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  • Effect of intra-articular corticosteroid injections and inflammation on periarticular and generalised bone loss in early rheumatoid arthritis

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Clinical and epidemiological research
Concise report
Effect of intra-articular corticosteroid injections and inflammation on periarticular and generalised bone loss in early rheumatoid arthritis
  1. Glenn Haugeberg1,
  2. Sarah Morton2,
  3. Paul Emery3,
  4. Philip G Conaghan3
  1. 1Department of Rheumatology, Sørlandet Hospital, Kristiansand, Norway
  2. 2Balmore Park Surgery, Caversham, UK
  3. 3Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds, UK
  1. Correspondence to Professor Philip G Conaghan, Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, 2nd Floor, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK; p.conaghan{at}leeds.ac.uk

Abstract

Objectives To explore the effect of intra-articular corticosteroid (IAST) injections on bone mineral density (BMD) in the hand and at the metacarpophalangeal (MCP) joints in early rheumatoid arthritis (RA).

Methods In the first 3 months of the study, 19 patients with RA received methotrexate (MTX) alone and 21 received MTX and IAST injections into clinically inflamed joints. In the following 9 months, all patients received MTX+IAST. BMD was assessed at the hand and periarticular regions at MCP joints 2–5 at baseline, 3 and 12 months.

Results In the first 3 months a numerically lower percentage rate of bone loss was seen in MTX+IAST-treated patients compared with MTX-treated patients. This observation was more pronounced at the MCP periarticular regions (eg, partial proximal phalanges: digit 2, −0.45% vs −2.69%, p=0.045; digit 3, −0.34% vs −3.32%, p=0.003; digit 4, −0.39% vs −2.57%, p=0.14; digit 5, −0.59% vs −2.70%, p=0.24) than for the whole hand (−1.53% vs −2.42%, p=0.32). In the 3–12-month period, only minor non-statistically significant differences were seen between the two groups.

Conclusion IAST given over 3 months protects against periarticular bone loss in inflamed finger joints in RA. These data emphasise the importance of suppressing inflammation in patients with active RA to maintain bone health.

http://dx.doi.org/10.1136/ard.2009.128124

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    The inflammatory disease process in rheumatoid arthritis (RA) causes joint erosions and periarticular and generalised osteoporosis,1 all three features being a result of increased osteoclast activation and formation.2 Oral corticosteroids may aggravate the RA osteoporotic process, but they also suppress inflammation and reduce the rate of RA erosive joint destruction3 4 and reduce the rate of cortical hand bone loss.5 6

    In daily clinical practice, intra-articular corticosteroid (IAST) injections are frequently used as they provide rapid reduction of symptoms in clinically inflamed joints.7 8 IAST injections in RA have also been shown to reduce synovitis and the development of erosions.4 Despite their widespread use, the impact of IAST on periarticular and generalised bone loss in patients with RA has, to our knowledge, not been previously studied.

    The aim of this study was to explore the effect of IAST on bone density assessed at periarticular regions adjacent to the metacarpophalangeal (MCP) joints and on generalised bone loss and to search for associates with bone loss.

    Methods

    Clinical study

    Clinical and MRI data from this study have been published previously.4 In summary, the study recruited 40 people with RA with disease duration <12 months, with symmetrical polyarthritis affecting the MCP joints. Patients were excluded if they had previously been treated with disease-modifying anti rheumatic drugs and oral or intramuscular corticosteroids.

    In the first 3-month period the patients were randomised to receive either methotrexate (MTX) alone or MTX and intra-articular methylprednisolone into all joints with clinically active arthritis (defined as both tender and swollen). From 3 to 12 months, both groups received the same standard treatment with MTX and IAST.4 Patient visits were performed at baseline and at 1, 2, 3, 6, 9 and 12 months. MRI of the dominant hand (MCP joints 2–5) was performed at baseline, 3 and 12 months.4 For the present study, synovitis was rescored according to RA MRI scoring (RAMRIS).9 The number of bone marrow oedema (BME) lesions was counted.

    Bone densitometry

    Standardised bone mineral density (BMD) measurements of both hands at baseline, 3, 6 and 12 months and at spine L2–4 and both femoral necks at baseline and 12 months were performed using a Lunar Expert-XL dual energy x-ray absorptiometry (DXA) scanner (Wisconsin, USA). The Lunar Expert software (Version 1.90) was used to produce customised regions of interest (ROIs) at MCP joints 2–5 of the dominant hand (SM blinded for treatment): the whole proximal phalanges, the periarticular portion of the proximal phalanges adjacent to the joint and the metacarpal heads (see figure S1 in online supplement). A detailed description of the ROIs and the precision of bone density measurements is given in the online supplement.

    Analysis and statistical tests

    Categorical variables were expressed as numbers and percentages, and continuous variables as means with SD or range or as median with range. Changes in BMD were expressed as percentage mean values with 95% CI. For group comparisons we used paired and independent two-tailed Student t tests for variables with normal distribution and the two-tailed Mann–Whitney U test for skewed variables. For categorical variables the χ2 test was used.

    Mean values for joint count, C reactive protein (CRP), Health Assessment Questionnaire (HAQ) and MRI scores were calculated for all available time points.

    The association between reduction in BMD and demographic and disease variables was tested by linear regression analysis, adjusting for treatment group.

    Results

    The baseline characteristics for all 40 patients with RA and both treatment groups are shown in table 1.

    View this table:
    Table 1

    Baseline characteristic for all patients with early rheumatoid arthritis and comparison between MTX and MTX+IAST groups

    At baseline, in the MTX+IAST group a mean number of 2.6 (range 1–4) joints at MCP2–5 in the dominant hand were injected; MCP2 was injected in 19, MCP3 in 20, MCP4 in 7 and MCP5 in 9 of the 21 patients. During the 12-month follow-up period the mean number of injections per patient was 9 (range 3–16), and at MCP2–5 at the dominant hand the mean number was 1.8 (range 1–4).

    The total mean dose of methylprednisolone injected intra-articularly at baseline in the MTX+IAST group was 154.3 mg (range 30–260). In the first 3 months the MTX+IAST patients received a mean dose of 181.9 mg (range 30–300) methylprednisolone and the MTX patients received no IAST, and in the second phase (3–12 months) the patients received 141.6 mg (range 0–540) methylprednisolone and 117.8 mg (range 0–800) IAST. For MTX, minor differences were seen between the two groups.4 None of the patients received osteoporosis treatment (eg, bisphosphonates) during the trial.

    Generalised and periarticular bone loss

    A statistically significant loss in BMD was seen at the hand at 3, 6 and 12 months and at spine L2–4 and femoral neck at 12 months. The difference between the two groups was not statistically significant (see figure S2 in online supplement).

    In the first 3 months a numerically lower rate of periarticular BMD loss was seen in the MTX+IAST group compared with the MTX group, being statistically significant at several ROIs (figure 1A). In the 3–12-month period, no statistically significant differences were seen between the two groups (figure 1B).

    Figure 1
    Figure 1

    Mean percentage change (with 95% CI) in bone mineral density (BMD) in patients with early rheumatoid arthritis with active disease followed for 12 months. (A) In the first phase (0–3 months) 19 patients were treated with methotrexate (MTX) alone and 21 patients were treated with with intra-articular corticosteroid injections (IAST) plus MTX into all clinically active joints. (B) In the second phase (3–12 months) both patient groups received the same treatment with MTX and IAST. Values in the table are baseline BMD with SD and BMD change (∆% BMD) with SEM for the two groups at the different measurement sites (p values from paired Student t test).

    The same pattern as that reported for the partial proximal phalanx was also seen for ROIs at the whole proximal phalanx and metacarpal head (data not shown).

    Associations with 12-month bone loss

    No statistically significant association was found between demographic variables, disease duration, rheumatoid factor, treatment group and 12-month bone loss at the whole hand, the ROIs, spine L2–4 or femoral neck.

    For 12-month mean hand bone loss but not for generalised bone loss, a statistically significant association was found with mean 12-month swollen joint count, CRP, HAQ and MRI synovitis score and BME.

    The association between BMD loss for the whole hand and ROIs and markers of inflammation (swollen joint, CRP, MRI BME and synovitis) and HAQ adjusted for treatment group is shown in table S2 in the online supplement.

    Discussion

    The 3-month results of this study provide strong evidence that injection of IAST into inflamed RA finger joints is not only capable of suppressing synovitis and reducing the rate of new erosions which previously has been reported from this study,4 but can also reduce periarticular bone loss. The fact that periarticular bone loss was reduced in patients treated with IAST supports the concept that, in conditions where inflammation dominates such as early RA, treating inflammation is more important than the negative effect of corticosteroids on bone.

    Corticosteroids are known to exacerbate osteoporosis by inducing apoptosis in osteoblasts and by increasing the activity of osteoclasts.10 However, corticosteroids are also among the most potent anti-inflammatory and immunosuppressive agents. Activation of the corticosteroid receptor which then inhibits nuclear factor κ B has been shown to inhibit several inflammatory pathways.10 Our findings are supported by previous studies which have shown that systemic administration of prednisolone reduces the rate of cortical hand bone loss in patients with RA.5 6 Some data from observational studies also indicate that the potent anti-inflammatory effect of prednisolone may even counteract the negative effect of prednisolone on generalised bone loss in patients with RA with active disease.11 12 The results from the hand bone density studies also suggest that prednisolone is equivalent to antitumour necrosis factor treatment in reducing the rate of hand bone loss.5 6 13 From a practical point of view, local administration of corticosteroids may be better than systemic administration as the drug is administered at the target site of the inflammatory process and is not disseminated throughout the body. This view is supported by Emkey et al14 who found that IAST had no net effects on bone resorption and only a transient systemic effect on bone formation.

    Data from the current study suggest that bone loss may be arrested by IAST more effectively in periarticular regions than in the whole hand. This may support the view that periarticular osteoporosis results from local production of proinflammatory cytokines which activate osteoclasts to break down bone locally and is not predominantly the result of circulating proinflammatory cytokines.1 However, it is also possible that the MCP joints were more frequently injected than the wrists. In our study we also found a strong association between periarticular BMD loss and CRP and HAQ. This indicates that inflammation in general and impaired finger and hand function is involved in the development of periarticular osteoporosis. This may explain why a less strong association was found between bone loss at the metacarpal head (which is closest to the synovium of the MCP joints) and IAST injections, MRI synovitis and BME scores than at the proximal phalanges.

    Our study has limitations. The number of patients was rather small and the reproducibility for BMD at periarticular regions was not as good as that of whole hand DXA. Certainly the clinical value of using DXA for periarticular BMD assessment is limited, and it has been shown by others that the precision of DXA for periarticular regions is poor compared with whole hand measurement.15 Furthermore, the method is not feasible for clinical use; it has therefore been recommended that assessment of the whole hand be used as a marker for periarticular bone loss.16

    We conclude that treatment with corticosteroids given intra-articularly protects against periarticular bone loss in inflamed finger joints in RA. These data further emphasise the importance of suppressing inflammation in patients with RA to maintain bone health.

    Acknowledgments

    The authors thank Mrs Sheena Stewart for her help and expertise with DXA scanning.

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    Supplementary materials

    Footnotes

    • Patient consent Obtained.

    • Ethics approval This study was conducted with the approval of the University of Leeds.

    • Provenance and peer review Not commissioned; externally peer reviewed.