates, calcium, and vitamin D. On the other hand, use of HRT was significantly associated.

Table 2. Univariate predictive variables of an increase or loss in mBMD compared to a stable mBMD*
 mBMD increase (≥4.6 mg/cm2/year) (n = 18)mBMD loss (less than or equal to −4.6 mg/cm2/year) (n = 74)
  • *

    Values are the odds ratio (95% confidence interval). Stable BMD is used as reference category. mBMD = metacarpal bone mineral density; BMI = body mass index; DAS = Disease Activity Score; AUC = area under the curve; SJC = swollen joint count; ESR = erythrocyte sedimentation rate; RAI = Ritchie Articular Index; VAS = visual analog scale; SHS = Sharp/van der Heijde score; RF = rheumatoid factor; anti-CCP = anti–cyclic citrullinated peptide antibodies; HRT = hormone replacement therapy.

  • P < 0.05.

Age, years0.98 (0.95–1.02)1.01 (0.99–1.04)
Female sex1.6 (0.5–5.1)1.4 (0.7–3.0)
BMI, kg/m20.8 (0.7–0.99)0.97 (0.9–1.1)
DAS at baseline0.5 (0.3–0.9)1.3 (1.03–1.6)
AUC of the DAS0.3 (0.2–0.7)1.4 (1.1–1.9)
SJC at baseline0.9 (0.8–1.03)1.1 (1.0–1.1)
ESR at baseline0.96 (0.93–1.01)1.01 (1.00–1.03)
RAI at baseline0.8 (0.7–0.99)1.03 (0.99–1.08)
VAS global health at baseline0.95 (0.91–0.99)1.01 (1.00–1.03)
Symptom duration1.2 (0.9–1.5)0.8 (0.6–1.1)
Erosive at baseline0.5 (0.2–1.6)1.04 (0.5–2.1)
Change in SHS0.7 (0.5–1.1)1.04 (0.96–1.1)
BMD at baseline7.0 (0.01–5,924.6)0.2 (0.00–8.9)
RF positive1.3 (0.4–3.8)0.7 (0.4–1.5)
Anti-CCP positive0.5 (0.1–1.5)1.7 (0.8–34)
Vitamin D and/or calcium supplements0.7 (0.2–2.3)1.2 (0.6–2.5)
HRT4.8 (1.3–18.4)1.5 (0.5–4.8)
Bisphosphonate use0.8 (0.2–4.4)1.4 (0.5–3.8)

In the multivariate multinomial analysis, with stable mBMD as the reference, continuous disease activity, presented as the area under the curve of the DAS, showed an independent association with mBMD gain. There was an independent association of higher disease activity with mBMD loss (OR 1.5, 95% confidence interval [95% CI] 1.1–2.0) and higher disease activity was inversely associated with mBMD gain (OR 0.2, 95% CI 0.1–0.6). HRT was independently associated with mBMD gain (OR 17.1, 95% CI 2.7–107.5). When components of the DAS were entered in the multivariate analysis instead of the complete DAS, none of the components was independently predictive of mBMD. Therefore, the DAS itself was chosen for further analysis.

An association between disease activity and mBMD change was identified, and next it was investigated if there was a dose-response relationship. Categorized DAS was entered in the multinomial regression analysis with possible confounders and found to be independently associated with mBMD gain (Table 3). Patients in continuous clinical remission had a significantly higher chance of mBMD gain compared to patients with continuous high disease activity (RR 14.9, 95% CI 3.0–18.7) and compared to patients with continuous low disease activity (RR 4.7, 95% CI 1.2–6.3). Compared to patients with continuous high disease activity, patients with continuous low disease activity had a similar chance of having mBMD gain (RR 3.9, 95% CI 0.3–15.1). Further, compared to patients with continuous high disease activity, mBMD loss was significantly less in patients in continuous clinical remission (RR 0.5, 95% CI 0.3–0.9), but not in patients with continuous low disease activity (RR 1.0, 95% CI 0.7–1.3).

Table 3. Associations between disease activity and mBMD, with stable mBMD and high disease activity as the reference category*
 mBMD gain (≥0.0046 gm/cm2)mBMD loss (less than or equal to −0.0046 gm/cm2)
  • *

    Values are the relative risk (95% confidence interval). mBMD = metacarpal bone mineral density; DAS = Disease Activity Score.

Remission (DAS <1.6)14.9 (3.0–18.7)0.3 (0.1–0.8)
Low disease activity (1.6 ≤ DAS ≤ 2.4)3.9 (0.3–15.1)1.1 (0.5–1.7)

With stable mBMD as the reference, continuous clinical remission was significantly associated with mBMD gain (RR 14.9, 95% CI 3.0–18.7; OR 211.5, 95% CI 10.9–4,097.5). With mBMD loss as the reference, continuous clinical remission was again significantly predictive of mBMD gain when compared to high disease activity (RR 27.9, 95% CI 8.3–31.8; OR 64.5, 95% CI 3.4–1,228.9). HRT (RR 9.3, 95% CI 1.2–25.9; OR 12.8, 95% CI 1.2–132.5) and lower age (OR 0.95, 95% CI 0.91–0.998) were also independent predictors for mBMD gain.

Association between BMD and radiographic damage.

The mean ± SD change in SHS in the year of followup was 0.02 ± 0.7 (median 0 [interquartile range (IQR) 0–0.13]) for patients with mBMD gain, 1.2 ± 4.2 (median 0 [IQR 0–0.9]) for patients with stable mBMD, and 4.4 ± 19.7 (median 0.3 [IQR 0–2]) for patients with mBMD loss (overall, P = 0.056) (Figure 3). Only 8% of patients progressed by ≥5 SHS points, 20% progressed by ≥2 points, and 38% of the patients showed radiographic progression of ≥0.5 point. Of the patients with mBMD gain, 22% showed radiographic progression of ≥0.5 point, 6% progressed by ≥2 points, and none showed radiographic progression of ≥5 points. Of the patients with mBMD loss, 50% had radiographic progression of ≥0.5 point, 30% progressed by ≥2 points, and 11% progressed by ≥5 points. Patients with mBMD gain had significant less often progression of ≥0.5 and 2 points than patients with mBMD loss (both P < 0.05), but no difference was found regarding progression of ≥5 points (P = 0.135).

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Figure 3. Mean changes in Sharp/van der Heijde score (SHS) in patients having 1) metacarpal bone mineral density (mBMD) gain, 2) stable mBMD, or 3) mBMD loss during 1-year followup.

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In addition, within the remission group, change in total SHS was not correlated (ρ = 0.032) with a change in mBMD. A correlation of ρ = −0.147 was found for the association between total SHS and change in mBMD in the low disease activity group and a significant correlation of ρ = −0.402 (P < 0.01) was found in the high disease activity group.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

In patients with RA treated according to a protocol aimed at achieving and maintaining low disease activity (DAS ≤2.4), we have shown that predominantly in patients who are in prolonged clinical remission, a gain in mBMD can occur. An increase in mBMD was rare in patients with continuous high disease activity (DAS >2.4), but also rare in patients with continuous low disease activity (DAS ≤2.4 but ≥1.6). These results are encouraging, as they indicate that bone damage in RA can be a reversible process.

In previous RA cohorts, generalized as well as mBMD loss, but not BMD gain, has been frequently observed (4, 5, 7, 21, 29–33). Considering findings that osteoclast and osteoblast activity is influenced by inflammatory cytokines and vary with disease activity (10–18, 34–36), we hypothesized that inflammation drives mBMD loss and that due to the dynamics of bone metabolism, patients who are in remission might show an increase in their mBMD. Our findings support this hypothesis. Previously, no difference in generalized BMD loss, measured by dual x-ray absorptiometry, was found between patients in remission or patients with high disease activity (37). In the BeSt study, we have shown that changes in mBMD may be more sensitive to differences in inflammatory activity than changes in generalized BMD (31, 32).

Besides continuous clinical remission, age and HRT were also independent predictors of mBMD gain. Older patients were unlikely to show mBMD gain, which may be due to hormonal changes in this predominantly female population. HRT possibly may have a positive effect on bone metabolism directly through actions on osteoclasts and osteoblasts as well as indirectly through effects on inflammatory cells and processes (38). Previously, HRT was found to stabilize mBMD (39). The use of bisphosphonates, calcium, and vitamin D was not predictive of mBMD changes. Previously, we showed that bisphosphonates have a protective effect on generalized but not mBMD loss (32).

In this cohort, any DAS >2.4 is considered to represent high (not moderate) disease activity, requiring adjustment of treatment. DAS ≤2.4 but ≥1.6 was considered low. Continuously low disease activity appeared not to have provided better mBMD outcomes than continuously high disease activity.

Although this first report on mBMD gain in patients in remission is encouraging, still only 26% showed mBMD gain. Possibly, factors such as lack of weight-bearing exercise or dietary or endocrinologic imbalances caused ongoing mBMD loss. It may also be that DAS <1.6 is insufficiently strict to identify true remission, with residual inflammation undetected by clinical evaluation. Magnetic resonance imaging in patients in clinical remission may show signs of synovitis (40, 41), and in some, radiologic joint damage progression has been reported (42, 43). Ongoing mBMD loss may be a signal of persistent disease activity, and mBMD measurement may help to identify patients at risk for radiographic progression who clinically appear to be in remission. Previous studies showed that mBMD loss precedes radiographic progression (6, 7) and subsequently functional disability (44, 45). We found that patients with mBMD gain experience hardly any radiographic progression, while patients with stable mBMD or mBMD loss did experience radiographic progression more often. However, differences between the 3 groups were not significant because progression rates were low and few patients showed significant progression, since treatment in this cohort was aimed at achieving a DAS ≤2.4.

Since in this cohort high disease activity occurred primarily early in the treatment period and sustained remission some years later, there are differences in antirheumatic medication used in the year of observation in the 3 groups (Table 1). Prednisone and infliximab both may have a direct effect on bone (46–48). Our results showed no association between previous or current use of prednisone or infliximab and mBMD, and no differences in percentages of mBMD loss, mBMD gain, or stable mBMD were found between patients in remission while receiving medication and patients in drug-free remission (data not shown). Therefore, it seems unlikely that mBMD gain or loss is primarily drug effects. The wide CIs for some of our results are probably due to small patient numbers in the different groups: hardly any patients in low and high disease activity groups showed mBMD gain (Figure 2). A larger cohort might reproduce more accurate results.

DXR measurements are able to quantify disease-related BMD loss dependent on RA severity. DXR measurement surpasses quantitative ultrasound as a measure to estimate bone loss, since DXR functions independently of the effects of disease-related changes of the soft tissue (49). Nevertheless, measuring mBMD with DXR always results in some measurement error (26). Radiographs in this study were acquired at multiple sites and differences in acquisition procedures could have influenced DXR measurements. For example, tube voltage affects image-capturing conditions and this might influence the characteristics of radiographs and consequently the calculations of BMD using DXR (50). Also, different digital image devices have an effect on the reproducibility of DXR measurements (50). Further, like all DXR studies based on images originally captured for another purpose than BMD measurements, this study shares the limitation that the precision of DXR-BMD measurements is lower than in real-world use, done in accordance with the labeling of the device. However, these measurement errors would be nondifferential and result in a bias similar for all disease activity groups.

In conclusion, in patients with RA, an increase in mBMD can occur, primarily in patients in continuous clinical remission (DAS <1.6) and rarely in patients with continuous high (DAS >2.4) or low (DAS ≤2.4 but ≥1.6) disease activity. These findings suggest a link between inflammatory activity and mBMD loss. This puts a different perspective on RA, which is generally considered to be a chronic progressive disease, rather than a reversible disorder, and it points toward remission as the optimal treatment goal in patients with RA.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Ms Dirven had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Dirven, Güler-Yüksel, de Beus, Ronday, Speyer, Huizinga, Dijkmans, Allaart, Lems.

Acquisition of data. Dirven, Güler-Yüksel, de Beus, Ronday, Speyer, Allaart, Lems.

Analysis and interpretation of data. Dirven, Güler-Yüksel, Huizinga, Dijkmans, Allaart.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

Schering-Plough and Centocor had no role in the study design, data collection, data analysis, and writing of the manuscript. They did give their approval of the content of the submitted manuscript.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES

We would like to thank all of the patients as well as the following rheumatologists (other than the authors) who participated in the Foundation for Applied Rheumatology Research (all locations are in The Netherlands): W. M. de Beus, M. de Buck (Medical Center Haaglanden, Leidschendam); C. Bijkerk, A. J. Peeters, MD (Reinier de Graaf Gasthuis, Delft); M. H. W. de Bois, G. Collée (Medical Center Haaglanden, The Hague); H. Boom (Spaarne Hospital, The Hague); J. A. P. M. Ewals, R. J. Goekoop, Y. P. M. Goekoop-Ruiterman, H. M. J. Hulsmans, H. K. Ronday (Haga Hospital, The Hague); A. H. Gerards, P. A. H. M. van der Lubbe (Vlietland Hospital, Schiedam); B. A. M. Grillet (Zorgsaam, Terneuzen); J. H. L. M. van Groenendael (Franciscus Hospital, Roosendaal); K. H. Han (Medical Center Rijnmond-Zuid, Rotterdam); J. M. W. Hazes (Erasmus University Medical Center, Rotterdam); M. H. de Jager (Albert Schweitzer Hospital, Dordrecht); M. V. van Krugten (Admiraal de Ruyter Hospital, Vlissingen); H. van der Leeden (retired); W. F. Lems, A. E. Voskuyl, MD (VU University Medical Center, Amsterdam); M. F. van Lieshout-Zuidema, J. Ph. Terwiel, MD (Spaarne Hospital, Hoofddorp); C. Mallée, K. S. S. Steen, MD, S. ten Wolde, MD (Kennemer Gasthuis, Haarlem); E. T. H. Molenaar, M. van Oosterhout, A. A. Schouffoer (Groene Hart Hospital, Gouda); D. van Schaardenburg (Jan van Bremen Institute, Amsterdam); P. E. H. Seys (Lievensberg Hospital, Bergen op Zoom); P. B. J. de Sonnaville, MD (Oosterschelde Hospital, Goes); I. Speyer, MD, G. M. Steup-Beekman, M. L. Westedt, MD (Bronovo Hospital, The Hague); J. M. G. W. Wouters, MD, D. van Zeben, MD (Sint Franciscus Gasthuis, Rotterdam). We would also like to thank all of the other rheumatologists and trainee rheumatologists who enrolled patients in this study, all of the research nurses for their contributions, and the Sectra Company (Sweden) for estimating BMD of the metacarpals by online DXR. Further, we would like to thank N. B. Klarenbeek for scoring the radiographs.

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  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. ROLE OF THE STUDY SPONSOR
  9. Acknowledgements
  10. REFERENCES
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