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Original Studies |
Austin and Repatriation Medical Center, University of Melbourne (G.P., A.T., E.S.), and Royal Women’s Hospital (H.W.G.B.), Melbourne, Australia; and INSERM U-403, E. Herriot Hospital (P.D.D.), Lyon, France
Address all correspondence and requests for reprints to: Ego Seeman, M.D., Department of Endocrinology, Austin and Repatriation Medical Center, Heidelberg 3084, Australia.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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To determine the pathophysiology of corticosteroid-related bone loss, we conducted a controlled, prospective study in men with no systemic illness treated with corticosteroids to reduce antisperm antibodies. We measured BMD using dual x-ray absorptiometry and circulating biochemical and hormonal determinants of bone turnover in 9 men before and during prednisolone treatment and in 10 age-matched controls. The results were expressed as the mean ± SEM.
There were no differences in BMD between the two groups at baseline. The patients received 50 mg prednisolone daily for 3.7 ± 0.6 months (range, 1–6). BMD decreased by 4.6 ± 0.8% at the lumbar spine (P = 0.0007), by 2.6 ± 0.6% at the trochanter (P = 0.004), and by 4.8 ± 1.9% at the Ward’s triangle (P < 0.04). The decrease in lumbar spine BMD correlated with the cumulative dose of corticosteroids (r = -0.49; P = 0.03). Serum osteocalcin and skeletal alkaline phosphatase decreased by 28.5 ± 15.5% (P = 0.08) and 24.2 ± 8.6% (P < 0.03), respectively. The decrease in lumbar spine BMD correlated with the decrease in osteocalcin (r = -0.48; P < 0.02). Serum testosterone and sex hormone-binding globulin decreased by 28.6 ± 4.4% (P < 0.003) and 28.5 ± 8.3% (P < 0.007), respectively. The testosterone/sex hormone-binding globulin ratio did not change. The decrease in total testosterone correlated with the decrease in osteocalcin (r = -0.40; P = 0.05). There were no detectable changes in urinary C-telopeptide, serum PTH, or serum calcium. Estradiol decreased by 23.5 ± 11.4% (P < 0.003).
Corticosteroid therapy results in rapid bone loss, probably due to reduced bone formation. Neither increased bone resorption nor secondary hyperparathyroidism appears to contribute to the rapid bone loss. Whether the reduction in bone formation may be partly mediated by changes in sex steroids remains unclear.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Lack of consistent information concerning the pathophysiology of corticosteroid-induced bone loss may be due to coexisting independent factors that influence bone mineral density (BMD). The disease being treated may result in increased biochemical measures of bone turnover and cause bone loss. The severity of the illness may influence the dose of corticosteroids chosen (1, 4). The hormonal changes responsible for reduced bone formation or increased bone resorption may be the result of disease activity before and during treatment, not the corticosteroids (4). Changes in gonadal and adrenal steroids, GH, and insulin-like growth factor I (IGF-I) have been implicated in the pathogenesis of reduced bone formation (6, 7, 8). Secondary hyperparathyroidism is often cited as contributing to increased bone resorption; however, reduced, normal, or elevated circulating PTH levels have been reported (9, 10, 11, 12, 13). Rather than causing bone loss, PTH may be suppressed as a consequence of bone loss due to illness and immobility (12).
To overcome some of these difficulties, we conducted a controlled prospective study in nine men commencing treatment with high doses of prednisolone for infertility due to the presence of antisperm antibodies. The patients had no prior exposure to corticosteroids; they received no other drugs and had no illnesses known to affect bone. We asked 1) whether corticosteroid-induced bone loss is due to a reduction in bone formation, an increase in bone resorption, or both; and 2) what mechanisms may be responsible for changes in bone formation and/or resorption.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We studied nine men involved in a fertility program designed to reduce antisperm antibodies. They had no prior exposure to corticosteroids and no systemic illness, and were taking no medications known to affect bone. The patients were evaluated at baseline, monthly for 3 months, and every 3 months thereafter. All patients started on 50 mg/day prednisolone (14, 15); 50 mg daily were given to one patient for 1 month, to one patient for 2 months, to three patients for 3 months, to two patients for 4 months, and to two patients for 6 months. At the end of the 50-mg regimen, the tapering regimen over 3 weeks was 15, 10, and 5 mg/day. The patients were compared to healthy untreated men of comparable age, height, and weight. It was not possible to randomize the two groups because it is unethical to give corticosteroids to healthy subjects or withhold treatment from the patients. Informed consent was obtained from all patient and control subjects before enrollment in the study.
Bone density, and biochemical and hormonal measurements
Total body and regional BMD were measured by dual x-ray absorptiometry (grams per cm2; DPX-L, Lunar Corp., Madison, WI) (16). The coefficient of variation ranged from 1.5–2.4%. Morning blood and urine samples were collected in all subjects. Bone formation was assessed by measuring serum osteocalcin, bone-specific alkaline phosphatase, and serum collagen propeptide of type 1 collagen. Serum osteocalcin was measured with a human-specific immunoradiometric assay (nanograms per mL; ELISA-OSTEO, Cis Biointernational, France) (17). Serum bone alkaline phosphatase was measured with an immunoradiometric assay (Tandem-R Ostase, Hybritech, San Diego, CA) (18). Serum collagen propeptide of type 1 collagen was measured with a two-site enzyme-linked immunoassay (Procollagen-C, Metra Biosystems, Palo Alto, CA) (19). Bone resorption was assessed by measuring urinary type 1 C-telopeptide breakdown products (CTX) with an enzyme-linked immunosorbent assay (Cross Laps, Osteometer A/S, Rodovre, Denmark) (20).
A RIA was used to measure GH (nanograms per mL; Orion Diagnostica, Espoo, Finland), IGF-I (nanograms per mL; using anti-human IGF-I polyclonal rabbit antibodies), serum dehydroepiandrosterone sulfate (DHEA-S; nanograms per mL; Biotecx, Houston, TX), and androstenedione (nanograms per mL; Diagnostics Biochem Canada, Ontario, Canada). Competitive chemiluminescent immunoassays (Ciba Corning ASC:180 machine, Australian Diagnostics) were used to measure serum testosterone (nanomoles per L), LH (milliinternational units per mL), and FSH (milliinternational units per mL). Immunoradiometric assays were used to measure sex hormone-binding globulin (SHBG; nanomoles per L; Orion Diagnostica) and serum intact PTH (picograms per mL; Nichols Institute Diagnostics, San Juan Capistrano, CA). Serum calcium (millimoles per L) was measured photometrically using the Hitachi autoanalyzer (Hitachi, Tokyo, Japan). Coefficients of variation for the assays were 5–10%.
Statistical analysis
Analyses were performed using StatView II (Abacus Concepts, Berkeley, CA). Paired t tests were used to compare the pre- and posttreatment results in the patients. Differences between the two groups were analyzed using ANOVA. The data were expressed as the mean ± SEM. The relationship among dose, changes in BMD, and biochemical measures was analyzed using regression analysis. For the regression analyses, each time point was expressed as a percent change from the initial (pre treatment) value.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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BMD did not differ between the two groups at baseline (Table 1
). In the patients, BMD decreased by
4.6 ± 0.8% at the lumbar spine (P < 0.0007), by
2.6 ± 0.6% at the trochanter (P = 0.004), and by
4.8 ± 1.9% at the Ward’s triangle (P < 0.04;
Fig. 1). BMD did not change in the
controls. The decrease in lumbar spine BMD correlated with the
cumulative dose of prednisolone (r = -0.49; P =
0.03; Fig. 2).
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). There was no detectable change in
collagen propeptide of type 1 collagen. Bone resorption, as assessed by
urinary CTX, did not increase. PTH did not increase during
corticosteroid treatment (Fig. 3). There was no detectable change in
serum calcium. The fall in lumbar spine BMD correlated with the fall in
serum osteocalcin (r = -0.48; P < 0.02; Fig. 4).
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). In the patients, total testosterone
decreased by 28.6 ± 4.4% (P < 0.003) and then
increased as the dose of corticosteroids was tapered (Fig. 5). There was a correlation between the
decrease in testosterone and the change in osteocalcin (r = -0.4;
P = 0.05; Fig. 6). SHBG
decreased by 28.5 ± 8.3% (P < 0.007); the
testosterone/SHBG ratio did not change (Fig. 5). Estradiol decreased by
23.5 ± 11.4% (P < 0.003), and FSH increased by
67.2 ± 35.1% (P = 0.08; Fig. 5). There were no
changes in the controls. At the final measurement, LH was lower in the
patients (2.8 ± 0.3) than in the controls (4.8 ± 0.6
IU/mL; P < 0.006).
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). After treatment, androstenedione decreased by
58.2 ± 14.6% (P < 0.008), and DHEA-S decreased
by 50.3 ± 9.8% (P < 0.002; Fig. 5). There were
no changes in the controls. At the end of treatment, androstenedione
and DHEA-S were lower in the patients than the controls [0.8 ±
0.2 vs. 2.1 ± 0.2 ng/mL (P = 0.0006)
and 1349 ± 234 vs. 4596 ± 982 ng/mL
(P < 0.003), respectively]. At baseline, serum IGF-I
and GH were higher in the patients than in the controls (Table 1). In
the patients, IGF-I increased by 52.0 ± 19.2% (P
< 0.05; Fig. 5). There were no detectable changes in GH. IGF-I and GH
did not change in the controls. At the final measurement, IGF-I was
higher in the patients (199.2 ± 19.2) than in the controls
(104.4 ± 2.9 ng/mL; P < 0.0007). |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Bone loss is likely to be due to reduced bone formation, as serum osteocalcin and skeletal alkaline phosphatase decreased after corticosteroid treatment, and the change in lumbar spine BMD correlated with the change in osteocalcin. Serum osteocalcin and alkaline phosphatase decrease after short courses of corticosteroids in normal volunteers (23, 24), confirming that it is the drug, not the disease, that is likely to reduce bone formation.
We found no biochemical evidence of increased bone resorption, as urinary CTX was unchanged during the study of healthy subjects. In a study of patients with polymyalgia rheumatica, we found that urinary CTX was elevated before treatment and decreased after treatment with 10 mg prednisolone daily, suggesting that the illness was responsible for the increased bone resorption (12). Patients with rheumatoid arthritis have elevated urinary CTX and deoxypyridinoline, with higher values in those receiving corticosteroids. The researchers suggested that the higher values may have been the result of the corticosteroid therapy. However, the patients with rheumatoid arthritis treated with corticosteriods may have had more severe disease (4).
There was no evidence of secondary hyperparathyroidism, suggesting that it is unlikely to be involved in the pathogenesis of the bone loss occurring in the first 3–6 months of corticosteroid therapy. Secondary hyperparathyroidism has been reported in some studies, but most have shown no difference in PTH (9, 13, 23, 25). PTH levels were suppressed before corticosteroid treatment in patients with polymyalgia rheumatica, suggesting that the disease may result in increased bone resorption with suppression of PTH (12).
Serum total testosterone has been shown to be reduced in men receiving corticosteroids in some (26, 27, 28, 29, 30), but not in all studies (31, 32). Most of these studies were cross-sectional (26, 27, 28, 29, 31, 32). When attempts were made to control for disease, it was unclear whether the disease was of comparable severity and contributed to the reduction in serum testosterone (26, 27, 28, 29, 32). In addition, few studies have measured free testosterone directly. When reported, a calculated free testosterone index was reported to be reduced (26, 27, 28, 32). Serum total testosterone and SHBG decreased in this study. As there was an association between the reduction in total testosterone, but not the testosterone/SHBG ratio, and the reduction in serum osteocalcin, we are reluctant to infer that there may be a causal relationship between the decline in testosterone and bone formation. Increased, decreased, and unaltered FSH and LH have been reported, but the episodic secretion of these gonadotropins makes interpretation of single values difficult (26). Corticosteroids may have direct effects on the testis and indirect effects on sex steroid production due to suppression of ACTH production (6).
Circulating GH and IGF-I levels increased in healthy subjects after corticosteroid treatment, which is similar to the increased GH and IGF-I observed in the present study (33). In normal subjects acute administration of dexamethasone has been shown to increase plasma GH levels compared to saline administration (34). However, GH was lower in patients receiving long term corticosteroid treatment compared to normal values (8). The pattern of serum IGF-I changes in the present study was similar to observations in patients with polymyalgia rheumatica treated with low dose prednisolone (12). IGF-I bioactivity may be reduced in normal men treated with corticosteroids, patients with Cushing’s disease, and patients receiving corticosteroid therapy despite an increase in plasma IGF-I concentrations (7, 33). The mechanisms responsible for the increase in IGF-I are uncertain (33).
In conclusion, corticosteroid therapy induced rapid bone loss. The loss of bone is most likely due to a reduction in bone formation; increased bone resorption does not appear to contribute. There was no evidence for secondary hyperparathyroidism. Prospective studies in men free of illness with direct measurements of free testosterone will be required to determine whether the reduction in bone formation may be partly mediated by changes in sex steroids.
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Acknowledgments |
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Received August 7, 1997.
Revised November 6, 1997.
Accepted November 17, 1997.
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References |
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,
P = 0.08; *, P < 0.05
(compared to baseline).
