388-392
Clinical rheumatology, 1992, 11, N ~ 3
Effects of Different Regimes of Corticosteroid Treatment on Calcium and Bone Metabolism in Rheumatoid Arthritis M.J.
VAN
DER
VEEN,
J.W.J.
BIJLSMA
Summary
A clinical study of 30 patients with rheumatoid arthritis was undertaken in order to assess the acute effects of corticosteroids on calcium and bone metabolism. The patients were randomly divided into 3 groups. The first group was not treated with corticosteroids, the second group was treated with 3 oral pulses of 100 mg prednisolone and the third group received 3 intravenous pulses of 1000 mg methylprednisolone (MP) on alternate days during one week. In both steroid treated groups the serum parathyroid h o r m o n e concentration tended to increase. In the M P treated group an increase in the 1.25-dihydroxyvitamin D concentration after the first pulse was followed by a significant drop; this effect was also seen, but somewhat retarded and less distinct, in the orally treated group. In the MP treated group the urinary calcium excretion raised significantly 6 hrs after the first pulse and then dropped significantly. In all groups no changes were found in the serum calcium level and the urinary excretion of hydroxyproline. We conclude that, acute changes in calcium and bone metabolism occur during treatment with intravenous pulses of methylprednisolone and with oral pulses of prednisolone. These changes are small and reversible in a few days. Key words : Corticosteroid Treatment, Intravenous Methylprednisolone Pulses, Oral Prednisolone Pulses, Rheumatoid Arthritis, Bone Metabolism.
INTRODUCTION Rheumatoid arthritis (RA) is associated with changes in bone metabolism, resulting in loss of bone. This socalled osteopenia can be localized, peri-articular, due to the local inflammatory process or more generalized, due to loss of mobility (1,2). Reduced mobility can subsequently lead to lack of sunshine, another factor which contributes to osteopenia. The use of corticosteroids in the treatment of R A cannot always be avoided and this may induce further loss of bone. Several studies have demonstrated that the effects of corticosteroids on bone differ with duration and dosage of the therapy (3), In this respect intravenous pulses of methylprednisolone (MP) in high dosages seem to be a safer treatment modality than daily therapy with low dose steroids. A disadvantage of the MP pulses is that patients have to be admitted to the hospital to undergo the treatment.
Department of RheumatologyF 02.223, UniversityHospital Utrecht, Postbox 85500, 3508 GA Utrecht, The Netherlands.
In the present investigation we studied the effects of intravenous MP pulses and of oral pulses of prednisolone on parameters of calcium and bone metabolism in patients with RA, compared with the findings in a control group. PATIENTS AND METHODS Thirty patients, 24 women and 6 men, with definite R A according to the 1958 A R A criteria were included in the study (4). The mean age was 56 years ; the mean disease duration was 12 years. Twenty-seven patients were positive for rheumatoid factor and most had erosive changes on their joint radiographs. All patients had active rheumatoid disease, as defined by the presence of at least 3 of the following characteristics : a) tenderness of more than 6 joints ; b) swelling of more than 3 joints ; c) early-morning stiffness lasting longer than 15 minutes; d) Ritchie articular index greater than 20 (5); e) erythrocyte sedimentation rate greater than 28 mm/lhr. In all patients treatment with at least 2 different disease modifying antirheumatic drugs (DMARD's) had not led
Corticosteroids and bone metabolism in R A
Table I: Demographic data of 30 patients with rheumatoid arthritis Age mean, SEM, (range) Duration of disease, years, mean, SEM, range) Male : female Rheumatoid factor positive (%) H L A - D R 4 positive (%)
56 _+ 3 (25-78) 12 • 2 (2-42) 6:24 27 (90) 15 (50)
to a satisfactory therapeutic effect or had caused side effects. All D M A R D ' s were stopped a month before the study. At the start of the study, no patients were treated with corticosteroids or other drugs that are known to influence bone metabolism ; all continued their nonsteroidal anti-inflammatory drugs. Patients with active peptic ulcer disease, diabetes mellitus, renal failure, hypertension, recent infections, heart failure, psychosis and pregnancy were not included "in the study. All patients were admitted to the hospital and all had the same regimen of bedrest and the same standard diet
389
of the hospital during 2 weeks. They started treatment with oral methotrexate in a dosage of 7.5 mg per week. The patients were randomly assigned to 3 groups. The first group did not receive any corticosteroids ; the second group received 100 mg prednisolone orally on days 1, 3 and 5 ; the third group received 1000 mg methylprednisolone in 500 ml 0:.9% NaCI infusion over 30 minutes on days 1, 3 and 5. These doses of prednisolone and methylprednisolone were empirically chosen. The longterm effects of this treatment on parameters of disease activity will be reported elsewhere. Blood samples were drawn before the first pulse (at days -2 and -1), at days 1 through 5 and at days 8 and 9. Urine was collected during 24 hrs on 2 days before the first pulse and on day 8 and 9 ; on day 1 and 2 the urine was collected in 6 hrs periods. The following determinations were performed : a) calcium (Ca) in serum and urine by atomic absorption; b) parathyroid hormone (PTH) by a two-step radioimmunoassay that recognizes the intact 1-84 parathyroid hormone molecule (6); c) 1.25-dihydroxycholecalciferol (1.25(OH2)D3) by a competitive protein binding assay (7); d) creatinine (Cr) in urine by autoanalyser
Table II : Serum concentrations of calcium, PTH and 1.25 l.qt D in Group I (no corticosteroids), Group H (100 rag prednisolone x 3 orally) and
Group III (1000 mg methylprednisolone x 3 intravenously) Start Calcium I II III PTH
Day 1
Day 2
Day 3
Day 4
Afterwards
2.29 • .02
2.26 • .02
2.25 • .02
2.27 • .04
2.27 • .03
2.27 • .03
2.35 • .02 2.29 • .05
2.35 • .03 2.35 • .05
2.31 • .02 2.22 • .05
2.33 • .02 2.30 • .06
2.28 • .03 2.17 • .05
2.30 • .02 2.23 • .05
I
2.6 • .6
3.2 • .6
2.5 • .4
2.7 • .5
2.1 • .3
2.2 • .5
II III 1.25 Vit D I II
2.8 • .5 3.2 • .4
2.4 • .4 3.2 • .7
2.8 • .3 3.3 • .5
2.9 • .5 3.1 • .5
3.4 --- .6 3.8 • .5
2.9 • .3 4.1 • .8
38.2 • 7.3 21.6 • 3.9
34.1 • 6.8 25.1 • 4.2
33.6 • 8.3 27.9 • 7.3
31.1 ___5.6 21.7 • 3.6
34.8 • 4.3 23.1 • 4.8
31.4 • 4.8 21.6 ---5.4
III
30.6 • 6.6
42.1 • 10.9
24.6 • 4.5*
33.9 • 6.7*
39.4 • 9.7
32.5 • 7.8
Mean values • SEM ; * Significantly different from preceding value, p < .05 (Wilcoxon). Table III : Urinary calcium and hydroxyproline excretion in Group I (no corticosteroids), Group H (100 mg prednisolone X3 orally) and Group III
(1000 mg methylprednisolone X3 intravenously) Start C~Crratio I II III OHPffCr ratio I II III
.29• .34• .25• .05 32.5• 28.2• 28.9•
0-6 h
6-12 h
12-18 h
18-24 h
Afterwards
.26• .32• .09 .39• .12"*
.32• .35• .07 .23 • .05*
.28• .40• .10 .24• .05
.36• .35• .07 .35•
.29• .39• .24• .05
19.9• 30.3• 24.5•
30.1• 30.8• 31.5•
34.6• 26.1• 40.1•
24.9• 23.9• 55.0•
26.0• 31.0• 28.6•
Mean Values ___ S E M ; * Significantly different from preceding value, p
Clinical rheumatology, 1992, 11, N ~ 3
Effects of Different Regimes of Corticosteroid Treatment on Calcium and Bone Metabolism in Rheumatoid Arthritis M.J.
VAN
DER
VEEN,
J.W.J.
BIJLSMA
Summary
A clinical study of 30 patients with rheumatoid arthritis was undertaken in order to assess the acute effects of corticosteroids on calcium and bone metabolism. The patients were randomly divided into 3 groups. The first group was not treated with corticosteroids, the second group was treated with 3 oral pulses of 100 mg prednisolone and the third group received 3 intravenous pulses of 1000 mg methylprednisolone (MP) on alternate days during one week. In both steroid treated groups the serum parathyroid h o r m o n e concentration tended to increase. In the M P treated group an increase in the 1.25-dihydroxyvitamin D concentration after the first pulse was followed by a significant drop; this effect was also seen, but somewhat retarded and less distinct, in the orally treated group. In the MP treated group the urinary calcium excretion raised significantly 6 hrs after the first pulse and then dropped significantly. In all groups no changes were found in the serum calcium level and the urinary excretion of hydroxyproline. We conclude that, acute changes in calcium and bone metabolism occur during treatment with intravenous pulses of methylprednisolone and with oral pulses of prednisolone. These changes are small and reversible in a few days. Key words : Corticosteroid Treatment, Intravenous Methylprednisolone Pulses, Oral Prednisolone Pulses, Rheumatoid Arthritis, Bone Metabolism.
INTRODUCTION Rheumatoid arthritis (RA) is associated with changes in bone metabolism, resulting in loss of bone. This socalled osteopenia can be localized, peri-articular, due to the local inflammatory process or more generalized, due to loss of mobility (1,2). Reduced mobility can subsequently lead to lack of sunshine, another factor which contributes to osteopenia. The use of corticosteroids in the treatment of R A cannot always be avoided and this may induce further loss of bone. Several studies have demonstrated that the effects of corticosteroids on bone differ with duration and dosage of the therapy (3), In this respect intravenous pulses of methylprednisolone (MP) in high dosages seem to be a safer treatment modality than daily therapy with low dose steroids. A disadvantage of the MP pulses is that patients have to be admitted to the hospital to undergo the treatment.
Department of RheumatologyF 02.223, UniversityHospital Utrecht, Postbox 85500, 3508 GA Utrecht, The Netherlands.
In the present investigation we studied the effects of intravenous MP pulses and of oral pulses of prednisolone on parameters of calcium and bone metabolism in patients with RA, compared with the findings in a control group. PATIENTS AND METHODS Thirty patients, 24 women and 6 men, with definite R A according to the 1958 A R A criteria were included in the study (4). The mean age was 56 years ; the mean disease duration was 12 years. Twenty-seven patients were positive for rheumatoid factor and most had erosive changes on their joint radiographs. All patients had active rheumatoid disease, as defined by the presence of at least 3 of the following characteristics : a) tenderness of more than 6 joints ; b) swelling of more than 3 joints ; c) early-morning stiffness lasting longer than 15 minutes; d) Ritchie articular index greater than 20 (5); e) erythrocyte sedimentation rate greater than 28 mm/lhr. In all patients treatment with at least 2 different disease modifying antirheumatic drugs (DMARD's) had not led
Corticosteroids and bone metabolism in R A
Table I: Demographic data of 30 patients with rheumatoid arthritis Age mean, SEM, (range) Duration of disease, years, mean, SEM, range) Male : female Rheumatoid factor positive (%) H L A - D R 4 positive (%)
56 _+ 3 (25-78) 12 • 2 (2-42) 6:24 27 (90) 15 (50)
to a satisfactory therapeutic effect or had caused side effects. All D M A R D ' s were stopped a month before the study. At the start of the study, no patients were treated with corticosteroids or other drugs that are known to influence bone metabolism ; all continued their nonsteroidal anti-inflammatory drugs. Patients with active peptic ulcer disease, diabetes mellitus, renal failure, hypertension, recent infections, heart failure, psychosis and pregnancy were not included "in the study. All patients were admitted to the hospital and all had the same regimen of bedrest and the same standard diet
389
of the hospital during 2 weeks. They started treatment with oral methotrexate in a dosage of 7.5 mg per week. The patients were randomly assigned to 3 groups. The first group did not receive any corticosteroids ; the second group received 100 mg prednisolone orally on days 1, 3 and 5 ; the third group received 1000 mg methylprednisolone in 500 ml 0:.9% NaCI infusion over 30 minutes on days 1, 3 and 5. These doses of prednisolone and methylprednisolone were empirically chosen. The longterm effects of this treatment on parameters of disease activity will be reported elsewhere. Blood samples were drawn before the first pulse (at days -2 and -1), at days 1 through 5 and at days 8 and 9. Urine was collected during 24 hrs on 2 days before the first pulse and on day 8 and 9 ; on day 1 and 2 the urine was collected in 6 hrs periods. The following determinations were performed : a) calcium (Ca) in serum and urine by atomic absorption; b) parathyroid hormone (PTH) by a two-step radioimmunoassay that recognizes the intact 1-84 parathyroid hormone molecule (6); c) 1.25-dihydroxycholecalciferol (1.25(OH2)D3) by a competitive protein binding assay (7); d) creatinine (Cr) in urine by autoanalyser
Table II : Serum concentrations of calcium, PTH and 1.25 l.qt D in Group I (no corticosteroids), Group H (100 rag prednisolone x 3 orally) and
Group III (1000 mg methylprednisolone x 3 intravenously) Start Calcium I II III PTH
Day 1
Day 2
Day 3
Day 4
Afterwards
2.29 • .02
2.26 • .02
2.25 • .02
2.27 • .04
2.27 • .03
2.27 • .03
2.35 • .02 2.29 • .05
2.35 • .03 2.35 • .05
2.31 • .02 2.22 • .05
2.33 • .02 2.30 • .06
2.28 • .03 2.17 • .05
2.30 • .02 2.23 • .05
I
2.6 • .6
3.2 • .6
2.5 • .4
2.7 • .5
2.1 • .3
2.2 • .5
II III 1.25 Vit D I II
2.8 • .5 3.2 • .4
2.4 • .4 3.2 • .7
2.8 • .3 3.3 • .5
2.9 • .5 3.1 • .5
3.4 --- .6 3.8 • .5
2.9 • .3 4.1 • .8
38.2 • 7.3 21.6 • 3.9
34.1 • 6.8 25.1 • 4.2
33.6 • 8.3 27.9 • 7.3
31.1 ___5.6 21.7 • 3.6
34.8 • 4.3 23.1 • 4.8
31.4 • 4.8 21.6 ---5.4
III
30.6 • 6.6
42.1 • 10.9
24.6 • 4.5*
33.9 • 6.7*
39.4 • 9.7
32.5 • 7.8
Mean values • SEM ; * Significantly different from preceding value, p < .05 (Wilcoxon). Table III : Urinary calcium and hydroxyproline excretion in Group I (no corticosteroids), Group H (100 mg prednisolone X3 orally) and Group III
(1000 mg methylprednisolone X3 intravenously) Start C~Crratio I II III OHPffCr ratio I II III
.29• .34• .25• .05 32.5• 28.2• 28.9•
0-6 h
6-12 h
12-18 h
18-24 h
Afterwards
.26• .32• .09 .39• .12"*
.32• .35• .07 .23 • .05*
.28• .40• .10 .24• .05
.36• .35• .07 .35•
.29• .39• .24• .05
19.9• 30.3• 24.5•
30.1• 30.8• 31.5•
34.6• 26.1• 40.1•
24.9• 23.9• 55.0•
26.0• 31.0• 28.6•
Mean Values ___ S E M ; * Significantly different from preceding value, p
