0021-972X/91/7202-0382$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright© 1991 by The Endocrine Society
Vol. 72, No. 2 Printed in U.S.A.
The Course of Biochemical Parameters of E>one Turnover during Treatment with Corticosteroids MARK F. PRUMMEL, WILMAR M. WIERSINGA, PAUL LIPS, GERARD T. B. SANDERS, AND HANS P. SAUERWEIN Departments of Endocrinology, Academic Medical Center, University of Amsterdam (M.F.P., W.M W., H.P.S.), and the Free University (P.L.), and the Department of Clinical Biochemistry, Academic Medical Center (G.T.B.S.), Amsterdam, The Netherlands
pressed as reflected by a fall in se::um osteocalcin (3.0 ± 2.1, 1.7 ± 1.1, and 2.4 ± 1.9 ng/h at weeks 0, 4, and 12, respectively; P = 0.02) and in total alkaline phosphatase (1.15 ± 0.33, 0.83 ± 0.22, and 0.88 ± 0.40 /xkat/L; P = 0.001). Parameters of bone resorption (urinary hydroxyprolire/creatinine ratio, serum acid phosphatase) and the levels of vitamin D metabolites remained unchanged. Serum intact PTH se3med to decrease slightly. Our findings suggest that glucocorticoid induced osteopenia is caused by a depressed bone formation in the presence of an unaltered but ongoing bone resorption. Secondary hyperparathyroidism and changes in vitamin D metabolism are apparently not involved. (J Clin Endocrinol Metab 72: 382-386, 1991)
ABSTRACT. The mechanisms by which glucocorticoids cause osteopenia are incompletely understood. It is generally accepted that bone formation is depressed during corticosteroid treatment, but the cause of the ongoing bone resorption is less clear. Secondary hyperparathyroidism and changes in vitamin D metabolism are thought to play a role. This is based mostly on data from cross-sectional studies in heterogeneous patient groups. We, therefore, studied longitudinally the course of biochemical parameters and the hormones influencing bone turnover in a homogeneous group of 10 euthyroid patients with Graves' ophthalmopathy, all euthyroid for at least 1 yr before, during, and after a 12-week course of prednisone. Bone formation was de-
O
(0H)2D] have been found, whereas 25-hydroxyvitamin D (25OHD) has been reported to be normal (5) or depressed (6) during corticosteroid treatment. However, most of these data have been derived from cross-sectional studies in heterogeneous patient groups, which may have contributed to the above mentioned controversies. Therefore, we performed a prospective study in a homogeneous group of 10 patients with severe Graves' ophthalmopathy, in whom we followed biochemical parameters of bone turnover before, during, and shortly after treatment with prednisone. All patients were euthyroid for at least 1 yr before treatment with prednisone.
STEOPOROSIS is a well known side-effect of treatment with glucocorticoids (1), but the exact mechanisms by which they induce osteopenia are not completely understood (2). On the one hand corticosteroid excess induces a reduction of bone formation, probably because of a direct effect on the osteoblasts (3), on the other hand it is thought to be associated with increased bone resorption (4). The latter has been ascribed to the development of secondary hyperparathyroidism (2), in response to a diminished intestinal calcium absorption (5, 6), and an increase in urinary calcium excretion (7). The reduction in bone formation during corticosteroid treatment is reflected in the low levels of serum osteocalcin (8, 9), a marker for bone synthesis, and of alkaline phosphatase (9,10). However, the evidence for secondary hyperparathyroidism causing an increase in bone resorption is less prominent. Some authors indeed found elevated levels of PTH (7,11,12), whereas others could not confirm this (5, 13). Data concerning vitamin D metabolites, which can influence intestinal calcium absorption are even more conflicting. Both increased (5, 14) and decreased (15) values of 1,25-dihydroxyvitamin D [1,25-
Patients ;ind Methods We prospectively studied 10 patients (mean age ± SD 54.3 ± 12.8 yr), with severe Graves' ophthalmopathy who underwent corticosteroid treatment. Tho study group consisted of 2 men, 2 premenopausal, and 6 postmenopausal women. Five of these patients never had a history of thyroid disease and 5 were euthyroid for at least 1 yr before prednisone treatment was started. These patients were part of a larger group of 20 patients with severe Graves' ophthalmopathy (4 men, 6 premenopausal, and 10 postmenopausal women; mean age ± SD 50.5 ± 12.7 yr), who were all clinically and biochemically euthyroid (most on antithyroid treatment) for at least 2 months before start of prednisone. Euthyroidism was defined as normal values of T4
Received April 6,1990. Address requests for reprints to: M. F. Prummel, M.D., Department of Endocrinology, F5-258, Academic Medical Center, Meibergdrief 9, 1105 AZ Amsterdam, The Netherlands.
382
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BONE TURNOVER DURING CORTICOSTEROID TREATMENT (75-135 nmol/L) and T3 (1.30-2.45 nmol/L), in the absence of an increased TSH response (>22 mU/L) to 200 ng TRH iv. The patients were treated with oral prednisone: 60 mg for the first 2 weeks, then 40 mg for 2 weeks, 30 mg for 4 weeks, and 20 mg for 4 weeks. After 12 weeks of treatment the drug was tapered in 7 weeks. Patients were hospitalized for the first 2 weeks of treatment and then seen regularly as out-patients. No other medication known to influence bone turnover was used. Calcium intake, as assessed by a dietician, ranged from 540-1600 mg/day (mean ± SD: 990 ± 280 mg/day) in all 20 patients. Before and after 1, 2, 4, and 12 weeks of treatment and 5 weeks after tapering, fasting morning blood samples were obtained and 2-h fasting urine samples were collected, as described before (16). Thyroid status was assessed before, after 12 weeks of treatment and 5 weeks after tapering. Plasma and/or urinary creatinine, calcium, albumin, and alkaline phosphatase (A Ph) were determined by SMAC II continuous flow analyzer. Each individual plasma calcium value was corrected for the corresponding albumin level [corrected calcium = calcium + (40 — albumin g/L) X 0.02 mmol/L; Ca corr]. Urines were not acidified before analysis. Hydroxyproline excretion was determined using an aminoacid analyzer after hydrolysis, in 2-h fasting urine samples to exclude dietary influences. Values for urinary hydroxyproline (Hp/Cr) and calcium (Ca/Cr) are given as ratio per mmol creatinine. The bone fraction of alkaline phosphatase (B A Ph) was measured according to Behr and Barnert (17). Serum osteocalcin was measured by RIA and intact PTH by immunoradiometric assay (IRMA) (IncStar Corp, Stillwater, MN). Acid phosphatase activity (Ac Ph) was measured by its enzyme activity with paranitrophenylphosphate as a substrate. 25OHD and 24,25dihydroxyvitamin D [24,25-(OH)2D] and 1,25-(OH)2D were
measured with a competitive protein binding assay after purification by high performence liquid chromatography (18). T4 and T 3 were measured by RIA and FT 4 and FT 3 index were calculated using the Thyroid Hormone Binding Ratio. TSH was determined by IRMA (Boots-Celltech Ltd., Slough, Berkshire, UK). Statistical analysis Data were analyzed using the SYSTAT software package, and the 0.05 level of significance was chosen. The course of the measured parameters before and during prednisone treatment were analyzed by a multivariate profile analysis for repeated measurements, using polynomial models. To compare the values at the end of treatment with the values after tapering, paired two-sided t tests were used. The data on thyroid hormones were analyzed by paired two-sided t tests. If the data were highly skewed Mann-Whitney U tests were used.
Results Although there was a trend towards lower values for the free T 3 (FT3) index during prednisone treatment [as observed before (10)], values returned to pretreatment levels at 24 weeks and all patients remained euthyroid during the study period (Table 1). The changes in param-
383
TABLE 1. Thyroid function in 10 patients with Graves' ophthalmopathy, before (0), after 12 weeks (12), and after tapering of prednisone treatment (24) Time (weeks)
0
FT4 index FT3 index TSH (mU/L)
124 ± 23 1.94 ± 0.38 0.5 (
Vol. 72, No. 2 Printed in U.S.A.
The Course of Biochemical Parameters of E>one Turnover during Treatment with Corticosteroids MARK F. PRUMMEL, WILMAR M. WIERSINGA, PAUL LIPS, GERARD T. B. SANDERS, AND HANS P. SAUERWEIN Departments of Endocrinology, Academic Medical Center, University of Amsterdam (M.F.P., W.M W., H.P.S.), and the Free University (P.L.), and the Department of Clinical Biochemistry, Academic Medical Center (G.T.B.S.), Amsterdam, The Netherlands
pressed as reflected by a fall in se::um osteocalcin (3.0 ± 2.1, 1.7 ± 1.1, and 2.4 ± 1.9 ng/h at weeks 0, 4, and 12, respectively; P = 0.02) and in total alkaline phosphatase (1.15 ± 0.33, 0.83 ± 0.22, and 0.88 ± 0.40 /xkat/L; P = 0.001). Parameters of bone resorption (urinary hydroxyprolire/creatinine ratio, serum acid phosphatase) and the levels of vitamin D metabolites remained unchanged. Serum intact PTH se3med to decrease slightly. Our findings suggest that glucocorticoid induced osteopenia is caused by a depressed bone formation in the presence of an unaltered but ongoing bone resorption. Secondary hyperparathyroidism and changes in vitamin D metabolism are apparently not involved. (J Clin Endocrinol Metab 72: 382-386, 1991)
ABSTRACT. The mechanisms by which glucocorticoids cause osteopenia are incompletely understood. It is generally accepted that bone formation is depressed during corticosteroid treatment, but the cause of the ongoing bone resorption is less clear. Secondary hyperparathyroidism and changes in vitamin D metabolism are thought to play a role. This is based mostly on data from cross-sectional studies in heterogeneous patient groups. We, therefore, studied longitudinally the course of biochemical parameters and the hormones influencing bone turnover in a homogeneous group of 10 euthyroid patients with Graves' ophthalmopathy, all euthyroid for at least 1 yr before, during, and after a 12-week course of prednisone. Bone formation was de-
O
(0H)2D] have been found, whereas 25-hydroxyvitamin D (25OHD) has been reported to be normal (5) or depressed (6) during corticosteroid treatment. However, most of these data have been derived from cross-sectional studies in heterogeneous patient groups, which may have contributed to the above mentioned controversies. Therefore, we performed a prospective study in a homogeneous group of 10 patients with severe Graves' ophthalmopathy, in whom we followed biochemical parameters of bone turnover before, during, and shortly after treatment with prednisone. All patients were euthyroid for at least 1 yr before treatment with prednisone.
STEOPOROSIS is a well known side-effect of treatment with glucocorticoids (1), but the exact mechanisms by which they induce osteopenia are not completely understood (2). On the one hand corticosteroid excess induces a reduction of bone formation, probably because of a direct effect on the osteoblasts (3), on the other hand it is thought to be associated with increased bone resorption (4). The latter has been ascribed to the development of secondary hyperparathyroidism (2), in response to a diminished intestinal calcium absorption (5, 6), and an increase in urinary calcium excretion (7). The reduction in bone formation during corticosteroid treatment is reflected in the low levels of serum osteocalcin (8, 9), a marker for bone synthesis, and of alkaline phosphatase (9,10). However, the evidence for secondary hyperparathyroidism causing an increase in bone resorption is less prominent. Some authors indeed found elevated levels of PTH (7,11,12), whereas others could not confirm this (5, 13). Data concerning vitamin D metabolites, which can influence intestinal calcium absorption are even more conflicting. Both increased (5, 14) and decreased (15) values of 1,25-dihydroxyvitamin D [1,25-
Patients ;ind Methods We prospectively studied 10 patients (mean age ± SD 54.3 ± 12.8 yr), with severe Graves' ophthalmopathy who underwent corticosteroid treatment. Tho study group consisted of 2 men, 2 premenopausal, and 6 postmenopausal women. Five of these patients never had a history of thyroid disease and 5 were euthyroid for at least 1 yr before prednisone treatment was started. These patients were part of a larger group of 20 patients with severe Graves' ophthalmopathy (4 men, 6 premenopausal, and 10 postmenopausal women; mean age ± SD 50.5 ± 12.7 yr), who were all clinically and biochemically euthyroid (most on antithyroid treatment) for at least 2 months before start of prednisone. Euthyroidism was defined as normal values of T4
Received April 6,1990. Address requests for reprints to: M. F. Prummel, M.D., Department of Endocrinology, F5-258, Academic Medical Center, Meibergdrief 9, 1105 AZ Amsterdam, The Netherlands.
382
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 10 September 2015. at 14:15 For personal use only. No other uses without permission. . All rights reserved.
BONE TURNOVER DURING CORTICOSTEROID TREATMENT (75-135 nmol/L) and T3 (1.30-2.45 nmol/L), in the absence of an increased TSH response (>22 mU/L) to 200 ng TRH iv. The patients were treated with oral prednisone: 60 mg for the first 2 weeks, then 40 mg for 2 weeks, 30 mg for 4 weeks, and 20 mg for 4 weeks. After 12 weeks of treatment the drug was tapered in 7 weeks. Patients were hospitalized for the first 2 weeks of treatment and then seen regularly as out-patients. No other medication known to influence bone turnover was used. Calcium intake, as assessed by a dietician, ranged from 540-1600 mg/day (mean ± SD: 990 ± 280 mg/day) in all 20 patients. Before and after 1, 2, 4, and 12 weeks of treatment and 5 weeks after tapering, fasting morning blood samples were obtained and 2-h fasting urine samples were collected, as described before (16). Thyroid status was assessed before, after 12 weeks of treatment and 5 weeks after tapering. Plasma and/or urinary creatinine, calcium, albumin, and alkaline phosphatase (A Ph) were determined by SMAC II continuous flow analyzer. Each individual plasma calcium value was corrected for the corresponding albumin level [corrected calcium = calcium + (40 — albumin g/L) X 0.02 mmol/L; Ca corr]. Urines were not acidified before analysis. Hydroxyproline excretion was determined using an aminoacid analyzer after hydrolysis, in 2-h fasting urine samples to exclude dietary influences. Values for urinary hydroxyproline (Hp/Cr) and calcium (Ca/Cr) are given as ratio per mmol creatinine. The bone fraction of alkaline phosphatase (B A Ph) was measured according to Behr and Barnert (17). Serum osteocalcin was measured by RIA and intact PTH by immunoradiometric assay (IRMA) (IncStar Corp, Stillwater, MN). Acid phosphatase activity (Ac Ph) was measured by its enzyme activity with paranitrophenylphosphate as a substrate. 25OHD and 24,25dihydroxyvitamin D [24,25-(OH)2D] and 1,25-(OH)2D were
measured with a competitive protein binding assay after purification by high performence liquid chromatography (18). T4 and T 3 were measured by RIA and FT 4 and FT 3 index were calculated using the Thyroid Hormone Binding Ratio. TSH was determined by IRMA (Boots-Celltech Ltd., Slough, Berkshire, UK). Statistical analysis Data were analyzed using the SYSTAT software package, and the 0.05 level of significance was chosen. The course of the measured parameters before and during prednisone treatment were analyzed by a multivariate profile analysis for repeated measurements, using polynomial models. To compare the values at the end of treatment with the values after tapering, paired two-sided t tests were used. The data on thyroid hormones were analyzed by paired two-sided t tests. If the data were highly skewed Mann-Whitney U tests were used.
Results Although there was a trend towards lower values for the free T 3 (FT3) index during prednisone treatment [as observed before (10)], values returned to pretreatment levels at 24 weeks and all patients remained euthyroid during the study period (Table 1). The changes in param-
383
TABLE 1. Thyroid function in 10 patients with Graves' ophthalmopathy, before (0), after 12 weeks (12), and after tapering of prednisone treatment (24) Time (weeks)
0
FT4 index FT3 index TSH (mU/L)
124 ± 23 1.94 ± 0.38 0.5 (
