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Rheumatology 2001; 40: 1231-1237
© 2001 British Society for Rheumatology

Original Papers

Bone turnover, joint damage and bone mineral density in early rheumatoid arthritis treated with combination therapy including high-dose prednisolone

A. C. Verhoeven1, M. Boers2,, J. M. te Koppele3, W. H. van der Laan3, H. M. Markusse4, P. Geusens1,5 and S. van der Linden1

1 Internal Medicine/Rheumatology Department, Maastricht University Hospital, Maastricht,
2 VU University Hospital, Amsterdam,
3 TNO Prevention & Health, Vascular and Connective Tissue Research Division, Leiden,
4 Rheumatology Department, Zuider Hospital, Rotterdam, The Netherlands and
5 Biomedical Research Institute, Limburg University Centre, Diepenbeek, Belgium


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. Exploration of bone metabolism changes at different levels of disease activity, both with and without oral corticosteroid therapy, and prediction of changes in joint damage and bone density from the observed changes in markers of bone turnover.

Methods. Data analysis from a randomized clinical trial with 155 rheumatoid arthritis (RA) patients; median age 50 yr, early and active disease (diagnosis <2 yr); one group treated with a combination of sulphasalazine (SSZ; 2000 mg/day), methotrexate (MTX; 7.5 mg/week) and prednisolone (initially 60 mg/day, tapered in six weekly steps to 7.5 mg/day), the other group with SSZ alone. Prednisolone and MTX were tapered and stopped after weeks 28 and 40, respectively, while SSZ was continued. Urine and serum samples were collected at baseline and weeks 16, 28, 40 and 56. Measurements of urinary pyridinoline (PYD) and deoxypyridinoline (DPD) and serum alkaline phosphatase (tAP) and osteocalcin (OC) were performed, as well as standard clinimetry and bone densitometry.

Results. Over time and in both treatment groups, bone formation and bone resorption markers showed a pattern similar to erythrocyte sedimentation rate (ESR): a significant decrease compared with baseline and a larger decrease with combined treatment at weeks 16 and 28. PYD excretion, tAP, OC, and joint damage scores were significantly lower in the combined treatment group. Changes in bone density (of spine and hips) did not significantly differ between treatment groups. Mainly cumulative ESR explained progression of joint damage.

Conclusions. Prednisolone and disease-modifying anti-rheumatic drug therapy in patients with early and active RA are both independently associated with decreased levels of urinary excretion of bone collagen resorption markers PYD and DPD. Markers of bone formation and resorption closely followed changes in ESR in both treatment groups. Reduced bone resorption together with reduced bone formation—initially at a somewhat faster pace—resulted in less bone turnover and explain the observed (non-significant and partially reversible) extra bone loss in the lumbar spine associated with prednisolone (combined treatment).

KEY WORDS: Early rheumatoid arthritis, Pyridinoline, Deoxypyridinoline, Collagen crosslinks, Bone mineral density, Outcomes, Glucocorticoids, Randomized clinical trial.


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Rheumatoid arthritis (RA) is a systemic disease with inflammation and destruction of joints in the hands and feet as a hallmark. As a result of pathological destruction of collagen in bone and cartilage, crosslinks in mature collagen are resorbed more rapidly. This causes a rise in circulating collagen crosslink levels and their urinary excretion. In RA, apart from the crosslink resorption at the site of inflamed joints, there may be increased resorption due to general bone loss associated with disease activity [1, 2].

The most important collagen crosslinks of bone and cartilage are the pyridinium derivatives, pyridinoline (PYD or hydroxylysylpyridinoline) and deoxypyridinoline (DPD or lysylpyridinoline). Most DPD is present in type I collagen which is the main protein component of bone and dentine. Most excreted DPD comes from bone as this tissue undergoes relatively rapid remodelling. Therefore, urinary excretion of DPD is considered a more or less specific estimate of resorption of bone by osteoclasts. PYD is more widely distributed and present in considerable amounts in cartilage-specific collagen: types II, IX and XI; it may present a marker of destruction in cartilage and other soft tissues [3]. Diet or physical exercise do not influence excretion of PYD and DPD. Because of circadian rhythm in bone remodelling [4, 5], excretion in 24 h collection is widely considered the standard, but samples collected during a fixed day time with concentrations corrected for creatinine (Cr) reflect 24 h excretion levels as well [6].

Treatment in RA traditionally starts with non-steroidal anti-inflammatory drugs (NSAIDs), and continues if necessary with a sequence of progressively toxic so-called disease-modifying anti-rheumatic drugs (DMARDs) [7]. Some DMARDs and corticosteroids provide a degree of disease control, i.e. they decrease disease activity, maintain physical function and attenuate joint damage visible on radiographs [8–11]. Recent studies suggest that early introduction of DMARDs and corticosteroids may be beneficial for patients with recently diagnosed RA [12, 13]. However, the use of corticosteroids is controversial due to side-effects, including osteoporosis. The COBRA study [13] (COmbinatietherapie Bij Reumatoïde Artritis) aimed at rapid disease control in early RA patients by a step-down bridge combination therapy with agents that have overlapping windows of efficacy onset; the regimen comprised a short period of high-dose oral prednisolone. The other components of the combination were methotrexate (MTX) and sulphasalazine (SSZ) as an anchor drug to remain when the other two drugs were tapered and stopped after 6 months to prevent adverse effects while retaining disease control. The combination therapy regimen demonstrated excellent clinical response, comparatively few adverse effects, and less progression in radiographic joint damage.

This study had two main goals. First, to clarify the changes in bone metabolism at different levels of improvement in disease activity over a 56-week follow-up period, both with and without oral corticosteroid therapy. Second, to investigate the possibility of predicting changes in joint damage and bone mineral density (BMD) from the observed changes in markers of bone turnover.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients, clinical efficacy measures and adverse effects
All measures were performed in the setting of the COBRA study [13]. This concerned a 1-yr clinical trial with 155 RA patients [1987 American College of Rheumatology (ACR) criteria [14]] aged 18–70 yr, who were randomly assigned to one of two treatment regimes. All patients had early, active disease (diagnosis <2 yr). No prior treatment with second-line anti-rheumatic medication apart from anti-malarials was allowed. One group was treated with a combination of SSZ (2000 mg/day), MTX (7.5 mg/week) and prednisolone (initially 60 mg/day, tapered in six weekly steps to 7.5 mg/day). The other group was treated with SSZ and double placebo. Prednisolone and MTX (or the placebos) were tapered and stopped after weeks 28 and 40, respectively, while SSZ was continued. The total amount of prednisolone prescribed according to the study protocol was 2345 mg, the mean dose over the first 28 weeks of follow-up was 12 mg/day. All patients had calcium supplementation (1 g/day) prescribed for as long as they used prednisolone, and folic acid (1 mg/day) as long as they used MTX. Vitamin D supplements were given when vitamin D deficiency was present at baseline.

Clinical improvement was expressed by the preliminary ACR criteria [15] that require a minimum of 20% improvement in tender and swollen joint counts plus a similar improvement in at least three of five remaining core set measures: patient and physician global assessment, pain, acute phase response, and physical function. We also report the number of core set measures with 20% improvement, and the change in the Disease Activity Score (DAS) [16], a composite outcome measure containing the Ritchie tender joint index (RAI) [17], swollen joint count (48 joints assessed), Westergren's erythrocyte sedimentation rate (ESR), and patient's global assessment (10 cm visual analogue scale)=0.54{surd}RAI+0.065 swollen joint count +0.33 ln(ESR)+0.07 patient global assessment. Improvement in physical function was reflected by a validated Dutch version of the Health Assessment Questionnaire (HAQ) [18, 19] completed by the patients.

Bone-related outcomes were joint damage and BMD. Progression in joint damage was assessed by van der Heijde et al.'s [8] modification of Sharp's scoring method; a quantitative score for erosions and joint space narrowing visible on radiographs of the hands and feet. Radiographs taken at baseline and weeks 28 and 56 were read in sequence by two trained observers, unaware of treatment allocation. BMD in the lumbar spine and femoral neck was measured at baseline and weeks 28 and 56 in centres where dual energy X-ray absorptiometry was available. Changes in BMD (g/cm2) were reported by percentage compared with baseline; for the femoral neck, the mean of both sides was calculated. For further analysis, every patient's propensity to lose bone was categorized as male, pre-menopausal female, post-menopausal female, or post-menopausal female with hormonal replacement therapy.

The study protocol was approved by research and medical ethics committees in all participating hospitals (nine clinical centres in The Netherlands and one in Belgium). All patients gave written informed consent before they entered the study protocol between May 1993 and May 1995.

Biochemistry
Urinary spot and serum samples were collected at baseline and weeks 16, 28, 40 and 56, and stored in 10 ml aliquots at -20°C. The total amount of excreted PYD and DPD was measured by high-performance liquid chromatography (HPLC). Urine samples were hydrolysed in 6 M HCl, dried and reconstituted in 50% acetic acid and injected onto a HPLC column with on-line purification on CC31 cellulose using a Prospekt solid-phase extractor (Separations, The Netherlands). The retained crosslinks were eluted from the CC31 material and on-line chromatographed on a cation exchange column (Whatman Partisil SCX). Eluted crosslinks were detected by a Jasco fluorimeter (Model FP-920, Separations). The PYD/DPD HPLC calibrator (Metra, Palo Alto, CA, USA) was used as the standard. The intra- and interassay coefficients of variation were <3 and <5% for PYD/Cr and DPD/Cr, respectively. Urinary excretion rates are expressed as nmol/mmol Cr. Cr was measured in the same urine samples by the Kodak Ektachem Clinical Chemistry Slide (CREA; Eastman Kodak Incorporate, Rochester, NY, USA). Bone formation was calculated using total serum alkaline phosphatase (tAP). These were routinely assessed and registered by standard laboratory techniques in each clinical centre at every monitoring visit, Thus, they were available more frequently than every 16 or 12 weeks. Finally, serum osteocalcin (OC) was measured in collected serum samples using a commercial kit (N-Mid-Osteo; Osteometer, Copenhagen, Denmark) and expressed as ng/ml. Intra- and interassay coefficients of variation of these measurements were <5 and <8%, respectively.

Statistical analysis
Change in comparison with baseline values was calculated for all variables. In the case of a non-Gaussian distribution, change scores were transformed (with natural logarithm). Paired and unpaired Student t-tests were used for comparisons of change with baseline and between groups, respectively. Post-hoc subgroup analysis was performed for hormonal status. The ratio of tAP and natural log-transformed PYD excretions (i.e. tAP/ln[PYD/Cr]) is presented to reflect changes in the balance between osteoblast and osteoclast activity.

To elucidate further the relationships between PYD excretion and disease activity, we calculated Pearson's moment correlation between changes in PYD/Cr and DPD/Cr at week 28, changes in all ACR core set measures, the number of ACR core set measures with at least 20% improvement, and the change in DAS. From the literature, as well as from primary analyses, acute phase reactants such as ESR emerge as adequate measures to reflect disease activity [15, 16]. Time-integrated values of ESR were calculated, as this representation of cumulative acute phase reaction is known to correlate well with progression in joint damage [20]. Time-integrated PYD/Cr, DPD/Cr, ESR and tAP were correlated with progression in joint damage score, and with changes in BMD of the spine and hips.

To determine if the changes in PYD excretion can be explained solely by glucocorticoid-induced changes in disease activity, a multiple regression analysis was carried out with PYD excretion at week 28 as a dependent variable, and ESR change, treatment group allocation and interaction between group and ESR as independent variables.

The potential contribution of PYD excretion as a predictor of outcome independent of ESR was evaluated by stepwise multiple regression analyses in which the natural log-transformed change in joint damage and changes in bone density served as dependent variables. Their respective baseline values, time-integrated ESR and PYD excretions and treatment served as predictors (independent variables); F to enter >4.0.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Clinical effects have been reported elsewhere [13]. Briefly, at week 16, a substantial and significant improvement in almost all measures was observed in both treatment groups. Improvement stabilized or increased towards week 28, with improvement in the combined treatment group being almost double that in the SSZ group. After 28 weeks of follow-up, the mean decrease in ESR was 40 mm/h in the combined treatment group vs 27 mm/h in the SSZ group (P=0.0022; Fig. 1Go). Radiographic damage scores in both groups were similar at baseline (Table 1Go). After 56 weeks, the median progression of the radiographic damage score was two points in the combined treatment group vs six in the SSZ group (P=0.004). During the first 28 weeks, BMD in the lumbar spine decreased 1.2% in the combined treatment group (n=63) vs 0.0% (n=62) in the SSZ group (P=0.06). In the femoral neck, the corresponding changes were -0.3 vs -0.7% (n=59 and 57). Significantly fewer patients in the combined treatment group stopped protocol medication because of adverse events or lack of therapy effect; six vs 23 in the SSZ group; P=0.0008. Withdrawal occurred later in the combined treatment group than in the SSZ group.



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  		FIG. 1. Parameters of bone metabolism, acute phase reaction (ESR), joint destruction, and BMD, per treatment group at baseline and follow-up at weeks 16, 28, 40, and 56; week 40 is after the tapering and withdrawal of prednisolone in the combined treatment group, week 56 is after the withdrawal of MTX. Open circles, SSZ treatment; dark grey diamonds, combined treatment. Mean±S.E.M. *unpaired t-test P<0.05, **P<0.01.

 

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  		TABLE 1. Baseline characteristics [median (minimum–maximum) or count (%)] of study patients according to treatment group

 
Changes in PYD/Cr and DPD/Cr were calculated in 115 patients; 55 in the combined treatment group and 60 in the SSZ group. These changes showed a similar pattern to those observed in the other outcome measures such as ESR. At weeks 16 and 28, PYD excretion decreased significantly compared with baseline values (all P<0.0001). There was a rapid decrease up to week 16 and a slower decrease up to week 28, with a significant difference between treatment groups at week 28; PYD/Cr 45 vs 18% reduction in the combined treatment and SSZ groups (P=0.02); DPD/Cr 33 vs 15% reduction (P=0.11; Fig. 1Go). Also, the PYD/DPD ratio showed a decrease in the combined treatment group at weeks 16 and 28 (between-treatment differences at weeks 16 and 28: P=0.04 and 0.02).

Change in tAP agreed with the general pattern of decreased disease activity in reaction to treatment (Fig. 1Go). At baseline, mean tAP was slightly elevated in both groups. Change scores on tAP were available for 74 patients in the combined treatment group and 73 patients in the SSZ group. Similar to ESR, TAP dropped rapidly in the combined treatment group (within 4 weeks). At week 16, there was a significant decrease in both groups (P<0.001) and a significantly larger decrease in the combined treatment group [difference: 21 IU/ml, P<0.001; 95% confidence interval (CI) 11–31; 31 vs 11% reduction]. In contrast with the changes observed in PYD/Cr and DPD/Cr, the between-group difference in tAP did not increase between weeks 16 and 28 of follow-up. At weeks 16 and 28, serum OC concentrations in the combined treatment group (n=56; SSZ group n=62) showed a significant decrease (all P<0.0001). Maximum and significant between-group contrast occurred at week 16 (P<0.0001; Fig. 1Go). This corresponds with a maximum between-group contrast in the tAP/ln[PYD/Cr] ratio at that time (P=0.09).

Post-menopausal women (n=39) tended to have larger reductions in PYD excretion, as well as in tAP, especially in the combined treatment group (not significant). This may be due to initially higher values along with greater disease activity in these patients.

Table 2Go shows correlations of changes in PYD excretion with ACR outcome measures and DAS. Of all core set measures, ESR showed the highest correlation with PYD excretion. Changes in tAP also showed significant correlation with changes in PYD excretion. Calculations per treatment group showed similar correlations (data not shown).


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  		TABLE 2. Correlations between changes in PYD excretion and changes in other outcome measures at 28 weeks of follow-up

 
Change scores for joint damage showed a significant correlation with time-integrated PYD excretion: 0.37 and 0.33 for PYD/Cr and DPD/Cr, respectively. Time-integrated ESR and OC yielded larger correlation coefficients. Changes in BMD of the lumbar spine did not yield a significant correlation with PYD excretion. Bone loss in the femoral neck, on the contrary, did show a weak and significant association with time-integrated PYD excretion (Table 3Go).


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  		TABLE 3. Spearman's rank correlations of ‘bony outcomes’ with time-integrated PYD excretion, ESR, tAP and OC at 28 weeks of follow-up

 
In multiple regression analyses with change in PYD/Cr and DPD/Cr over 28 weeks as dependent variables, the change in ESR was the only significant attributing variable (P=0.002 and 0.011, respectively; R2=31 and 29%). Treatment group and interaction between treatment and change in ESR did not significantly increase the proportion of explained variance.

In a stepwise regression analysis with (log-transformed) progression in joint damage at week 28 as the dependent variable, time-integrated ESR, log-transformed baseline joint damage score, and treatment group entered the model. The proportion of variance explained (R2) was 53%. Time-integrated PYD excretion did not enter this model. At week 28 of follow-up, changes in BMD of the lumbar spine and femoral neck proved to be less easy to predict with R2=5 and 10%, respectively. For the prediction of spinal bone loss the only variable which was selected was treatment group; for the prediction of changes in femoral bone density, only log-transformed time-integrated PYD/Cr was selected.


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
Over time and in both treatment groups, PYD excretion showed a pattern similar to the other variables assessed in the COBRA study. Combined treatment with step-down prednisolone, MTX and SSZ caused significantly larger reductions in initially elevated urinary PYD excretion than treatment with SSZ alone. The decreased levels of bone resorption together with decreased bone formation point to a state with less bone turnover. Treatment with SSZ alone also led to a decrease in bone turnover, but this effect was smaller. Markers of bone formation and bone resorption reflect overall disease activity, but the measurable response of osteoblasts (i.e. bone formation) was quicker than that of osteoclasts. A rapid decrease in osteoblast activity—compared with a slower decrease in osteoclast activity—can explain the ‘early phase’ of bone loss observed in RA patients who start treatment with corticosteroids [21].

AP is produced in cells other than osteoblasts and a direct effect of trial medication on this marker cannot be excluded. However, as simultaneously measured transaminase and bilirubin levels as well as {gamma}-glutamyl transpeptidase levels measured afterwards did not show significant changes during prednisolone therapy, we can be rather confident that the changes in tAP reflect mainly AP's bone fraction. We prefer tAP instead of OC as a marker of bone formation, as OC is more properly a marker of bone turnover rather than a specific marker of bone formation [22]. Over time, serum OC levels in both treatment groups also mimicked tAP/ln(PYD/Cr) ratios that served as proxy for bone turnover rates—even with storage conditions that were not optimal for OC.

The level of disease control during the first 28 weeks of follow-up achieved with combined treatment was substantial. Markers of bone resorption (PYD and DPD urinary excretion) reflect this, as well as the ‘proxy’ bone formation marker tAP, and clinical outcome measures. In the correlation analysis, changes in bone resorption markers were strongly related to acute phase reaction and functional ability (i.e. HAQ) and to a lesser extent to markers of bone formation. The observed changes in PYD excretion may be mediated by reduced disease activity alone. An effect of prednisolone on bone turnover at doses as prescribed, separate from altered disease activity, was not demonstrable; treatment group allocation did not significantly improve prediction of changes in PYD excretion once changes in ESR were taken into the regression model.

In the prediction of progression in joint damage in this patient group with early disease, the contribution of observed changes in bone resorption turned out to be modest, especially when markers of acute phase reaction, such as ESR, were available. The relatively high correlation coefficients between cumulative ESR and joint damage score in the SSZ group may be explained by larger variation in therapy effects with less adequate suppression of disease activity through single SSZ therapy. The modified Sharp score comprises joint erosions as well as joint space narrowing. Bone-specific DPD levels were expected to correlate less with narrowing scores than PYD, because narrowing reflects loss of (a joint's) cartilage. This however, could not be demonstrated. Decreasing PYD/DPD ratios reflect relatively large resorption of bone as compared with other collagenous tissues. Decreasing levels of PYD, DPD, and PYD/DPD together, as seen in the combined treatment group, suggest a beneficial effect on predominantly non-bone collagenous tissue; presumably cartilage. In contrast, Sharif et al. [23] could not show changes in putative markers of cartilage loss such as 5D4 keratan sulphate epitope in a RA patient group treated with prednisolone, although there were clear signs of reduced synovitis and bone turnover.

We observed a small extra decrease in spinal BMD in the combined treatment group (P=0.06). This was most probably a prednisolone effect. After prednisolone was tapered and stopped, the cumulative bone loss stabilized [13]. At this site there was no significant correlation between BMD and cumulative PYD excretion (or disease activity). In contrast, in the femoral neck no difference in BMD loss between the groups emerged, but there was a significant correlation between time-integrated PYD excretion and BMD change. Gough et al. [1] earlier described an association between urinary PYD excretion and bone loss at the femoral neck. These BMD changes appear not to be directly mediated by cumulative disease activity, as the correlation with time-integrated ESR is low, and furthermore time-integrated PYD/Cr proved to be the only significant predictor for bone loss in the hip. It may be that specifically at the site of the femoral neck corticosteroid-induced bone loss has been balanced by the bone-saving effect of prednisolone through a reduction in disease activity [24].

Many pathways of bone metabolism, such as inhibition of matrix metalloproteinases, remain to be clarified. PYD and DPD are valuable markers to show actual bone resorption, especially mechanisms that are not mediated by cytokines or take action at a different level. As an example, those and future bone-specific markers may be necessary to elucidate further the complex relationships between bone metabolism at different sites, RA disease activity and its suppression, e.g. by corticosteroids.

In conclusion, the changes in bone metabolism in reaction to treatment with and without corticosteroids, are predominantly mediated by therapy-induced reduction of disease activity. In early RA, the contribution of urinary PYD excretion in the prediction of disease outcome may be modest, especially when markers of acute phase reaction are readily available. Nonetheless, PYD may give us insight into bone metabolism and help us to understand better the actual changes in bone and cartilage caused by RA and its treatment.


   Acknowledgments
 
The COBRA study was funded by grant number 92-045 Ontwikkelingsgeneeskunde, Ziekenfondsraad, The Netherlands. We thank the patients and the research personnel. We thank Mrs Marjolein Braeken for trial management, Mrs Lily Heusschen-Houben for data entry. The COBRA trial group comprised the following centres and rheumatologists: Daniël den Hoed Kliniek, Rotterdam (H. M. Markusse), Medisch Spectrum Twente and Twenteborg Hospital, Enschede and Almelo (M. A. F. J. van de Laan), University Hospital, Maastricht (M. Boers), Pellenberg Hospital Catholic University, Leuven (R. Westhovens), Jan van Breemen Instituut Amsterdam (J. C. van Denderen), Bronovo Hospital, The Hague (D. van Zeben), University Hospital Leiden (B. A. C. Dijkmans), Reinier de Graaf Gasthuis, Delft (A. J. Peeters), Sint Laurentius Hospital, Roermond (P. Jacobs), Medisch Centrum, Alkmaar (H. R. van den Brink).


   Notes
 
Correspondence to: M. Boers, Department of Clinical Epidemiology VE9-78, VU University Hospital, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. Back


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 1 November 2000; Accepted 9 May 2001


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