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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 10 4923-4928
Copyright © 2004 by The Endocrine Society

Immediate Fall of Bone Formation and Transient Increase of Bone Resorption in the Course of High-Dose, Short-Term Glucocorticoid Therapy in Young Patients with Multiple Sclerosis

Andrea Dovio, Laura Perazzolo, Giangiacomo Osella, Massimo Ventura, Angela Termine, Eva Milano, Antonio Bertolotto and Alberto Angeli

Medicina Interna I (A.D., L.P., G.O., M.V., A.T., A.A.) and Centro Riferimento Regionale Sclerosi Multipla Neurobiologia Clinica (E.M., A.B.), Dipartimento di Scienze Cliniche e Biologiche, University of Turin, 10043 Orbassano (TO), Italy

Address all correspondence and requests for reprints to: A. Dovio, Medicina Interna I, Dipartimento di Scienze Cliniche e Biologiche, University of Turin, A.S.O. San Luigi, Regione Gonzole 10, 10043 Orbassano (TO), Italy. E-mail: dovioaa{at}libero.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Glucocorticoid (GC)-induced osteoporosis is the leading form of secondary osteoporosis. Bone loss can be rapid. However, longitudinal studies at the very beginning of treatment are scarce. Patients relapsing from multiple sclerosis are treated with high-dose, short-term iv GCs. A number of them are young, without concomitant disease affecting bone and with no substantial impairment of mobility. Such patients were selected for the present study. Thirteen patients suffering from multiple sclerosis [11 females, two males; age 32 ± 2 yr (mean ± SE)] and receiving iv methylprednisolone 15 mg/kg daily for 10 d completed the study. We measured serum osteocalcin (OC), aminoterminal propeptide of type I collagen (PINP), bone isoform of alkaline phosphatase (bALP), carboxyterminal telopeptide of type I collagen (CTX), and urinary calcium/creatinine ratio (uCa/Cr) during the 10-d cycle and 3 months later. Dual-energy x-ray absorptiometry and calcaneal quantitative ultrasonometry were performed before and 6 months after therapy. We found an immediate, impressive fall of OC and PINP (–80 ± 3 and –54 ± 5% at d 2, respectively), which persisted throughout the whole treatment period (P < 0.0001 for both markers). bALP levels showed only a modest decrease at d 6 (–19 ± 7%, P < 0.05), with subsequent return to baseline in d 7–10. After 3 months, OC, PINP, and bALP levels rose to +51 ± 22, +37 ± 16 (not significant), and +61 ± 17% (P < 0.01) with respect to baseline, respectively. uCa/Cr and CTX showed a progressive, marked increase during treatment, peaking at d 7–9 (+92 ± 44 and +149 ± 63%, respectively), with subsequent decrement at d 10 (P < 0.01 and P < 0.05, respectively) despite continuing GC administration. After 3 months, uCa/Cr and CTX levels were also higher than baseline. No change in quantitative ultrasonometry parameters and bone mineral density was observed 6 months after therapy. In conclusion, high-dose, short-term iv GC regimens cause an immediate and persistent decrease in bone formation and a rapid and transient increase of bone resorption. Our data also support the concept that discontinuation of such regimens is followed by a high bone turnover phase.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GLUCOCORTICOID (GC)-INDUCED OSTEOPOROSIS is the leading form of secondary osteoporosis. Chronic GC treatment is associated with atraumatic fractures in 30–50% of patients (1). Increased risk of fracture is already apparent after 3 months of therapy (2). A number of studies performed with the use of dual-energy x-ray absorptiometry (DXA) or quantitative ultrasonometry (QUS) has suggested that the increased fracture risk is only partly accounted for by decreased bone mass (3, 4). The concept has been emerging that GC excess causes rapid and significant impairment of the so-called bone quality (5). Such quality is subserved by bone matrix; microarchitecture; rate of bone turnover; and mechanostatic adaptation, which in turn depends on osteocyte network (5, 6). GC excess affects the skeleton by both systemic and local actions. The former accounts for decreased muscle mass, reduced gonadal function, impaired GH secretion, and less IGF-I availability (1, 7, 8, 9). The pathogenetic role of secondary hyperparathyroidism as a consequence of impaired intestinal absorption and increased renal excretion of calcium is debated (10). In the last decade, however, it has become clear that GCs act predominantly through direct effects on bone cells, the main target being the stromal-osteoblastic lineage (1, 6, 7, 8, 9). GCs at supraphysiological concentrations change differentiation, survival, and function of these cells. They are able to cause a shift from osteoblastic to adipocytic differentiation of precursors; induce apoptosis of mature osteoblasts; and inhibit synthesis and secretion of bone matrix proteins, growth factors, and cytokines (1, 6, 7, 8, 9, 11). Moreover, GCs can stimulate bone resorption by promoting osteoclast survival and activity (12, 13).

Patients suffering from multiple sclerosis (MS) and relapsing in the course of disease are currently treated with high-dose, short-term iv methylprednisolone (14). The effects of such a regimen on bone metabolism were investigated about 10 yr ago by Cosman et al. (15), who reported a decrease of serum osteocalcin and an increase of serum tartrate-resistant acid phosphatase and urinary calcium, together with direct effects on the kidney. Interest was prompted by distinctive features, notably drug loading in few days and the exceedingly high concentrations of GCs in a number of tissues. In the last decade, novel biochemical markers of bone turnover that complement technologies to assess bone mass and bone structure such as DXA and QUS have become available. QUS has been suggested to give information about bone structure (4).

A number of patients affected by MS are young, without concomitant disease affecting bone and with no substantial impairment of mobility. Such patients were carefully selected for the present study, which aimed to investigate the acute effects of high-dose, short-term iv methylprednisolone on osteoblast and osteoclast function, respectively. We evaluated the longitudinal patterns of serum and urinary biochemical markers by daily measurements along the 10-d cycle of therapy. Further measurements were performed 3 months later. Data obtained with DXA and calcaneal QUS before and 6 months after therapy served to assess putative changes as a consequence of GC medication.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study population

The study was performed at the Internal Medicine Unit and Multiple Sclerosis Center of San Luigi Hospital, Orbassano (Turin, Italy) from January 2001 through June 2002. All participants gave their written informed consent before enrollment. The study protocol and informed consent documents were prepared according to the Declaration of Helsinki and approved by the local ethical review board. Patients with relapsing MS were diagnosed according to criteria by Poser et al. (16). Exclusion criteria were menopausal status; expanded disability status scale (EDSS) greater than 5.5; history of diseases affecting bone; prolonged immobilization (more than 3 wk), and/or treatment with drugs known to influence bone metabolism in the previous 6 months.

Fourteen patients were recruited; 13 completed the study, since one needed a second GC cycle within 3 months and was excluded from analysis. Demographics, clinical data, baseline laboratory results, and densitometric findings of the study population are reported in Table 1Go. Ten of 13 patients were on interferon (IFN)-ß therapy at recruitment, the mean duration of previous treatment being 27 months; none of these patients stopped IFNß therapy during the study. Two of three patients who were not on IFNß at recruitment started IFNß 4 months later (before the 6-month DXA and QUS follow-up). All women were eumenorrheic. No calcium and vitamin D supplements were given during the study. Methylprednisolone (15 mg/kg·d) diluted in 250 ml saline was infused in 2 h in the morning for 10 d. No adverse reactions were observed and no concomitant medication was administered.


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  		TABLE 1. Demographics, clinical data, baseline laboratory results, and densitometric findings of the study population

 
Biochemical analysis

Fasting morning blood samples were obtained by antecubital venipuncture, and 2-h fasting urine samples were collected from patients at baseline and before GC infusion each day during treatment (10 d) and after about 3 months. The following assays were measured: serum osteocalcin (OC), aminoterminal propeptide of type I collagen (PINP), bone alkaline phosphatase (bALP), carboxyterminal telopeptide of type I collagen (CTX), and urinary calcium (uCa)/creatinine (Cr) ratio. Serum calcium, phosphorus, PTH, and IGF-I were measured at baseline, at d 10, and 3 months later. Serum 25-hydroxyvtamin D (25-OHD) was measured at baseline.

Serum calcium, phosphorus, albumin and total alkaline phosphatase, uCa, and Cr were measured by Aeroset system (Abbott Laboratories, Abbott Park, IL), routinely used in our hospital laboratory. Aliquots of serum and urine were immediately frozen at –20 C. Serum calcium levels were always corrected for serum albumin. Serum PTH was measured by chemiluminescence immunoassay for intact PTH (Nichols Institute Diagnostics, San Clemente, CA). 25-OHD and IGF-I were measured by RIA (Immunodiagnostic Systems, Boldon, UK, and Nichols Institute Diagnostics, respectively). All bone turnover marker samples from each patient were assessed in the same run to minimize the confounding effect of interassay variability. bALP and PINP were measured by RIA [Beckman Coulter (Fullerton, CA) and Orion Diagnostica (Espoo, Finland), respectively], OC and CTX were measured by ELISA (Osteometer Biotech, Herlev, Denmark).

DXA and QUS

Lumbar spine, femur, and total-body DXA was performed by QDR 4500 W (Hologic Inc., Waltham, MA) at baseline and after 6 months. Data were expressed as bone mineral density (BMD, grams per square centimeter) and T- and Z-score. Precision error was 1% at lumbar spine and 1.5% at hip.

Calcaneal QUS was performed by Achilles Express (Lunar Corp., Madison, WI), which measures speed of sound and broadband ultrasound attenuation. Speed of sound and broadband ultrasound attenuation were combined by the analysis software into a composite stiffness index, which was expressed as T- and Z-score. All measurements were performed by the same operator.

Statistical methods

Statistical analysis of data were performed with Statistica 6.0 software package (Statsoft Inc., Tulsa, OK). Results are presented as mean ± SE. Assessment of changes during GC treatment was performed by Friedman ANOVA, followed by Wilcoxon matched pair test when appropriate, and a P < 0.05 was regarded as significant. Because of the longitudinal design of the study and interindividual variability of absolute values, data in the figures were expressed as percentage of baseline values.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
In our series of patients, according to DXA results and World Health Organization classification, one was osteoporotic and four were osteopenic. Serum 25-OHD levels were in the insufficient range [between 10 and 20 ng/ml (25 and 50 nmol/liter)] in six of 13 patients. At baseline, PTH concentrations were in the normal range in nine of 13 patients; in four they were between 65 and 80 pg/ml (65 and 80 ng/liter), with normal serum calcium. No correlation among baseline serum calcium, PTH, and 25-OHD levels was found. No correlation between DXA and QUS results, on the one hand, and duration of disease and EDSS, on the other hand, was found (Table 1Go).

As for bone formation markers, we found an immediate and impressive fall of OC and PINP (–80 ± 3 and –54 ± 5% at d 2, respectively), which persisted throughout the whole treatment period; after 3 months, OC and PINP levels rose to +51 ± 22 and +37 ± 16% with respect to baseline values (Fig. 1Go, A and B). At variance with OC and PINP, bALP levels showed only a modest decrease (–19 ± 7%) on d 6, with subsequent return to baseline at d 7–10. Similar to OC and PINP, bALP levels at 3 months rose to +61 ± 17% with respect to baseline (Fig. 1CGo). Both uCa/Cr and CTX (Fig. 2Go, A and B, respectively) showed a progressive, marked increase during treatment, peaking at d 7–9 (+92 ± 44 and +149 ± 63%, respectively), with subsequent decrement at d 10. After 3 months, both uCa/Cr and CTX levels were still higher than baseline; for the latter the difference (+82 ± 26%) was statistically significant. After 10 d of therapy, no apparent changes of serum calcium and phosphorus were noticed (data not shown). On the contrary, we observed a consistent, significant decrease of IGF-I serum levels at d 10 (Fig. 3AGo), which returned to normal after 3 months. No significant change in PTH was found (Fig. 3BGo). No correlation was found between baseline PTH and 25-OHD, on the one hand, and percent change of PTH and bone resorption markers, on the other hand. QUS and DXA reassessments at 6 months were available for 12 of 13 and 10 of 13 patients, respectively; no change in stiffness index and BMD at any site was observed.



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  		FIG. 1. Effects of GC administration on bone formation markers. OC (A), PINP (B), and bALP (C) were measured on morning fasting blood samples before (d 1) and each day during treatment (d 2–10) and after 3 months. a, P < 0.05; b, P < 0.01 by Wilcoxon matched pair test.

 


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  		FIG. 2. Effects of GC administration on uCa/Cr and CTX. uCa/Cr (A) and CTX (B) were measured on morning fasting blood and urine samples before (d 1) and each day during treatment (d 2–10) and after 3 months. a, P < 0.05; b, P < 0.01 by Wilcoxon matched pair test.

 


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  		FIG. 3. Effects of GC administration on serum IGF-I and PTH. Serum IGF-I (A) and PTH (B) were measured on fasting morning blood samples before treatment (d 1), at cessation (d 10), and after 3 months. a, P < 0.05 by Wilcoxon matched pair test.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The mechanisms of GC action on the bone microenvironment have been extensively studied in the last 2 decades. In patients undergoing chronic oral GC therapy, bone loss is admittedly rapid because it is apparent within 6 (1, 6) or even 3 (17) months of starting treatment. However, longitudinal studies dealing with bone turnover at the very beginning of treatment are lacking, and information is still scarce on early effects as a function of dose-specific GC derivative and route of administration.

In the present study, we did concentrate attention on a homogeneous albeit small group of young adults who received high-dose, iv methylprednisolone for 10 d. We noticed an abrupt drop in serum OC and PINP concentrations immediately after starting treatment. This observation is consistent with previous studies (15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28). It is known that both OC and procollagen-{alpha}1 (I) gene expression is directly down-regulated by GCs (29, 30). On the contrary, serum bALP showed only minor changes. Previous studies have shown that during the first month of GC treatment, serum bALP was either decreased (20, 21, 24) or unchanged (22, 23). The question arises whether GC-induced decrease of bALP requires more than 10 d or even months to become apparent, as suggested by previous reports (20, 21, 24). A longer half-life of bALP in the circulation could explain the discrepancy between markers (31). Moreover, dissociation between OC and PINP, on the one hand, and bALP, on the other hand, could reflect different regulation by GCs because no GC-sensitive elements have been found in the bALP gene (32). PINP, bALP, and OC reflect different steps in the differentiation process of the osteoblastic lineage; however, the expression of different markers is conceivably multiphasic and partially overlapping throughout differentiation (33), thus making inference on differentiation-specific effects of GCs uncertain.

We also found a progressive increase of uCa/Cr and serum CTX peaking at d 7–9, consistent with previous reports (15, 19, 20, 22, 23, 34, 35). uCa/Cr provides a measure of bone resorption but also depends on the renal threshold for calcium and dietary calcium intake (36). In previous reports, the absence of parallel increase of other more specific bone resorption markers prompted the authors to suggest that increased uCa/Cr during GC administration is due to a combination of direct inhibition of tubular reabsorption and increased filtered load of calcium secondary to the negative net bone balance created by abrupt decrease in bone formation and unchanged resorption (15, 19, 20). In the present work, we noticed a rough parallelism between uCa/Cr and serum CTX, thus demonstrating that increase in bone resorption does occur during GC administration. Interestingly enough, both markers showed the same trend to decrease at d 10, when GC administration was still on course. Taken together, our data emphasize the concept that bone resorption is increased rapidly but transiently after starting GC treatment and also offer an explanation to inconsistent findings obtained in studies looking at changes of resorption after 1 month or more (37). The mechanisms accounting for early increase of bone resorption are still unclear and may involve both direct effects of GCs on osteoclasts and indirect effects via modulation of juxta- and paracrine osteoclastogenic signals by stromal-osteoblastic cells (38, 39). This latter effect could be transient in that differentiation of stromal precursors toward the osteoblastic lineage is increasingly diverted toward adipocytic lineage while continuing GC administration (1, 11). Secondary hyperparathyroidism is unlikely to play an important role (10). Consistent with this, the increase of serum PTH at the end of the high-dose GC course was not significant and did not correlate with the increase of resorption markers.

Significant reduction of serum IGF-I is consistent with the well-known negative modulation of GC on the hypothalamic-pituitary-IGF-I axis (7, 8, 9). The importance of circulating IGF-I for growth and maintenance of the bone mass has been recently confirmed in knockout mice (40) and is also supported by human studies (41, 42). It is plausible that rapid fall of serum IGF-I after starting a high-dose GC treatment contributes to decreased bone formation. Further studies are needed to better define this fall.

Intriguingly, 3 months after therapy, all bone markers levels were significantly higher than baseline, suggesting a high turnover phase. Similar results have been previously reported in patients with endogenous Cushing’s syndrome after surgical cure (43, 44, 45). Hermus et al. found maximum increase of bone markers 3 months after intervention (44). Such a high turnover phase suggests an increase of bone formation coupled with an increased resorption, consistent with the reported reversibility of bone loss after cessation of long-term GC therapy and cure of Cushing’s syndrome (2, 43, 44, 45, 46). However, we cannot exclude that high turnover represents a delayed detrimental effect of previous GC administration.

At baseline, six of 13 patients showed vitamin D insufficiency, consistent with previous observations (47, 48, 49). In patients suffering from MS, low levels of 25-OHD are likely to be due to less sunlight exposure because heat-related fatigue and intolerance are well-recognized symptoms, leading patients to avoid sun exposure. Mean Z-score at both lumbar spine and femur was higher in our series than previously reported by Nieves et al. (47), probably due to smaller EDSS score, which has been found to be a major predictor of bone loss in MS patients (48, 49). The rapid suppression of bone formation together with early stimulation of bone resorption did not result in decreased bone density at 6 months as assessed by DXA and QUS. These results are consistent with previous observation that single GC pulse does not affect BMD (50) and the hypothesis of a reparative phase after GC cessation; however, we cannot exclude that a higher number of patients and/or longer follow-up is required to detect deleterious effects. Interestingly enough, Van Staa et al. (2) have shown that sustained GC medication yields an increase of fracture risk that is already apparent at 3 months, independent of changes in BMD. Histomorphometric and microarchitectural studies aimed to assess bone quality in patients given short-term, high-dose GC regimens are lacking. Any conclusion on fracture risk in patients like those studied by us is not warranted.

In conclusion, high-dose, short-term iv GC therapy results in immediate fall of bone formation and transient increase of bone resorption, as assessed by turnover markers. Our data support the concept that, at least in the initial rapid phase of GC-induced bone loss, both decreased formation and increased resorption are involved, whereas late increase of bone markers suggests that discontinuation of such regimens is followed by a reparative phase with high bone turnover.


   Acknowledgments
 
We thank patients and staff of Multiple Sclerosis Center, Mr. R. Fiorito (Radiology Unit), and Dr. L. Saba (Internal Medicine Unit) for their cooperation in collecting data for this study. We are indebted to Professor R. Weinstein (Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR) for his valuable suggestions about the manuscript.


   Footnotes
 
This work was supported by grants from Ministero dell’Istruzione, Università e Ricerca, Cassa di Risparmio di Cuneo, Cassa di Risparmio di Saluzzo, Fondazione Ricerca Biomedica, and Fondazione Cavalieri Ottolenghi per le Neuroscienze.

This study was partly presented at the 3rd International Congress on Glucocorticoid-Induced Osteoporosis, Turin, Italy, March 6–8, 2003.

Abbreviations: bALP, Bone alkaline phosphatase; BMD, bone mineral density; Cr, creatinine; CTX, carboxyterminal telopeptide of type I collagen; DXA, dual-energy x-ray absorptiometry; EDSS, expanded disability status scale; GC, glucocorticoid; IFN, interferon; MS, multiple sclerosis; OC, osteocalcin; 25-OHD, 25-hydroxyvtamin D; PINP, aminoterminal propeptide of type I collagen; QUS, quantitative ultrasonometry; uCa, urinary calcium.

Received February 3, 2004.

Accepted June 30, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Weinstein RS 2001 Glucocorticoid-induced osteoporosis. Rev Endocr Metab Disord 2:65–73[CrossRef][Medline]
  2. Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C 2000 Use of oral corticosteroids and risk of fractures. J Bone Miner Res 15:993–1000[CrossRef][Medline]
  3. Clowes JA, Peel N, Eastell R 2001 Glucocorticoid-induced osteoporosis. Curr Opin Rheumatol 13:326–332[CrossRef][Medline]
  4. Wuster C 2002 The use of quantitative ultrasonometry in patients with glucocorticoid-induced osteoporosis. Front Horm Res 30:20–36[Medline]
  5. Watts NB 2002 Bone quality: getting closer to a definition. J Bone Miner Res 17:1148–1150[CrossRef][Medline]
  6. Manolagas SC 2000 Corticosteroids and fractures: a close encounter of the third cell kind. J Bone Miner Res 15:1001–1005[CrossRef][Medline]
  7. Manelli F, Giustina A 2000 Glucocorticoid-induced osteoporosis. Trends Endocrinol Metab 11:79–85[CrossRef][Medline]
  8. Angeli A, Osella G, Reimondo G, Terzolo M 2000 Glucocorticoid-induced osteoporosis: recent findings. Ann Ital Med Int 15:47–55[Medline]
  9. Canalis E, Bilezikian JP, Angeli A, Giustina A 2004 Perspectives on glucocorticoid-induced osteoporosis. Bone 34:593–598[Medline]
  10. Rubin MR, Bilezikian JP 2002 Clinical review 151: the role of parathyroid hormone in the pathogenesis of glucocorticoid-induced osteoporosis: a re-examination of the evidence. J Clin Endocrinol Metab 87:4033–4041[Free Full Text]
  11. Pereira RM, Delany AM, Canalis E 2001 Cortisol inhibits the differentiation and apoptosis of osteoblasts in culture. Bone 28:484–490[Medline]
  12. Weinstein RS, Chen JR, Powers CC, Stewart SA, Landes RD, Bellido T, Jilka RL, Parfitt AM, Manolagas SC 2002 Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids. J Clin Invest 109:1041–1048[CrossRef][Medline]
  13. Gronowicz G, McCarthy MB, Raisz LG 1990 Glucocorticoids stimulate resorption in fetal rat parietal bones in vitro. J Bone Miner Res 5:1223–1230[Medline]
  14. Goodin DS, Frohman EM, Garmany Jr GP, Halper J, Likosky WH, Lublin FD, Silberberg DH, Stuart WH, van den Noort S; Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines 2002 Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology 58:169–178[Free Full Text]
  15. Cosman F, Nieves J, Herbert J, Shen V, Lindsay R 1994 High-dose glucocorticoids in multiple sclerosis patients exert direct effects on the kidney and skeleton. J Bone Miner Res 9:1097–1105[Medline]
  16. Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW 1983 New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13:227–231[CrossRef][Medline]
  17. Fujita T, Satomura A, Hidaka M, Ohsawa I, Endo M, Ohi H 2000 Acute alteration in bone mineral density and biochemical markers for bone metabolism in nephrotic patients receiving high-dose glucocorticoid and one-cycle etidronate therapy. Calcif Tissue Int 66:195–199[CrossRef][Medline]
  18. Godschalk MF, Downs RW 1988 Effect of short-term glucocorticoids on serum osteocalcin in healthy young men. J Bone Miner Res 3:113–115[Medline]
  19. Nielsen HK, Charles P, Mosekilde L 1988 The effect of single oral doses of prednisone on the circadian rhythm of serum osteocalcin in normal subjects. J Clin Endocrinol Metab 67:1025–1030[Abstract]
  20. Prummel MF, Wiersinga WM, Lips P, Sanders GT, Sauerwein HP 1991 The course of biochemical parameters of bone turnover during treatment with corticosteroids. J Clin Endocrinol Metab 72:382–386[Abstract]
  21. Pearce G, Tabensky DA, Delmas PD, Baker HW, Seeman E 1998 Corticosteroid-induced bone loss in men. J Clin Endocrinol Metab 83:801–806[Abstract/Free Full Text]
  22. Paglia F, Dionisi S, De Geronimo S, Rosso R, Romagnoli E, Raejntroph N, Ragno A, Celi M, Pepe J, D’Erasmo E, Minisola S, Raejentroph N 2001 Biomarkers of bone turnover after a short period of steroid therapy in elderly men. Clin Chem 47:1314–1316[Free Full Text]
  23. Ardissone P, Rota E, Durelli L, Limone P, Isaia GC 2002 Effects of high doses of corticosteroids on bone metabolism. J Endocrinol Invest 25:129–133[Medline]
  24. Sasaki N, Kusano E, Ando Y, Nemoto J, Iimura O, Ito C, Takeda S, Yano K, Tsuda E, Asano Y 2002 Changes in osteoprotegerin and markers of bone metabolism during glucocorticoid treatment in patients with chronic glomerulonephritis. Bone 30:853–858[Medline]
  25. Sasaki N, Kusano E, Ando Y, Yano K, Tsuda E, Asano Y 2001 Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis. Nephrol Dial Transplant 16:479–482[Abstract/Free Full Text]
  26. Saarela T, Risteli J, Koivisto M 2003 Effects of short-term dexamethasone treatment on collagen synthesis and degradation markers in preterm infants with developing lung disease. Acta Paediatr 92:588–594[CrossRef][Medline]
  27. Saarela T, Risteli J, Kauppila A, Koivisto M 2001 Effect of short-term antenatal dexamethasone administration on type I collagen synthesis and degradation in preterm infants at birth. Acta Paediatr 90:921–925[Medline]
  28. Meduri GU, Tolley EA, Chinn A, Stentz F, Postlethwaite A 1998 Procollagen types I and III aminoterminal propeptide levels during acute respiratory distress syndrome and in response to methylprednisolone treatment. Am J Respir Crit Care Med 158:1432–1441[Abstract/Free Full Text]
  29. Webster JC, Cidlowski JA 1999 Mechanisms of glucocorticoid-receptor-mediated repression of gene expression. Trends Endocrinol Metab 10:396–402[CrossRef][Medline]
  30. Peterkofsky B, Gosiewska A, Singh K, Pearlman S, Mahmoodian F 1999 Species differences in cis-elements of the pro{alpha}1(I) procollagen promoter and their binding proteins. J Cell Biochem 73:408–422[CrossRef][Medline]
  31. Walton RJ, Preston CJ, Russell RGG, Kanis JA 1975 An estimate of the turnover rate of bone-derived plasma alkaline phosphatase in Paget’s disease. Clin Chim Acta 63:227–229[CrossRef][Medline]
  32. Weiss MJ, Ray K, Henthorn PS, Lamb B, Kadesch T, Harris H 1988 Structure of the human liver/bone/kidney alkaline phosphatase gene. J Biol Chem 263:12002–12010[Abstract/Free Full Text]
  33. Aubin JE 2001 Regulation of osteoblast formation and function. Rev Endocr Metab Disord 2:81–94[CrossRef][Medline]
  34. Ueland T, Bollerslev J, Godang K, Muller F, Froland SS, Aukrust P 2001 Increased serum osteoprotegerin in disorders characterized by persistent immune activation or glucocorticoid excess—possible role in bone homeostasis. Eur J Endocrinol 145:685–690[Abstract]
  35. Fahrleitner A, Prenner G, Leb G, Tscheliessnigg KH, Piswanger-Solkner C, Obermayer-Pietsch B, Portugaller HR, Berghold A, Dobnig H 2003 Serum osteoprotegerin is a major determinant of bone density development and prevalent vertebral fracture status following cardiac transplantation. Bone 32:96–106[Medline]
  36. Ebeling PR 2001 Potential candidates for bone turnover markers—N-telopeptide cross-links of type I collagen (NTX). In: Eastell R, Baumann M, Hoyle NR, Wieczorek L, eds. Bone markers: biochemical and clinical perspectives. London: Martin Dunitz; 27–38
  37. Pearce G, Ryan PF, Delmas PD, Tabensky DA, Seeman E 1998 The deleterious effects of low-dose corticosteroids on bone density in patients with polymyalgia rheumatica. Br J Rheumatol 37:292–299[Abstract/Free Full Text]
  38. Udagawa N, Takahashi N, Katagiri T, Tamura T, Wada S, Findlay DM, Martin TJ, Hirota H, Taga T, Kishimoto T, Suda T 1995 Interleukin (IL)-6 induction of osteoclast differentiation depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors. J Exp Med 182:1461–1468[Abstract/Free Full Text]
  39. Hofbauer LC, Heufelder AE 2000 Clinical review 114: hot topic. The role of receptor activator of nuclear factor-{kappa}B ligand and osteoprotegerin in the pathogenesis and treatment of metabolic bone diseases. J Clin Endocrinol Metab 85:2355–2363[Free Full Text]
  40. Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, Liu JL, Ooi GT, Setser J, Frystyk J, Boisclair YR, LeRoith D 2002 Circulating levels of IGF-I directly regulate bone growth and density. J Clin Invest 110:771–781[CrossRef][Medline]
  41. Langlois JA, Rosen CJ, Visser M, Hannan MT, Harris T, Wilson PW, Kiel DP 1998 Association between insulin-like growth factor I and bone mineral density in older women and men: the Framingham Heart Study. J Clin Endocrinol Metab 83:4257–4262[Abstract/Free Full Text]
  42. Garnero P, Sornay-Rendu E, Delmas PD 2000 Low serum IGF-I and occurrence of osteoporotic fractures in postmenopausal women. Lancet 355:898–899[CrossRef][Medline]
  43. Luisetto G, Zangari M, Camozzi V, Boscaro M, Sonino N, Fallo F 2001 Recovery of bone mineral density after surgical cure, but not by ketoconazole treatment, in Cushing’s syndrome. Osteoporos Int 12:956–960[CrossRef][Medline]
  44. Hermus AR, Smals AG, Swinkels LM, Huysmans DA, Pieters GF, Sweep CF, Corstens FH, Kloppenborg PW 1995 Bone mineral density and bone turnover before and after surgical cure of Cushing’s syndrome. J Clin Endocrinol Metab 80:2859–2865[Abstract/Free Full Text]
  45. Pocock NA, Eisman JA, Dunstan CR, Evans RA, Thomas DH, Huq NL 1987 Recovery from steroid-induced osteoporosis. Ann Intern Med 107:319–323
  46. Laan RFJM, van Riel PLCM, van de Putte LBA, van Erning LJTO, van’t Hof MA, Lemmens JAM 1993 Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis. Ann Intern Med 119:963–968[Abstract/Free Full Text]
  47. Nieves J, Cosman F, Herbert J, Shen V, Lindsay R 1994 High prevalence of vitamin D deficiency and reduced bone mass in multiple sclerosis. Neurology 44:1687–1692[Abstract/Free Full Text]
  48. Cosman F, Nieves J, Komar L, Ferrer G, Herbert J, Formica C, Shen V, Lindsay R 1998 Fracture history and bone loss in patients with multiple sclerosis. Neurology 51:1161–1165[Abstract/Free Full Text]
  49. Weinstock-Guttman B, Gallagher E, Baier M, Green L, Feichter J, Patrick K, Miller C, Wrest K, Ramanathan M 2004 Risk of bone loss in men with multiple sclerosis. Mult Scler 10:170–175[Abstract/Free Full Text]
  50. Schwid SR, Goodman AD, Puzas JE, McDermott MP, Mattson DH 1996 Sporadic corticosteroid pulses and osteoporosis in multiple sclerosis. Arch Neurol 53:753–757[Abstract]



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