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11ß-Hydroxysteroid Dehydrogenase Type 1 Activity Predicts the Effects of Glucocorticoids on Bone

Division of Medical Sciences (M.S.C., M.H., P.M.S.), University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom; Bone Metabolism Group (A.B., R.E.), University of Sheffield, Sheffield S5 7AU, United Kingdom; Department of Clinical Biochemistry and Immunology (P.E.G., W.A.B.), Birmingham Heartlands and Solihull NHS Trust, Birmingham B9 5SS, United Kingdom; and Children’s Hospital Oakland Research Institute (C.H.S.), Oakland, California 94609

Address all correspondence and requests for reprints to: Prof. Paul M. Stewart, M.D., F.R.C.P., F.Med.Sci., Endocrinology, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom E-mail: p.m.stewart{at}bham.ac.uk.

	Abstract

Top Abstract Introduction Materials and Methods Results Conclusion References

 
Individual susceptibility to glucocorticoid-induced osteoporosis is difficult to predict clinically. We recently characterized expression of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) in human osteoblasts. This enzyme generates active cortisol (or prednisolone) from inactive cortisone (or prednisone) and regulates glucocorticoid action in vitro. We, thus, hypothesized that osteoblastic 11ß-HSD1 mediates susceptibility to glucocorticoid-induced osteoporosis. Twenty healthy males ingested 5 mg prednisolone twice daily for 7 d, and relationships between changes in bone turnover markers and urinary measures of corticosteroid metabolism were examined. The bone formation markers osteocalcin and N-terminal propeptide of type I collagen decreased in all subjects (P < 0.001), but resorption markers were unchanged. The extent of fall in formation markers correlated with baseline 11ß-HSD1 activity with high activity predicting the greatest fall [for osteocalcin d 4 and 7, r = -0.58 and -0.56 (P < 0.01); for N-terminal propeptide of type I collagen d 4, r = -0.51 (P < 0.05)]. There was no correlation with measures of glucocorticoid inactivation or total corticosteroid metabolite production. Urinary measures of 11ß-HSD1 activity predict the response of bone formation markers to glucocorticoids, and this appears to reflect increased generation of active glucocorticoids within osteoblasts. Measures of 11ß-HSD1 activity may predict individual susceptibility to glucocorticoid-induced osteoporosis, and these data should facilitate the development of bone-sparing glucocorticoids.

	Introduction

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IN EXCESS, GLUCOCORTICOIDS decrease bone mineral density (BMD) and substantially increase fracture risk (1, 2). These effects are mediated predominantly by inhibition of osteoblastic bone formation (3, 4) as reflected by a rapid decrease in biochemical markers of bone formation during glucocorticoid therapy (3, 5, 6, 7). There may additionally be some effects on osteoclast function, especially if estrogen deficiency is also present (8, 9, 10). However, individual susceptibility to the skeletal effects of glucocorticoids is difficult to predict clinically. Tissue responses to glucocorticoids are partly determined at a prereceptor level through expression of the 11ß-hydroxysteroid dehydrogenase enzymes (11ß-HSDs), which catalyze the interconversion of hormonally inactive cortisone with active cortisol (11, 12). In recent studies we have characterized the expression and functional significance of the 11ß-HSD isozymes in normal human bone and human and rodent osteosarcoma cells (13, 14, 15, 16, 17). In adult human bone, the type 1 isozyme of 11ß-HSD (11ß-HSD1) is expressed in osteoblasts in which it serves to activate cortisone to cortisol and prednisone to prednisolone (14, 17). The potential functional significance of this enzyme is demonstrated by expression of human 11ß-HSD1 cDNA in stably transfected ROS 17/2.8 osteosarcoma cells. Compared with empty vector controls, 11ß-HSD1 expression sensitized cells to cortisone, resulting in stimulation of glucocorticoid-sensitive markers of differentiation and inhibition of cell proliferation (18).

We have now tested the hypothesis that 11ß-HSD1 expression is a determinant of the sensitivity of bone to therapeutic glucocorticoids in vivo. We examined potential determinants of variation in the response of bone markers to low-dose glucocorticoid therapy and the relative effects of systemic vs. osteoblastic glucocorticoid metabolism on bone.

	Materials and Methods

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Bone markers and glucocorticoid study

Twenty healthy male volunteers (age, 31 ± 8 yr; mean ± SD) attended the Wellcome Trust Clinical Research Facility at the Queen Elizabeth Hospital, Birmingham. All subjects gave written informed consent, and the study was approved by the Local Research Ethics Committee. Subjects were healthy with no serious illnesses, and none were taking topical, inhaled, or oral glucocorticoids. A 24-h urine sample and 0900-h fasting blood samples were taken before prednisolone treatment. Various anthropometric measurements were taken (height, weight, body mass index, waist to hip ratio) and a health check carried out. Oral prednisolone (APS Pharmaceuticals Ltd., Eastbourne, UK) was commenced at a dose of 5 mg twice daily (0900 and 2200 h) for 7 d. Additional 0900-h fasting blood samples were collected on d 4 and 8. No restrictions were placed on the behavior of the subjects. In a subsequent pharmacokinetics study, prednisolone 5 mg was administered at 0900 h to fasted volunteers. Thirty minutes later, breakfast was allowed. Blood samples were taken at baseline (before prednisolone) and 30, 60, 120, 180, 240, and 300 min after prednisolone.

Collection of samples

Blood samples were taken, allowed to clot, and serum was stored at -70 C until analysis. For 24-h collections of urine, the total volume was measured and aliquots were stored at -20 C until analysis. Aliquots were stored at -50 C until analyzed.

Biochemical tests

An automated system was used to determine bone markers (Elecsys 2010 electrochemiluminescent assay; Roche Diagnostics GmbH, Mannheim, Germany). This system is capable of measuring a marker of bone resorption, serum ß-cross-linked C-telopeptide of type I collagen (ßCTX), and two markers of bone formation, N-terminal propeptide of type I collagen (PINP), and osteocalcin (OC) as well as PTH. This PTH assay detects intact PTH and the N-terminal truncated PTH fragment (PTH 7–84), a fragment normally secreted by the parathyroid, which makes up about 10% of the circulating PTH in normal individuals. The OC assay detects both intact OC and the big N-terminal midfragment. The N-terminal midfragment is an in vitro degradation product (i.e. not a major in vivo degradation product) so the measurement of this fragment improves the stability of the assay. The interassay (within day) analytical coefficient of variation (CV) for each of these markers were 8.1%, 1.1%, 1.3%, and 1.9%, respectively, over this analytical range. The intraindividual CV over 10 d for OC, PINP, and ßCTX were 6.3%, 10.6%, and 19.1%, respectively.

Serum steroid levels

Serum steroid levels were analyzed by HPLC as described previously (14, 19). One hundred microliters of fludrocortisone (40 µmol/liter) were added to 1 ml serum, mixed with dichloromethane (10 ml), and then the aqueous phase was discarded. One milliliter of 0.1 M sodium hydroxide was added and after mixing, the aqueous phase was discarded, and this step was repeated. A similar wash step was repeated twice, replacing sodium hydroxide with filtered degassed water. Following the wash steps, the dichloromethane layer was evaporated to dryness and resuspended in 200 µl HPLC mobile phase. One hundred microliters of aqueous steroid standard or reconstituted extracted steroid were injected onto a 150 x 4.6 mm column packed with 5 µm ODS-2 (LUNA; Phenomenex, Macclesfield, UK). Mobile phase of tetrahydrofuran/water/methanol in the ratio 23:65:2 and containing 100 mmol/liter ammonium acetate was pumped at 1.0 ml/min. Steroids were detected at absorption at 254 nm. Using this assay, CV for within-day estimates of precision were 4.4% or less for the four steroids measured. CV over time ranged from 6.5% to 8.4% for the steroids measured, thus allowing determination of serum levels of prednisolone, prednisone, cortisol, and cortisone.

Urinary steroid metabolites

The gas chromatography/mass spectroscopy method used was based on that of Palermo et al. (20). Urinary-free steroids were measured by a method suitable for cortisol and its 3-oxo-4-ene metabolites including cortisone. For cortisol and cortisone, we used stable isotope-labeled internal standards ([9,11,12,12])²H₄-cortisol and [9,12,12]²H₃-cortisone, respectively). These standards were calibrated against accurately weighed and solubilized nonlabeled standards by HPLC analysis. After the addition of the deuterated internal standard mixture to 5 ml urine (0.12 µg d₃-cortisone, 0.18 µg d₄-cortisol), steroid extraction was carried out by Sep-pak C18 cartridges. To this extract, 200 ng stigmasterol and cholesteryl-butyrate were added as external standards and methyloxime-trimethylsilyl ether was prepared according to established procedures. After derivatization, the excess reagent was removed by Lipidx chromatography; and the samples were automatically introduced in a mass spectrometer (5970, Hewlett-Packard, Houston, TX) with a 15-m DB1 capillary column. Quantification was achieved by monitoring selected ions for the analytes (fragment 531 for cortisone and 605 for cortisol) and internal standards (m/Z 534 and 609, respectively). Relative peak areas were determined and reported as micrograms per 24 h of the individual compound. Validation of the method was performed by comparing the areas under the curve of increasing amounts of the analyte to the ratio between the areas of different amounts of the analyte and fixed concentrations of the internal standard (r = 0.998 for cortisol and 0.999 for cortisone). Intra and interassay CV were less than 10% for both cortisol and cortisone. 11ß-HSD1 activity was calculated as the tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydrocortisone (THF+alloTHF)/THE ratio (20). 11ß-HSD2 activity was calculated as the urinary-free cortisol/cortisone ratio (UFF/UFE). Total cortisol metabolites (THF, alloTHF, THE, alloTHE, cortols, cortolones, UFF, UFE) were used as an index of total cortisol secretion.

Bone density measurement

BMD was measured at the hip (femoral trochanter, neck, and Ward’s triangle) spine (L2–4), and total body using a Lunar DPX dual-energy x-ray absorptiometry scanner. The scanner was regularly calibrated using phantoms to ensure accuracy of bone density measurements over time.

Statistics

ANOVA was used to examine changes in bone markers. Associations between variables were assessed using Pearson correlation coefficients. All statistical tests were carried out using SigmaStat 2.03 software (SPSS Inc., Chicago, IL).

	Results

Top Abstract Introduction Materials and Methods Results Conclusion References

 
Glucocorticoid treatment decreases serum bone formation, but not resorption, markers

As anticipated, following prednisolone treatment the mean serum concentrations of both OC and PICP decreased significantly (Fig. 1). ßCTx and PTH showed no change, in keeping with previous studies (3, 6, 7).

View larger version (17K): [in this window] [in a new window]   FIG. 1. The effect of 5 mg prednisolone twice daily on biochemical bone markers in healthy males. Data are percentage change from baseline and values are mean ± SE, n = 20.

There was a significant correlation between the maximal decrease in OC and the urinary (THF+alloTHF)/THE ratio, a measure of 11ß-HSD1 activity. This relationship was evident as early as d 4 (r = 0.57, P < 0.01) and persisted at d 7 (r = 0.57, P < 0.01) (Fig. 2).

View larger version (19K): [in this window] [in a new window]   FIG. 2. Relationship between change in serum OC and baseline urinary 11ß-HSD1 activity [measured as the (THF+alloTHF)/THE ratio] at d 4 and 7 post prednisolone. The regression line and 95% confidence intervals are indicated.

View larger version (19K): [in this window] [in a new window]   FIG. 3. Relationship between change in serum PINP and baseline urinary 11ß-HSD1 activity [measured as the (THF+alloTHF)/THE ratio] at d 4 and 7 post prednisolone. The regression line and 95% confidence intervals are indicated.

The relationship between 11ß-HSD1 activity and circulating prednisolone levels was examined in a pharmacokinetic study. There was no relationship between prednisolone half-life and (THF+alloTHF)/THE ratio (r = -0.05). To determine whether individuals with high 11ß-HSD1 activity had an increase in systemic bioavailable prednisolone, the area under the prednisolone time curves in each individual (an estimate of the total circulating prednisolone) was measured. There was no indication that total circulating prednisolone level increased with increasing (THF+alloTHF)/THE ratio (r = 0.04). Thus, systemic regeneration of prednisolone is unlikely to explain the changes in bone formation markers.

	Conclusion

Top Abstract Introduction Materials and Methods Results Conclusion References

 
Endogenous 11ß-HSD1 activity correlates with the change in bone formation markers in response to prednisolone in healthy males. This relationship was independent of the UFF/UFE ratio; thus, the (THF+alloTHF)/THE ratio is likely to accurately reflect systemic 11ß-HSD1 activity. No other measure of glucocorticoid absorption, serum level, or metabolism predicted changes in any bone marker. Although all subjects had reductions in bone markers with glucocorticoid treatment, the reduction was only modest in subjects with low 11ß-HSD1 activity but was substantial in subjects with high 11ß-HSD1 activity. These data suggest that 11ß-HSD1 activity in vivo is likely to be an important mediator of individual susceptibility to glucocorticoid-induced osteoporosis.

Increased systemic 11ß-HSD1 activity could theoretically prolong the prednisolone half-life by augmenting systemic glucocorticoid levels through conversion of prednisone to prednisolone. However, this did not appear to be a major effect as assessed by circulatory prednisolone half-life or area under the prednisolone-time curve. It seems likely therefore that osteoblastic 11ß-HSD1 expression determines the degree of suppression of bone formation markers post prednisolone challenge.

This trial intentionally used a prednisolone dose typical of maintenance steroid doses used during treatment for many long-term inflammatory conditions such as rheumatoid arthritis, polymyalgia rheumatica, and asthma. It was anticipated that these doses would not maximally inhibit OC levels in all individuals and, thus, differences in susceptibility between individuals could be examined. We gave the steroid in a daily divided dose to reduce the peak postdose level of prednisolone and increase the daily duration that osteoblasts would be exposed to circulating prednisone. We previously demonstrated that after a 5-mg dose of prednisolone, prednisone concentrations increase rapidly and remain relatively constant for up to 6 h, but prednisolone levels fall relatively quickly (14). With higher doses of prednisolone, it is possible that the direct action of circulating prednisolone on osteoblasts would maximally inhibit bone formation markers making the contribution from locally generated prednisolone of less importance.

The role of (THF+alloTHF)/THE measurement in determining steroid sensitivity in a clinical setting remains unclear. Although this may be an effective predictive measurement in healthy individuals, inflammation may lead to dysregulation of the (THF+alloTHF)/THE ratio. Proinflammatory cytokines increase 11ß-HSD1 activity in osteoblasts (17), but this effect is not seen in human hepatocytes (21). Additionally, at least in vitro, glucocorticoids increase expression of 11ß-HSD1 expression in osteoblasts (14). It is, thus, possible that local glucocorticoid activation will increase further during glucocorticoid treatment. Whether the (THF+alloTHF)/THE ratio will still have a predictive value in a clinical setting is, thus, uncertain and needs further exploration. With this in mind, the correlation of PINP with the (THF+alloTHF)/THE ratio was significant at d 4 but not d 7, although the trend was similar. It seems likely that the lack of statistical significance relates to the smaller reduction in PINP levels with prednisolone, compared with OC and the greater intraindividual variation of PINP than OC levels. However, it is also possible that this reflects a change in the relationship between PINP and the (THF+alloTHF)/THE ratio over time.

Although changes in bone markers are a useful surrogate measure of bone formation, it is not clear whether these correlate with changes in BMD or fracture risk. Recent studies indicate that BMD changes may only partly reflect changes in fracture risk with bisphosphonate treatment (22). This appears to be due to the importance of bone turnover in bone health, which is not measured by BMD. Changes in bone markers may have additional value independent of BMD because these measures take account of bone turnover and, thus, may be more informative. Because of the large number of subjects needed, it would be impossible to do a similar trial with fracture end points, so it remains an assumption that bone marker changes will reliably measure susceptibility to fracture.

Our finding of unchanged bone resorption during glucocorticoid treatment are similar to those of previous studies (5). No relationship between changes in ßCTx or PTH and corticosteroid metabolism was seen. This is despite osteoclasts expressing 11ß-HSD1 (assessed by immunohistochemistry and in situ hybridization) (13). It is possible that there is a different set point in the directionality of osteoclastic 11ß-HSD1, compared with osteoblastic 11ß-HSD1, but more likely the time course of the study was too short to detect changes induced by differences in osteoclast differentiation mediated by differences in 11ß-HSD1 activity. It is also possible that changes in resorption markers will only be seen in the presence of sex steroid deficiency.

These findings extend the link between tissue-specific metabolism of glucocorticoids and steroid-induced side effects. Decreased 11ß-HSD1 expression may protect against glucocorticoid excess in Cushing’s syndrome (23), and increased 11ß-HSD1 activity in osteoblasts may partly underlie age-related bone loss (14). Decreased systemic 11ß-HSD1 activity is seen in obesity (24), and it is possible that such a decrease in osteoblastic 11ß-HSD1 activity accounts for the positive relationship between obesity and bone density. What is clear is that much of the variability in the skeletal response to glucocorticoids is explained by differences in metabolism of glucocorticoids probably at an autocrine level within bone. This knowledge is likely to improve our ability to predict the skeletal effects of glucocorticoids and more effectively target prophylactic agents. This work also illustrates that synthetic glucocorticoids designed such that they are unable to be reactivated locally within osteoblasts would be expected to have a bone-sparing effect.

	Acknowledgments

 
We thank the staff of the Wellcome Trust Clinical Research Facility for the development and execution of this study and the participants who volunteered their time.

	Footnotes

 
This work was supported by the Peel Medical Research Trust and the Medical Research Council, United Kingdom, and was conducted in a Wellcome Trust Clinical Research Facility.

Abbreviations: BMD, Bone mineral density; ßCTX, ß-cross-linked C-telopeptide of type I collagen; CV, coefficient of variation; 11ß-HSD, 11ß-hydroxysteroid dehydrogenase enzyme; 11ß-HSD1, 11ß-hydroxysteroid dehydrogenase type 1; OC, osteocalcin; PINP, N-terminal propeptide of type I collagen; (THF+alloTHF)/THE ratio, tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydrocortisone ratio; UFF/UFE ratio, urinary-free cortisol/cortisone ratio.

Received January 2, 2003.

Accepted May 6, 2003.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cooper, M. S. Articles by Stewart, P. M. Search for Related Content PubMed PubMed Citation Articles by Cooper, M. S. Articles by Stewart, P. M.