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Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn’s disease

2005; Elsevier BV; Volume: 3; Issue: 2 Linguagem: Inglês

10.1016/s1542-3565(04)00662-7

1542-7714

Erik J. Schoon, S. Bollani, Peter R. Mills, Eran Israeli, Dieter Felsenberg, Sverker Ljunghall, Tore Persson, Louise Haptén-White, H. Graffner, Gabriele Bianchi Porro, Morten Vatn, Reinhold W. Stockbrügger,

Spondyloarthritis Studies and Treatments

Background & Aims: Osteoporosis frequently occurs in Crohn's disease, often because of corticosteroids. Budesonide as controlled release capsules is a locally acting corticosteroid with low systemic bioavailability. We investigated its effects on bone compared with prednisolone. Methods: In 34 international centers, 272 patients with Crohn's disease involving ileum and/or colon ascendens were randomized to once daily treatment with budesonide or prednisolone for 2 years at doses adapted to disease activity. One hundred eighty-one corticosteroid-free patients had active disease (98 had never received corticosteroids, corticosteroid naive; 83 had received corticosteroids previously, corticosteroid exposed), and 90 had quiescent disease, receiving long-term low doses of corticosteroids, corticosteroid-dependent; in 1 patient, no efficacy data were obtained. Bone mineral density and fractures were assessed in a double-blinded fashion; disease activity, side effects, and quality of life were monitored. Results: Neither the corticosteroid-free nor the corticosteroid-dependent patients treated with budesonide differed significantly in bone mineral density from those receiving prednisolone. However, corticosteroid-naive patients receiving budesonide had smaller reductions in bone mineral density than those on prednisolone (mean, −1.04% vs −3.84%; P = .0084). Treatment-emergent corticosteroid side effects were less frequent with budesonide. Efficacy was similar in both groups. Conclusions: Treatment with budesonide is associated with better preserved bone mass compared with prednisolone in only the corticosteroid-naive patients with active ileocecal Crohn's disease. In both the corticosteroid-free and corticosteroid-dependent groups, budesonide and prednisolone were equally effective for up to 2 years, but budesonide caused fewer corticosteroid side effects. Background & Aims: Osteoporosis frequently occurs in Crohn's disease, often because of corticosteroids. Budesonide as controlled release capsules is a locally acting corticosteroid with low systemic bioavailability. We investigated its effects on bone compared with prednisolone. Methods: In 34 international centers, 272 patients with Crohn's disease involving ileum and/or colon ascendens were randomized to once daily treatment with budesonide or prednisolone for 2 years at doses adapted to disease activity. One hundred eighty-one corticosteroid-free patients had active disease (98 had never received corticosteroids, corticosteroid naive; 83 had received corticosteroids previously, corticosteroid exposed), and 90 had quiescent disease, receiving long-term low doses of corticosteroids, corticosteroid-dependent; in 1 patient, no efficacy data were obtained. Bone mineral density and fractures were assessed in a double-blinded fashion; disease activity, side effects, and quality of life were monitored. Results: Neither the corticosteroid-free nor the corticosteroid-dependent patients treated with budesonide differed significantly in bone mineral density from those receiving prednisolone. However, corticosteroid-naive patients receiving budesonide had smaller reductions in bone mineral density than those on prednisolone (mean, −1.04% vs −3.84%; P = .0084). Treatment-emergent corticosteroid side effects were less frequent with budesonide. Efficacy was similar in both groups. Conclusions: Treatment with budesonide is associated with better preserved bone mass compared with prednisolone in only the corticosteroid-naive patients with active ileocecal Crohn's disease. In both the corticosteroid-free and corticosteroid-dependent groups, budesonide and prednisolone were equally effective for up to 2 years, but budesonide caused fewer corticosteroid side effects. Patients with Crohn's disease are at increased risk of osteoporosis and spontaneous or low-energy fracture.1Bernstein C.N. Blanchard J.F. Leslie W. et al.The incidence of fracture among patients with inflammatory bowel disease a population-based study.Ann Intern Med. 2000; 133: 795-799Crossref PubMed Scopus (401) Google Scholar, 2Vestergaard P. Krogh K. Rejnmark L. et al.Fracture risk is increased in Crohn′s disease, but not in ulcerative colitis.Gut. 2000; 46: 176-181Crossref PubMed Scopus (172) Google Scholar, 3Vestergaard P. Mosekilde L. Fracture risk in patients with celiac disease, Crohn's disease, and ulcerative colitis a nationwide follow-up study of 16,416 patients in Denmark.Am J Epidemiol. 2002; 156: 1-10Crossref PubMed Scopus (269) Google Scholar Factors implicated in the development of osteoporosis include age, physical inactivity, sex hormone deficiency, and female sex, but the main risk factors appear to be disease activity and the use of systemic corticosteroids, with some difficulty in discriminating between the two.4Andreassen H. Hylander E. Rix M. Gender, age, and body weight are the major predictive factors for bone mineral density in Crohn′s disease.Am J Gastroenterol. 1999; 94: 824-828Crossref PubMed Google Scholar, 5Bjarnason I. Macpherson A. Mackintosh C. et al.Reduced bone density in patients with inflammatory bowel disease.Gut. 1997; 40: 228-233PubMed Google Scholar, 6Compston J.E. Judd D. Crawley E.O. et al.Osteoporosis in patients with inflammatory bowel disease.Gut. 1987; 28: 410-415Crossref PubMed Scopus (292) Google Scholar, 7Pigot F. Roux C. Chaussade S. et al.Low bone mineral density in patients with inflammatory bowel disease.Dig Dis Sci. 1992; 37: 1396-1403Crossref PubMed Scopus (157) Google Scholar, 8Robinson R.J. Iqbal S.J. Abrams K. et al.Increased bone resorption in patients with Crohn′s disease.Aliment Pharmacol Ther. 1998; 12: 669-705Google Scholar, 9Robinson R.J. Al-Azzawi F. Iqbal S.J. et al.Osteoporosis and determinants of bone density in patients with Crohn′s disese.Dig Dis Sci. 1998; 43: 2500-2506Crossref PubMed Scopus (122) Google Scholar, 10Silvennoinen J.A. Lehtola J.K. Niemela S.E. Smoking is a risk factor for osteoporosis in women with inflammatory bowel disease.Scand J Gastroenterol. 1996; 31: 367-371Crossref PubMed Scopus (63) Google Scholar, 11Silvennoinen J.A. Karttunnen T.J. Niemela S.E. et al.A controlled study of bone mineral density in patients with inflammatory bowel disease.Gut. 1995; 37: 71-76Crossref PubMed Scopus (235) Google Scholar, 12Vogelsang H. Ferenci P. Woloszeznk W. et al.Bone disease in vitamin D-deficient patients with Crohn's disease.Dig Dis Sci. 1989; 34: 1094-1099Crossref PubMed Scopus (104) Google Scholar, 13Hyams J.S. Wyzga N. Kreutzer D.L. et al.Alterations in bone metabolism in children with IBD an in vitro study.J Pediatric Gastroenterol Nutr. 1997; 24: 289-295Crossref PubMed Scopus (122) Google Scholar Systemic corticosteroids still form the mainstay of treatment for those patients with active disease in whom surgery is not indicated; short courses of high-dose corticosteroids are frequently prescribed to induce remission and are rapidly reduced to nil if possible.14Yang X. Lichtenstein G.R. Corticosteroids in Crohn's disease.Am J Gastroenterol. 2002; 97: 803-823Crossref PubMed Google Scholar Corticosteroids are not used for maintenance treatment of Crohn's disease. However, in some patients with particularly active disease, it might be necessary to continue low doses for longer periods (corticosteroid dependency).15Plevy S.E. Corticosteroid-sparing treatments in patients with Crohn's disease.Am J Gastroenterol. 2002; 97: 1607-1617Crossref PubMed Google Scholar Both high-dose and long-term low-dose regimens with corticosteroids are associated with adverse effects, including moon face, fluid retention, hypertension, changes of mood, and suppression of the pituitary-adrenal axis.16Cortot A. Colombel J.-F. Rutgeerts P. et al.Switch from systemic steroids to budesonide in corticosteroid dependent patients with inactive Crohn's disease.Gut. 2001; 48: 186-190Crossref PubMed Scopus (89) Google Scholar, 17Pardi D.S. Loftus Jr, E.V. Camilleri M. Treatment of inflammatory bowel disease in the elderly an update.Drugs Aging. 2002; 19: 355-363Crossref PubMed Scopus (30) Google Scholar Budesonide is a topically acting corticosteroid that undergoes extensive first-pass metabolism in the liver and thus has low systemic bioavailability.18Spencer C.M. Mc Tavish D. Budesonide a review of its pharmacological properties and therapeutic efficacy in inflammatory bowel disease.Drugs. 1995; 50: 854-872Crossref PubMed Scopus (96) Google Scholar Since 1995 it has been available as an oral controlled release (CR) formulation that delivers the drug to the ileocolonic region of the gastrointestinal tract (Entocort EC/Entocort capsules; AstraZeneca, Lund, Sweden).19Baker D.E. Budesonide modified-release capsules.Rev Gastroenterol Disord. 2001; 1: 147-155PubMed Google Scholar Clinical trials have shown that budesonide CR capsules are better tolerated than conventional corticosteroids and can be as effective in controlling Crohn's disease.20Greenberg G.R. Feagan B.G. Martin F. et al.Oral budesonide for active Crohn's disease.N Engl J Med. 1994; 331: 836-841Crossref PubMed Scopus (517) Google Scholar, 21Campieri M. Ferguson A. Doe W. et al.Oral budesonide is as effective as oral prednisolone in active Crohn's disease.Gut. 1997; 41: 209-214Crossref PubMed Scopus (281) Google Scholar, 22Rutgeerts P. Lofberg R. Malchow H. et al.A comparison of budesonide with prednisolone for active Crohn's disease.N Engl J Med. 1994; 331: 842-845Crossref PubMed Scopus (555) Google Scholar However, the incidence and extent of osteoporosis in patients with Crohn's disease treated with budesonide CR capsules or prednisolone have not yet been rigorously investigated, and this is the issue that we address here. An open, randomized, controlled trial was conducted in 34 centers in 8 European countries and Israel to compare budesonide CR capsules with oral prednisolone in patients with ileocecal Crohn's disease. The primary aim of the study was to compare the changes in bone mineral density (BMD) between the 2 treatment modalities (also assessing lumbar spine fractures). In parallel, efficacy of the treatments and its safety and tolerability were assessed as secondary end points to balance clinically important advantages and disadvantages during the study period of 24 months. The study protocol ensured that corticosteroid-dependent patients were evaluated separately from those corticosteroid-free at inclusion. The study was approved by ethics committees at all participating centers, and all patients gave written informed consent before enrollment. Between July 1996 and July 1999, 309 consecutive patients aged 20–70 years with Crohn's disease affecting the distal ileum, ileocecal region, and/or the ascending colon, as confirmed with the criteria of Lennard-Jones,23Lennard-Jones J.E. Classification of inflammatory bowel disease.Scand J Gastroenterol. 1989; 17: 2-6Crossref Scopus (1799) Google Scholar were screened, and 285 were eligible to enter the study. The main exclusion criteria were disease proximal to the ileum, active Crohn's disease in the rectum, previous gastric surgery, resection of more than 100 cm of small bowel or of tissues distal to the mid-transverse colon, and complicated Crohn's disease (eg, presence of abscess, obstruction, or perforation). Patients with hypersensitivity to corticosteroids were also excluded, as were those initiated with a variety of agents, including hormone replacement therapies, biphosphonates, androgens, and anabolic steroids during the past 6 months or immunosuppressants (3 months). At enrollment, patients were classified into 2 categories: (1) corticosteroid-free patients had mild to severe active Crohn's disease (CDAI ≥ 150) and had not received corticosteroids during the previous 6 months; (2) corticosteroid-dependent patients had quiescent disease (CDAI ≤ 200) when receiving prednisolone/prednisone 7–20 mg/day (currently and for at least 4 of the preceding 6 months). At the start of the study after a 1-week run-in period (for baseline investigations and CDAI), corticosteroid-free patients were randomized to receive budesonide CR capsules 9 mg once daily or prednisolone 40 mg once daily. Randomization was conducted within centers, according to computer-generated lists. Corticosteroid-dependent patients were randomized to continue with their pre-existing prednisolone regimen or to switch to budesonide 9 mg/day, tapering their current prednisolone/prednisone dose by 5 mg/week until cessation. After this initial period, treatment doses could then be adjusted by the managing clinicians according to disease activity until the study termination at 2 years; this is the reason for the unblinded design of the study. Discontinuation and reintroduction of the study drug were permitted. Therapy with 5-aminosalicylic acid and immunosuppressants was allowed at stable pre-study doses. Stable vitamin D and calcium supplementation was also permissible. Reasons for withdrawing patients from the study were insufficient response to the highest dose of the study drugs within 4 weeks at any time during the study, need for intravenous corticosteroids, need for total parenteral nutrition, need for other drugs than the study medication, and surgery for the bowel disease. A full history and physical examination (including physical activity index)24Baecke J.A. Burema J. Frijters J.E. A short questionnaire for the measurement of habitual physical activity in epidemiological studies.Am J Clin Nutr. 1982; 36: 936-942PubMed Google Scholar were performed at baseline (0 months). At each follow-up study visit (1, 3, 6, 12, 18, and 24 months), efficacy was evaluated by using the CDAI,25Best W.R. Becktel J.M. Singleton J.W. et al.Development of a Crohn's disease activity index National Cooperative Crohn's Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (2946) Google Scholar and quality of life was assessed by using the Inflammatory Bowel Disease Questionnaire (IBDQ).26Irvine E.J. Development and subsequent refinement of the inflammatory bowel questionnaire a quality of life instrument for adult patients with inflammatory bowel disease.J Pediatr Gastroenterol Nutr. 1999; 28: S23-S27Crossref PubMed Scopus (104) Google Scholar A further quality-of-life assessment was performed at 0, 12, and 24 months by using the Short Form 36 questionnaire (SF-36).27Ware Jr, J.E. Sherbourne C.D. The MOS 36-item short-form health survey (SF-36) I. Conceptual framework and item selection.Med Care. 1992; 30: 473-483Crossref PubMed Scopus (27317) Google Scholar Adverse events were monitored throughout the study following good clinical practice, with particular attention paid to a predefined list of 11 corticosteroid-related side effects already used in previous studies.16Cortot A. Colombel J.-F. Rutgeerts P. et al.Switch from systemic steroids to budesonide in corticosteroid dependent patients with inactive Crohn's disease.Gut. 2001; 48: 186-190Crossref PubMed Scopus (89) Google Scholar Standard laboratory blood tests were performed, and vital signs were monitored (weight, blood pressure, pulse rate). Pituitary-adrenal function was measured at 0, 12, and 24 months by using an ACTH test, involving administration of 0.25 mg Synacten [Novartis, Basle, Switzerland] intravenously at t = 0). Normal basal cortisol levels were defined as 150 nmol/L and normal ACTH response as an increase in cortisol of 200 nmol/L or to a maximum value of 400 nmol/L within 60 minutes. At 0, 6, 12, 18, and 24 months, BMD of the lumbar spine was measured by using dual-energy x-ray absorptiometry (DXA) (Hologic [Bedford, MA] QDR 1000/W, 1500, 2000, 2000plus, 4000; or Lunar [Minster, OH] DPX, DPX/L, or DPXplus). DXA operators were instructed centrally before the start of the study, and a study-specific Quality Assurance and Procedures Manual was distributed. All DXA scans were sent for blinded centralized review and data collection by Hologic MDM (replaced by Synarc [Portland, OR] during the study), where cross-calibration of the different instrument types used also took place. Cross-calibration was based on the results of daily calibration of the DXA instruments by a spine phantom. Mean lumbar spine BMD was calculated from at least 3 evaluable vertebrae (although in most cases L1–L4 were all evaluable). DXA results obtained on Lunar machines were rescaled according to the formula 0.906*BMDLunar − 0.025 to match Hologic data. All results were expressed as BMD in absolute values (g/cm2) and as sex-controlled T scores according to World Health Organization criteria.28Blake G.M. Fogelman I. Interpretation of bone densitometry studies.Semin Nucl Med. 1997; 27: 248-260Abstract Full Text PDF PubMed Scopus (55) Google Scholar At 0 and 24 months (or at premature study termination), standard lateral and anterior/posterior x-rays of the thoracic and lumbar spine were taken.29Kiel D. Assessing vertebral fractures National Osteoporosis Foundation Working Group on Vertebral Fractures.J Bone Miner Res. 1995; 4: 518-523Google Scholar The x-rays were examined by expert radiologists in a blinded fashion. Vertebrae with a height reduction of more than 20% were considered to be fractured. A morphometric evaluation of borderline cases was made by using the Felsenberg algorithm with a threshold of 80% vertebral area.30Felsenberg D. Wieland E. Gowin W. et al.Morphometric analysis of spine X-rays for diagnosis of osteoporotic fractures.Med Klin. 1998; 93: 25-30Google Scholar The DXA and x-ray follow-up data were not available for the managing physicians and the investigators until the end of the study period. Mean values of BMD, T scores, CDAI, and IBDQ were compared by analysis of covariance. Baseline values were used as covariates and treatment as a factor. At 6 and 24 months, the potential significance of factors influencing changes in BMD (corrected for age and gender) was tested by using analysis of variance (ANOVA). Time to study withdrawal was calculated as Kaplan-Meier estimates and compared by using a log rank test. Efficacy was assessed by using a last-observation-carried-forward, intention-to-treat analysis. However, because dropout rate during the 2 years was almost 50%, the BMD data were also analyzed per protocol. The incidence of treatment-emergent side effects was compared by using a χ2 test. In total, 285 patients were randomized, of whom 272 received at least one dose of study drug and were analyzed (Figure 1). The efficacy analysis is based on 271 patients, because 1 patient did not have any "on treatment" data. Similar proportions of patients in both treatment arms remained in the study (at 6 months, budesonide 81% vs prednisolone 83%; at 12 months, budesonide 61% vs prednisolone 61%; at 24 months, budesonide 52% vs prednisolone 48%). Most withdrawals were the result of deteriorating Crohn's disease or failure to improve in accordance with the trial protocol (budesonide 37%, prednisolone 33%). At the end of the inclusion period, it was evident that a large number of patients had never received corticosteroids. Because control for previous steroid exposure appeared important in the analyses, in the Statistic Analysis Plan before any evaluations of baseline data or of treatment effects, the corticosteroid-free group was split into 2 strata, corticosteroid-naive patients and previously corticosteroid-exposed patients (median, 3600 mg prednisolone; range, 200–62, 100 mg; but not in the previous 6 months). Baseline characteristics are detailed in Table 1. Across the strata, the treatment groups were similar with respect to all baseline characteristics. Twelve percent of the budesonide-treated patients and 15% of the prednisolone-treated patients received supplementary vitamin D, and 46% and 51% of the budesonide- and prednisolone-treated patients, respectively, received calcium. Patients assigned to budesonide were treated for a mean period of 483 days compared with 522 days for the prednisolone group. Mean doses of budesonide and prednisolone were 6.8 and 14.9 mg/day, respectively, from time of first dose to time of last dose. Of the 136 patients remaining in the study for the entire 24 months, 66 received budesonide and 70 received prednisolone.Table 1Patient and Disease Characteristics in 271 Patients With Corticosteroid-Free and Corticosteroid-Dependent Crohn's DiseaseCharacteristicCorticosteroid-freeCorticosteroid-dependentP valueNaiveExposedN988390General Male/female47/5138/4547/43NS Mean age (y)35.436.638.7NS BMI (kg/m2)22.222.223.8<.01 Physical activity index14.514.113.5NS Post menopausal women (yes/no)10/418/3710/33NS Hormone replacement therapy (yes/no)4/463/413/40NS Supplemental calcium (n)553838NS Supplemental vitamin D (n)19116.037 Supplemental azathioprine (n)111427.0045Disease status Median duration of disease (y)3.39.57.3<.001 Time since last exacerbation (mo)30.235.337.9.0048 CDAI234240133 Patients with previous resection (%)244728.0028 Median lifetime corticosteroid dose (mg)036008480Smoking Active smoker (n)46 (47%)43 (52%)43 (48%) Ex-smoker (n)15 (15%)11 (13%)17 (19%) Non-smoker (n)37 (38%)29 (35%)30 (33%)NSaNo difference across all 3 categories.BMI, body mass index. CDAI, Crohn's disease activity index.a No difference across all 3 categories. Open table in a new tab BMI, body mass index. CDAI, Crohn's disease activity index. In the intention-to-treat analysis, neither the corticosteroid-dependent nor the corticosteroid-free patients exhibited a significantly smaller decline of BMD during treatments with budesonide than with prednisolone during the 24-month study period (Figure 2A and B). However, after dividing the corticosteroid-free group into corticosteroid-exposed and corticosteroid-naive patients, the corticosteroid-naive patients treated with prednisolone lost more bone than those treated with budesonide, particularly during the first 6 months of therapy (Figure 2C and D). In this patient group, a significant difference in change of BMD between the treatment arms was evident from 6 months, when the percentage change from baseline was −0.90% in budesonide-treated patients compared with −3.35% in prednisolone-treated patients (P = .002). By 24 months, the BMD had decreased from baseline by 1.04% in the budesonide-treated patients and 3.84% in the prednisolone-treated patients (change from baseline, P = .0084). Until month 18, the differential effect of budesonide and prednisolone was also significant in the per protocol analysis. At 24 months, however, the difference in T score between the 2 treatments was narrowed to 0.176, which was no longer significant, probably because of the low number of remaining patients in this subgroup (budesonide, n = 26; prednisolone, n = 23). Of the corticosteroid-exposed and -dependent patients, a significantly larger proportion exhibited evidence of osteopenia or osteoporosis at baseline (44% and 58%, respectively) compared with 34% in the corticosteroid-naive group (P = .006), with T scores in the former 2 strata being significantly lower than in the corticosteroid-naive patients (P = .032 and .0001, respectively). In the corticosteroid-exposed and -dependent strata, there were no significant differences in the change in T score over time between budesonide- and prednisolone-treated patients (Figure 2B and C). This was also found in the per protocol analysis. In the entire study population, baseline BMD was a predictor of budesonide action; patients with normal BMD lost significantly less bone with budesonide (−0.85%) than with prednisolone (−2.29%) (P = .047). In osteopenic and osteoporotic patients, this differential change of BMD as a result of drug treatment could not be seen (Table 2).Table 2Change in BMD During 2-Year Treatment With Budesonide CR Capsules or Prednisolone in Relation to Baseline Values (Mean % Changes)Normal BMD at baseline (T score ≥−1)Osteopenic at baseline (T score <−1 to −2.5)Osteoporotic at baseline (T score <−2.5)All patientsBudPredBudPredBudPredBudPredP valueCTN−1.59−3.97−0.73−3.104.54−10.1−1.04−3.84.0084CTE−0.76−1.13−2.480.92−1.75−3.00−1.66−0.15.11CTD0.03−1.120.381.140.251.460.170.49.76Pooled−0.85−2.29−0.91−0.430.351.11−0.81−1.21P value.047.69.70.50Bud, budesonide controlled release capsules; Pred, prednisolone; CTD, corticosteroid-dependent patients; CTE, corticosteroid-exposed patients; CTN, corticosteroid-naive patients. Open table in a new tab Bud, budesonide controlled release capsules; Pred, prednisolone; CTD, corticosteroid-dependent patients; CTE, corticosteroid-exposed patients; CTN, corticosteroid-naive patients. At 6 months, the change of BMD across all strata was influenced negatively by baseline CDAI (P = .006) and positively by budesonide therapy compared with prednisolone therapy (P = .038). The same factors influenced corticosteroid-naive patients in a similar manner (CDAI, P = .001; budesonide treatment, P = .003). In corticosteroid-dependent patients, the duration of Crohn's disease (P = .045) and smoking (P = .03) had a positive effect on BMD at 6 months, whereas height (P = .008) had a positive effect at 24 months. The use of calcium and/or azathioprine at inclusion and their continuation during follow-up did not significantly influence the development of BMD in any of the patient groups. At baseline, 56 asymptomatic vertebral fractures were discovered in 38 of the 268 (14.2%) evaluable patients.31Stockbrugger R.W. Schoon E.J. Bollani S. et al.Discordance between the degree of osteopenia and the prevalence of spontaneous vertebral fractures in Crohn's disease.Aliment Pharmacol Ther. 2002; 16: 1519-1527Crossref PubMed Scopus (90) Google Scholar During follow-up, one new asymptomatic vertebral fracture occurred in the prednisolone group (T score at start, −1.43; T score at 24 months, −1.75), and one pre-existing fracture worsened in the budesonide group (T score at start, −1.89, T score at 12 months, −2.02). No other spontaneous or low energy fractures occurred during the study period. However, 2 traumatic fractures occurred in budesonide-treated (finger, wrist) and 2 more in the prednisolone-treated patients (wrist, rib). During the first month of treatment, disease activity declined rapidly in corticosteroid-naive and -exposed patients in both treatment groups. Thereafter, disease activity remained very similar throughout the study period. In addition, CDAI scores in the corticosteroid-dependent stratum were similar throughout the follow-up period in both treatment groups, except for a transient difference in favor of prednisolone at 1 month (P = .018) (Figure 3). After 3 months, budesonide-treated, corticosteroid-naive patients recorded a significantly better quality of life on the IBDQ scale than prednisolone-treated patients (P = .043). No other differences in quality of life were detected in any stratum at any time point. The SF-36 questionnaire did not indicate any differences between the 2 treatment modalities, and the physical activity index did not either. Adverse events were reported by 96% of budesonide-treated patients and 98% of prednisolone-treated patients. The types of adverse events reported were similar in both groups, with the majority being gastrointestinal in nature and mainly caused by symptoms associated with Crohn's disease. Serious adverse events also occurred with a similar frequency in both groups (35% and 29% in the budesonide- and prednisolone-treated patients, respectively). Worsening of Crohn's disease requiring hospitalization was the most common serious adverse event, and very few events were considered to be causally related to the study drug by the investigator. Seven patients in the budesonide group and 2 patients in the prednisolone group withdrew as a result of adverse events. The overall incidence of treatment-emergent corticosteroid side effects was lower in budesonide-treated patients compared with prednisolone-treated patients (51% vs 71%, P < .001) (Table 3). The corresponding incidences for budesonide- and prednisolone-treated corticosteroid-naive patients were 58% and 72%, 43% and 77% for corticosteroid-exposed patients (P = .0015) and 52% and 64% for corticosteroid-dependent patients, respectively.Table 3Number (%) of Patients With Treatment-Emergent Corticosteroid Side EffectsSide effectBudesonide (n = 138aIn 1 patient, only adverse event evaluation was performed.)Prednisolone (n = 134)P valueAny corticosteroid side effect71 (51)95 (71).001Insomnia25 (18)42 (31).011Mood swings24 (17)34 (25)NSAcne21 (15)35 (26).026Moon face12 (9)44 (33)<.0001Depression25 (18)30 (22)NSBruising easily16 (12)31 (23).012Swollen ankles11 (8)18 (13)NSHirsutism10 (7)18 (13)NSHair loss7 (5)13 (10)NSSkin striae2 (1)4 (3)NSBuffalo hump1 (1)3 (2)NSa In 1 patient, only adverse event evaluation was performed. Open table in a new tab A significantly greater proportion of patients had normal basal (unstimulated) cortisol values at 12 months if they were assigned to treatment with budesonide than to prednisolone (P = .029). This was not the case, however, for corticosteroid-dependent and -exposed patients. At the same time point, normal increase in cortisol on stimulation was significantly more frequent in corticosteroid-dependent patients if they received budesonide than if they received prednisolone (P = .005). The proportion of normal ACTH test results (defined as both a normal basal cortisol level and a normal ACTH response) is given in Figure 4. It has previously been shown that, at diagnosis, BMD in patients with Crohn's disease is similar to that of the general population.32Schoon E.J. Blok B.M. Geerling B.J. et al.Bone mineral density in patients with recently diagnosed inflammatory bowel disease.Gastroenterology. 2000; 119: 1203-1208Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar The development of osteopenia, frequently seen at a later stage, could be a consequence of the disease itself or its treatment. The present study intended to explore whether topically acting glucocorticosteroids had advantages over prednisolone with respect to degradation of the bone matrix, with the condition that clinical efficacy should be comparable. During the 2-year study period, no significant difference in the development of BMD was observed between the prednisolone- and the budesonide-treated patients in either the corticosteroid-dependent or corticosteroid-free patient groups. However, budesonide CR capsules were indeed associated with a smaller loss of BMD than prednisolone in patients with active Crohn's disease who had not previously been exposed to corticosteroids (about one third of the consecutively included study population). Fewer corticosteroid-related side effects and less suppression of the pituitary-adrenal function were observed for budesonide-treated patients in all patient strata. Clinical efficacy of budesonide and prednisolone was comparable in both active and quiescent disease. In the present study, in corticosteroid-free patients, loss of BMD was rapid at the start of corticosteroid therapy but thereafter became relatively stable on a lower level. After corticosteroid cessation, BMD might again increase,33Laan R.F. Van Riel P.L. Van de Putte L.B. et al.Low-dose prednisone induces rapid reversible axial bone loss in patients with rheumatoid arthritis a randomized, controlled study.Ann Intern Med. 1993; 119: 963-968Crossref PubMed Scopus (408) Google Scholar but no attempt was made in this study to confirm the reversibility of BMD. Baseline BMD clearly influenced subsequent development of osteopenia; patients without previous osteopenia lost significantly less bone with budesonide treatment than with prednisolone treatment, whereas patients with established osteopenia or osteoporosis did not differ in this respect. It was also found that, as in the untreated situation, disease activity is an important (negative) determinant of BMD during treatment. The complicated design of this study was chosen to reflect the clinical reality in the participating international centers as closely as possible. At inclusion, unexpectedly, the 3 most frequently occurring glucocorticosteroid indications in Crohn's disease were nearly evenly represented, patients with active disease with or without previous corticosteroid use and those with quiescent disease but corticosteroid-dependent in spite of all access to immunosuppressant and/or surgical therapy. The combined double-blind (primary outcome parameters) and open (secondary outcome parameters) design of the study was chosen to render dose adaptation throughout the study possible, another feature reflecting a realistic clinical situation. A recent study by Cino and Greenberg34Cino M. Greenberg G.R. Bone mineral density in Crohn's disease a longitudinal study of budesonide, prednisone, and nonsteroid therapy.Am J Gastroenterol. 2002; 97: 915-921Crossref PubMed Google Scholar focusing on patients with quiescent Crohn's disease arrived at conclusions different from ours. They suggest that budesonide offers no advantage over low doses of prednisone for maintaining BMD and is, in fact, associated with a greater loss of BMD than the conventional agent. These conclusions were, however, disputed,35Valentine J.F. Treatment of Crohn's disease with budesonide this rose has still thorns!.Am J Gastroenterol. 2002; 97: 785-789Crossref PubMed Google Scholar because patients were not randomized to treatment groups, and because there were significant differences at baseline between the patients receiving budesonide and prednisone regarding the duration of previous corticosteroid use, the use of calcium supplements, and also in the localization of the disease. In addition, in that study, fixed doses of corticosteroids were applied. In contrast, our data suggest that, with respect to BMD, medium-term treatment of Crohn's disease with corticosteroids could be valid if doses are adapted to disease activity, and if compounds are chosen with topical release and low systemic availability. In the present study, the percentage of patients with asymptomatic vertebral fractures at baseline was high (14%). Interestingly, the fracture rate was found to be independent of cumulative corticosteroid dosing and the degree of osteopenia.31Stockbrugger R.W. Schoon E.J. Bollani S. et al.Discordance between the degree of osteopenia and the prevalence of spontaneous vertebral fractures in Crohn's disease.Aliment Pharmacol Ther. 2002; 16: 1519-1527Crossref PubMed Scopus (90) Google Scholar A search for hip fractures was not performed because these are normally symptomatic and tend to occur later in life.36Van Staa T. Leufkens H. Cooper C. The epidemiology of corticosteroid-induced osteoporosis—a metaanalysis.Osteoporos Int. 2002; 13: 777-787Crossref PubMed Scopus (953) Google Scholar During follow-up, few new spine fractures were observed, but the study was not powered to detect differences in the fracture rate during treatment. We can, perhaps, conclude that in the medium-term, fracture risk is low if the disease activity is controlled by individualized corticosteroid therapy. It has still to be seen whether optimization of glucocorticosteroid therapy in Crohn's disease can prevent incident fractures in periods of life when other factors will interfere (aging, hormonal changes). With regard to efficacy, budesonide and prednisolone were similar in controlling Crohn's disease activity at the dosages used during the 24-month study period. It should be noted that the mean doses of budesonide CR necessary in this study (6.8 mg) compared favorably with the rigid dose of 9 mg applied in the study by Cino and Greenberg.34Cino M. Greenberg G.R. Bone mineral density in Crohn's disease a longitudinal study of budesonide, prednisone, and nonsteroid therapy.Am J Gastroenterol. 2002; 97: 915-921Crossref PubMed Google Scholar The mean period of drug treatment and quality of life were also similar in both treatment arms. These data indicate that replacement of prednisolone with budesonide CR capsules to minimize the loss of BMD and corticosteroid side effects should not compromise efficacy in patients with active disease or in those patients who have quiescent disease but are "steroid-dependent". These results suggest that in a mixed population of patients with Crohn's disease, the development of BMD associated with budesonide CR treatment is not generally more advantageous than that observed with prednisolone. However, in a considerable subgroup (those patients not previously exposed to corticosteroids) the therapeutic gain achieved with budesonide CR capsules appears convincing. Such treatment, together with continual surveillance of the BMD from diagnosis onwards and application of general osteopenia prophylaxis (eg, physical exercise, and prevention of calcium and vitamin D deficiency), might contribute to the prevention of manifest osteoporosis in patients with Crohn's disease. For the future, it is hoped that early suppression of Crohn's disease activity by anti-tumor necrosis factor-α or other immune-modulating therapy could have a role in preserving BMD. At this time, controlled clinical data to support this hypothesis are lacking. In conclusion, we were able to show that oral budesonide in a CR preparation compared favorably with prednisolone in steroid-naive patients with mild or moderately active Crohn's disease, in that it preserved BMD better. This was not the case in patients previously exposed to corticosteroids or those who are corticosteroid-dependent. Moreover, in the entire study population, budesonide CR treatment, at equal efficacy, results in fewer corticosteroid side effects. The MATRIX study group consists of the following members (Country: main investigator (city), number of patients contributed): Italy: G. Bianchi Porro (Milan), n = 22; P. Bianchi (Milan), n = 2. Israel: S. Bar-Meir (Tel-Hashomer), n = 1; Z. Halperin (Tel Aviv), n = 10; Y. Niv (Petach Tikva), n = 10; E. Goldin (Jerusalem), n = 19. Spain: J. Panez-Diaz (Barcelona), n = 18; J. Maria Bilbao (Malaga), n = 3; R. Urribarena (Zaragoza), n = 1; J. Hinojosa (Valencia), n = 3; P. Nos (Valencia), n = 2; A. Lanas (Zaragoza), n = 5; A. Benages (Valencia), n = 1; M. Roca Garcias (Barcelona), n = 7; J. Martinez Salmeron (Motril), n = 3; J. Garcia Paredes (Madrid), n = 5; V. Gonzales Lara (Madrid), n = 1. Belgium: P. Rutgeerts (Leuven), n = 11; M. de Vos (Ghent), n = 3. Denmark: J. Dahlerup (Aarhus), n = 8. The Netherlands: R. Stockbrügger (Maastricht), n = 20; C. Lamers (Leiden), n = 1. Norway: J. Jahnsen (Oslo), n = 5; M. Vatn (Oslo), n = 10; J. Florholmen (Tromsoe), n = 17. Sweden: L. Loof (Uppsala), n = 11; R. Lofberg (Huddinge), n = 8; C. H. Floren (Malmö), n = 3. United Kingdom: S. Gosh (Edinburgh), n = 12; P. Mills (Glasgow), n = 19; A. B. Hawthorne (Cardiff), n = 13; J. Walters (London), n = 7; V. Mani (Leigh), n = 8; B. Norton (Derby), n = 10. The scientific integrity of this study, especially with respect to conflicts of interest, was granted by an independent Steering Committee: G. Bianchi Porro, Milan, R. Stockbrugger, Maastricht, M. Vatn, Oslo, and the late A. Ferguson, Edinburgh.