Abstract

Objective. To determine the changes in bone mineral density (BMD) in patients with rheumatoid arthritis (RA; without osteoporosis) treated with infliximab.

Methods. Twenty-six patients (19 women, seven men) aged 54.2 yr (range 27–75), with persistently active RA despite a high dose of non-steroidal anti-inflammatory drugs and/or treatment with methotrexate or leflunomide, were studied. Mean duration of disease was 9.8 yr. Patients receiving or having received bisphosphonates or hormone replacement therapy were excluded. The patients were treated with 3.5 mg/kg infliximab at weeks 0, 2, 6 and then every 6–8 weeks. Lumbar and femoral BMD was measured by dual-energy X-ray absorptiometry at baseline and 12 months later. Serum osteocalcin and serum crosslaps were measured at baseline (week 0) and after 12 months. Twelve patients were taking calcium (1 g/day) and vitamin D (800 IU/day). Twenty patients were receiving methotrexate (mean dose 12.5 mg/day), six patients were receiving leflunomide (mean dose 20 mg/day) and nine patients were concomitantly receiving corticosteroids at a mean daily dose of 10 mg.

Results. After 12 months of infliximab therapy, there was a significant increase in BMD in the spine (BMD, P<0.001; T-score, P<0.001; Z-score, P<0.001) and the femoral neck (BMD, P<0.001; T-score, P<0.001; Z-score, P<0.01). With regard to the root mean square average, there was a significant increase in BMD at the left femoral neck (11.6% for a root mean square of 6%) but only a trend towards improvement in the spine (2.7% for a root mean square of 4%) during the study period. There was a significant increase in osteocalcin serum levels between baseline and after 12 months (P<0.01) and a significant decrease in the marker for bone resorption (P<0.01) but no change in serum calcium was observed. However, the changes in markers of bone metabolism and BMD were not correlated.

Conclusion. The data support the hypothesis that anti-TNF therapy may exert beneficial effects on bone metabolism in RA patients.

In recent studies it has been proposed that bone metabolism is increased in various inflammatory rheumatic diseases [1, 2]. It has been hypothesized that the stimuli that initiate and perpetuate the severe alterations in bone turnover are based on the inflammatory diseases themselves resulting in multisystem damage, a process which specifically induces resorptive factors [3, 4]. In addition, glucocorticoid treatment, which suppresses disease activity, is also known to be as an inducer of osteoporosis [5, 6], affects calcium and bone metabolism and leads to substantial and rapid bone loss. However, some years ago it was clearly demonstrated that generalized osteoporosis can occur in rheumatic patients without glucocorticoid medication [7]. In contrast, it was recently shown that anti-tumour necrosis factor α (TNF-α) therapy increased bone mineral density (BMD) in ankylosing spondylitis [8]. As TNF-α plays also a central role in the destructive process of rheumatoid arthritis (RA), and as this cytokine has been shown to mediate bone resorption both in systemic postmenopausal osteoporosis and in periarticular or periprosthetic bone erosions [9], we performed an open-label prospective study to evaluate changes in BMD of patients with RA under long-term anti-TNF therapy. We chose infliximab as investigational drug due to its successful use in the treatment of RA, Crohn's disease and ankylosing spondylitis [10–12].

Moreover, we investigated bone metabolism by using biochemical markers of bone formation and resorption, and we studied the relationship between BMD, markers of bone turnover, and response to the treatment.

Materials and methods

Study population

Twenty-six patients (19 women, seven men) aged 54.2 yr (range 27–75) from the out-patient clinic of the Department of Rheumatology, Kerckhoff Clinic, Bad Nauheim, with persistently active RA (according to the revised Criteria for the Classification of Rheumatoid Arthritis [13]) despite a high dose of non-steroidal anti-inflammatory drugs and/or treatment with methotrexate or leflunomide, were included in the study. Mean duration of disease was 9.8 yr (range 2–16). Median body mass index was 24.2 kg/m2, without significant changes during the study period. Two women were menopausal at baseline. The patients were treated with 3.5 mg/kg infliximab i.v. at weeks 0, 2 and 6 and then every 6–8 weeks. Patients receiving or having received bisphosphonates or hormone replacement therapy were excluded. Twelve patients were taking calcium (1 g/day) and vitamin D (800–1000 IU/day). Twenty-one of the patients were receiving corticosteroids at a mean daily dose of 10 mg, and five of them were receiving glucocorticoids during the study (average 5 mg/day). Twenty patients received methotrexate (mean daily dose 12.5 mg) and six patients leflunomide (mean daily dose 20 mg) during the study period. The activity and severity of RA were assessed by the Disease Activity Score [DAS 28; at baseline the median (range) score was 5.0 (3.7–6.3); after 12 months it was 2.8 (2–3.5)], ESR [baseline median (range) 59 mm/1st h (33–89); after 12 months 27 mm/1st h (12–44)] and CRP [baseline median (range) 5.7 mg/dl (2.6–14.1); after 12 months 0.7 mg/dl (0–4.5)], illustrating the general effect of infliximab in these patients.

BMD (g/cm2) was measured at baseline and after 12 months at the lumbar spine (first to fourth vertebrae, anteroposterior view) and the left femoral neck by dual-energy X-ray absorptiometry (DXA) (Prodigy Lunar, Milwaukee, WI, USA). The coefficient of variation of repeated measurements in vivo was 0.9% for the lumbar spine and 1.6% for the femoral neck.

T-scores (number of s.d.s from the normal mean obtained from young healthy adults) were also calculated. A low BMD was defined according to the World Health Organization guidelines: osteopenia as a T-score between −1 and −2.5 s.d. and osteoporosis as a T score <2.5 s.d. Reference values have been published previously for women and men; the reference values of the manufacturer were used. At baseline, none of the patients was osteoporotic and five were osteopenic at the spine and femur.

At baseline, plasma parathormone (1–84) [57.8 pg/ml (44–68); RIA, Nichols Institute, Wijchen, Netherlands] and 25-hydroxycholecalciferol D levels [34.9 ng/ml (9–45); Incstar Corporation, Stillwater, MN, USA] were within the normal range, and all patients had a normal serum creatinine. Osteocalcin was measured by a kit from Incstar Corporation (normal range 1.8–6.6 ng/ml). Serum crosslaps (enzyme-linked immunosorbent assay) were evaluated with a device from Rosch, Mannheim, Germany (normal range 0.1–10 ng/ml).

Statistical methods

The alterations of BMD, osteocalcin, crosslaps, DAS 28, ESR and CRP were evaluated during the 12-month study period. Data were compared using the Wilcoxon signed rank sum test. Although absolute changes were measured, data are presented as mean ± s.d. unless otherwise noted. Correlations between changes of BMD and biochemical parameters were also tested using the Spearman correlation coefficient (rs). P<0.05 was regarded as significant for all analyses. Data were evaluated using SPSS for PC (release 10.0.7, 2001; SPSS, Chicago, IL, USA). The root mean square average of the DXA used was determined as 4% for the spine measurement and 6% for the femoral neck. Calculations were performed according to the recommendations of the International Bone Densitometry Certification [14].

Results

A significant increase in BMD, T-score and Z-score at the spine (P<0.01) and at the left femoral neck (P<0.01) could be observed between baseline compared with 12 months (Table 1). With regard to the root mean square average, there was a significant increase in BMD at the left femoral neck (11.6% for a root mean square of 6%) but only a trend at the spine (2.7% for a root mean square of 4%) during the study period. Moreover, a significant increase in osteocalcin serum levels between baseline and after 12 months, and a significant decrease in the marker of bone resorption (crosslaps) could be seen, but there were no changes in serum calcium levels in the study period (Table 2). Changes in neither osteocalcin nor serum crosslaps correlated with the improvements in BMD. The decreases in DAS 28, ESR and CRP between baseline and 12 months (all significant: P = 0.01, P = 0.01 and P = 0.01, respectively) were accompanied by a trend in the correlation between changes in DAS 28 with the axial and peripheral BMD (rs = −0.3, P = 0.07), but no correlation between other laboratory parameters and the BMD was observed. In the five patients receiving corticosteroids during the follow-up, there was no change in BMD in three cases, and two patients showed an increase in axial and peripheral BMD.

Table 1.

Changes in DXA parameters during the study period

 Baseline After 12 months P 
BMD left femoral neck (g/cm20.84 ± 0.33 0.95 ± 0.15 0.001 
T-score left femoral neck (g/cm2−0.93 ± 1.06 −0.77 ± 0.97 0.001 
Z-score left femoral neck (g/cm2−0.24 ± 0.77 −0.16 ± 0.68 0.010 
BMD L1–4 1.07 ± 0.14 1.10 ± 0.23 0.001 
T-score L1–4 −0.92 ± 1.09 −0.71 ± 1.07 0.001 
Z-score L1–4 −0.58 ± 1.23 −0.49 ± 1.14 0.001 
 Baseline After 12 months P 
BMD left femoral neck (g/cm20.84 ± 0.33 0.95 ± 0.15 0.001 
T-score left femoral neck (g/cm2−0.93 ± 1.06 −0.77 ± 0.97 0.001 
Z-score left femoral neck (g/cm2−0.24 ± 0.77 −0.16 ± 0.68 0.010 
BMD L1–4 1.07 ± 0.14 1.10 ± 0.23 0.001 
T-score L1–4 −0.92 ± 1.09 −0.71 ± 1.07 0.001 
Z-score L1–4 −0.58 ± 1.23 −0.49 ± 1.14 0.001 
Table 2.

Changes in biochemical parameters and DAS 28 during the study period

 Baseline After 12 months P 
Osteocalcin (ng/ml) 3.05 ± 1.57 5.04 ± 1.22 0.001 
Crosslaps (ng/ml) 5.33 ± 1.54 3.94 ± 1.08 0.001 
Calcium (mmol/l) 2.46 ± 0.12 2.48 ± 0.31 0.39 
DAS 28 5.02 ± 0.70 2.80 ± 0.33 0.001 
ESR (mm/1 h) 59 ± 15 28 ± 8 0.001 
CRP (mg/dl) 5.7 ± 2.7 0.7 ± 1.1 0.001 
 Baseline After 12 months P 
Osteocalcin (ng/ml) 3.05 ± 1.57 5.04 ± 1.22 0.001 
Crosslaps (ng/ml) 5.33 ± 1.54 3.94 ± 1.08 0.001 
Calcium (mmol/l) 2.46 ± 0.12 2.48 ± 0.31 0.39 
DAS 28 5.02 ± 0.70 2.80 ± 0.33 0.001 
ESR (mm/1 h) 59 ± 15 28 ± 8 0.001 
CRP (mg/dl) 5.7 ± 2.7 0.7 ± 1.1 0.001 

Discussion

Disease-related osteoporosis is a serious problem in inflammatory rheumatic diseases with various relevant complications [1, 15], and RA itself is associated with osteoporosis that may be localized or generalized [2, 16]. In RA, periarticular osteoporosis has long been recognized one of the earliest radiological signs [17], and it is thought that the release of inflammatory mediators, particularly cytokines, from the different inflammatory cells is the most likely cause [3, 4]. In addition, factors that may cause generalized osteoporosis in inflammatory arthritis include circulating proinflammatory molecules; hormones; altered calcium metabolism; changes in load-bearing of the skeleton; and the effects of antirheumatic and anti-inflammatory drugs [17, 18].

The present prospective open-label study showed a significant BMD increase in the femoral neck, and an ameliorating trend in the spine in patients with RA 12 months after initiation of therapy with infliximab.

These results are consistent with animal experiments, in which TNF-α has been shown to increase bone resorption and decrease bone formation [19, 20]. In this animal model, it was shown that the administration of TNF binding proteins stimulated bone formation [19], which supports the idea that bone formation under anti-TNF-α therapy might be the result of increased osteoblast activity, recruitment of osteoblasts or their activation.

In addition, the results of the present study, in which inhibition of TNF-α resulted in a decrease in systemic inflammation and an increase in bone density, adds some evidence in favour of the hypothesis of bone loss mainly due to systemic inflammation through direct effects of TNF-α on bone. However, we also found a trend for correlation between changes in the DAS 28 and the BMD of the spine and left femoral neck. This suggests that other factors may also contribute to the increase in BMD, e.g. increased mobility of the patient or effects on synthesis of osteoprotegerin [21]. With regard to the biochemical markers used in the study, there was a shift towards increased bone formation (osteocalcin) and decreased bone resorption (crosslaps). Of interest, the changes in bone markers and BMD were not correlated, suggesting an uncoupling effect on bone cells.

Oral bisphosphonates are the drugs used most in inflammatory-mediated osteoporosis, and they are available to both prevent and treat bone loss. Recently, in women with postmenopausal osteoporosis an increase of BMD between 5 and 9% was observed under continued bisphosphonate treatment (alendronate or risedronate) for 3 yr [22, 23]. In contrast, the data presented in the present paper showed a significant increase in BMD in the spine (2.8%) and left femoral neck (13%) after 1 yr of anti-TNF-α therapy, which supports the idea of osteoprotective potency.

In summary, the results of this study demonstrate that the beneficial effects of infliximab in RA therapy are accompanied by a significant amelioration of different parameters of bone metabolism, suggesting a profound effect—similar to the findings in patients with spondyloarthropathies—on osteoprotective pathways. In addition, the results increase our knowledge of mechanisms of RA-associated bone loss.

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Author notes

Kerckhoff Clinic and Foundation, Department of Rheumatology, Clinical Immunology and Osteology, Bad Nauheim, University of Giessen, Giessen and 1Medical Clinic C, City Hospital Ludwigshafen, Ludwigshafen, Germany.

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