R. Laan, P. V. van Riel, L. V. D. van de Putte
Nov 15, 1993
Citations
9
Influential Citations
420
Citations
Quality indicators
Journal
Annals of Internal Medicine
Abstract
Published data on the effects of low-dose ( 10 mg/d of prednisone) glucocorticoid agents on bone in patients with rheumatoid arthritis (RA) are controversial, and it has been suggested that the favorable effects of glucocorticoid agents on the inflammatory process and on physical activity may outweigh the negative effects of these drugs on bone. Previous, mostly cross-sectional studies have shown contradictory results [1]. Longitudinal studies have been done in patients who had been receiving glucocorticoid treatment for some time, and no increased rates of bone loss were noted [2, 3]. Several explanations may be offered for the discrepancies in the literature. First, nonrandomized studies may be subject to selection bias, because RA itself, and its concomitant decreased mobility, may adversely affect bone mass [1]. Second, it has been documented that negative influences of glucocorticoid agents may be most pronounced in the first months of therapy [4], and studies evaluating bone loss in the chronic phase of treatment may thus underestimate the effects of these drugs on bone. Randomized, controlled studies are necessary to avoid selection bias. We report the results of the first randomized, placebo-controlled study of the initial effects of low-dose prednisone on bone mineral density in patients with active RA. Methods Patients Patients were selected from a single university outpatient clinic, from April 1988 to April 1991. All patients with classical or definite RA [5] who started taking intramuscular gold salts were considered for participation in the trial. The decision to start intramuscular gold therapy was left to the rheumatologists in charge of the patients. Patients were admitted to the study only if they fulfilled at least three of five criteria: five or more joints that were tender or painful during motion; three or more swollen joints; an erythrocyte sedimentation rate more than 28 mm/h; morning stiffness for at least 60 minutes; and a hemoglobin level less than normal limits. Patients with other diseases or medication, including calcium supplements and postmenopausal hormone replacement therapy, that might affect bone mass, were excluded from the study. Introduction of these medications during the study was not permitted. Premenopausal patients were allowed to continue taking oral contraceptive drugs. Female patients who were postmenopausal for fewer than 3 years, or who had irregular menstrual cycles, were also excluded from the study. All patients were white. Informed consent was obtained from all patients. The study was approved by the local Ethics Committee. Study Design and Medication All patients were treated with intramuscular aurothioglucose (Auromyose; 20% oily suspension, Noury Pharma, Oss, the Netherlands) according to a standard dosage regimen. All patients started with a test dose of 10 mg before the trial. They then continued with a dose of 50 mg weekly, for 20 weeks. Modification of this regimen was possible if side effects occurred. Aurothioglucose was discontinued after 20 weeks if it was not effective. If a satisfactory response occurred, the dose was decreased. Patients were monitored for side effects weekly during the first 8 weeks of treatment and once every 2 weeks thereafter. The trial was a double-blind, placebo-controlled study for 20 weeks. Patients were followed for an additional 24 weeks after this period. All patients were randomly assigned to receive either prednisone or placebo treatment. No stratification or block randomization was used. All assessments were done without knowledge of the patients' treatment status. Prednisone was given in a dose of 10 mg once daily for 12 weeks. Thereafter, the dose was gradually reduced: 7.5 mg/d in weeks 13 and 14, 5.0 mg/d in weeks 15 and 16, 2.5 mg/d in weeks 17 and 18, and no prednisone in weeks 19 and 20. This resulted in a total dosage after 20 weeks of 1050 mg and a mean daily dose of 7.5 mg. All patients used nonsteroidal anti-inflammatory drugs throughout the study. Assessments of Rheumatoid Arthritis All clinical assessments were done by a single observer. Disease activity was measured by a composite index (disease activity score) consisting of the erythrocyte sedimentation rate (millimeters in first hour), the Ritchie articular index [6], the number of swollen joints, and a visual analogue scale for general health (range, 0 to 100 mm; a zero score indicating excellent health), which has been constructed and validated previously [7, 8]. Assessments were done at baseline; after 1, 2, and 4 weeks; and thereafter every 4 weeks. Functional capacity was assessed at baseline and after 12, 20, and 44 weeks using a health-assessment questionnaire (range, 0 to 3; a zero score indicating no functional impairment) [9]. Assessments of Bone Mineral Density Bone mineral density (BMD) was measured in the lumbar spine by dual-energy, quantitative computed tomography (effective radiation dose less than 300 microSievert) with a Somatom DR3 (Siemens AG, Erlangen, Germany). The details of this method have been published previously [10-12]. In short, patients were positioned with the lumbar spine over a calibration phantom, consisting of two stable plastics: a water-equivalent and a bone-equivalent standard containing 200 mg of hydroxyapatite per milliliter. Scans were made through the midvertebral level of lumbar vertebrae L2 to L4, with a slice thickness of 8 mm. Separate regions of interest were automatically defined for the trabecular bone and the anterior cortical bone of the vertebral body. The BMD was then calculated by comparison of the absorption in the region of interest with the absorption in the calibration phantom and was expressed in milligrams of hydroxyapatite per milliliter. Measurements were made at 125 and 85 kilovolt (kVp), and three images were reconstructed from each scan: at 125 kVp, at 85 kVp, and a calcium-equivalent density image after processing by material decomposition techniques. Dual-energy quantitative computed tomography results were calculated from the calcium density image. For duplicate measurements, the in vivo coefficient of variation ranged between 6.1% for the trabecular bone and 5.2% for the cortical bone. To exclude the possibility that new vertebral fractures caused changes in the BMD, lateral spine radiographs were obtained in all patients at baseline and after 44 weeks and were evaluated by an experienced radiologist. Statistical Analysis The change in BMD (expressed as percentage from baseline) was chosen as an outcome measurement. This variable followed a normal distribution sufficiently enough to allow the use of t-tests. Paired and unpaired t-tests were used for within- and between-group comparisons, respectively. Ninety-five percent confidence intervals (95% CI) were also calculated. The possible influence of an imbalance between the two groups with respect to menopausal state was evaluated using analysis of variance. Cumulative disease activity and cumulative functional capacity were defined as areas under the curve for the disease-activity scores and the health-assessment questionnaire scores, respectively. Differences between placebo and prednisone-treated patients were analyzed using the t-test. All analyses were done using intention-to-treat principles. Results During the recruitment period, 55 patients started aurothioglucose treatment. Three patients were inadvertently not reported by their treating physician. Nine patients refused to be included in the study for various reasons. One patient did not fulfill the required criteria for active disease. Two patients were excluded because of irregular menstrual cycles, indicating that menopause might be starting. The remaining 40 patients consented to participate in the study. The baseline BMD was similar in both groups. The mean trabecular BMD was 111 mg/mL in the prednisone group and was 111 mg/mL in the placebo group. The mean cortical BMD was 272 mg/mL in the prednisone-treated patients and was 276 mg/mL in the placebo-treated patients. Other baseline characteristics were also similar in the two treatment groups for most variables (Table 1). There were more postmenopausal women in the prednisone group, and the duration of postmenopause was longer in the placebo group. During the first period of the study, aurothioglucose was discontinued in nine patients (four in the prednisone and five in the placebo group) due to side effects. One of the five patients in the placebo group developed an acute, irreversible, and lethal pancytopenia. At the end of the first period of the trial, 16 patients in the prednisone group and 15 in the placebo group still used aurothioglucose. One patient in the prednisone group started methotrexate (7.5 mg weekly) after 18 weeks. Three patients in the prednisone group and four in the placebo group used no second-line antirheumatic treatment at the end of the first trial period. One patient in the placebo group with progressive disease refused further treatment with the trial medication after 4 weeks. She was then treated with prednisone, 10 mg/d, but assessments were carried out according to the protocol and data from this patient were included in the placebo group for all analyses (according to intention-to-treat principles). Table 1. Patient Characteristics During the second period of the trial, six patients who were originally assigned to the prednisone group, and who had all discontinued the trial medication according to the protocol, again started to use prednisone. Two patients from the placebo group used prednisone between weeks 20 and 44. For one patient, who was originally assigned to prednisone therapy, no BMD data were available at week 44. The composite disease-activity score and its four constituents all showed a marked and rapid improvement of disease activity in the prednisone-treated patients. Cumulative disease activity, as expressed by the area under the curve for the disease-activity scores, in