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Limiting fracture risk in Crohn’s disease: Is there anything better than calcium and vitamin D?

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

10.1016/s1542-3565(04)00661-5

1542-7714

Çharles N. Bernstein,

Microscopic Colitis

In this issue of the journal, fracture risk in Crohn’s disease is addressed from the perspectives of limiting corticosteroid-induced bone loss with an alternative corticosteroid (budesonide)1Schoon E.J. Bollani S. Mills P.R. et al.Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 113-121Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar and enhancing bone mass with a bisphosphonate.2Siffledeen J.S. Fedorak R.N. Siminoski K. et al.Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 122-132Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Neither of these studies prove that the specific interventions prevent fractures, but they do address 2 issues that continue to be unresolved in practice.Schoon et al1Schoon E.J. Bollani S. Mills P.R. et al.Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 113-121Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar reported the outcome of a multicenter study comparing budesonide, a topically acting corticosteroid with high first pass metabolism, and prednisolone in the treatment of active Crohn’s disease. Changes in bone mineral density (BMD) over time were a secondary end point in the study. There were no differences in BMD among patients who were corticosteroid dependent, or corticosteroid-exposed in the past. For those who never received corticosteroids in the past (corticosteroid-naïve), there was less BMD loss at 24 months among those randomized to budesonide versus prednisolone. However, these data do not prove that budesonide has tangible effect on preventing fractures, the one bone-related outcome that matters. For corticosteroid-naïve patients, the reductions in BMD were 1.04% and 3.35% in the budesonide and prednisolone groups, respectively (P = .0084). By per protocol analysis there was no significant difference in BMD reduction for either treatment group; the lack of difference was attributed to the small numbers of subjects remaining in the study by 24 months. What is the clinical relevance of this diminution of BMD loss afforded by budesonide? Did any of these subjects whose BMD values reduced actually sustain fractures? This information is not provided in the article, although the implication is that if corticosteroids were continued during a longer period of time, there would be a greater risk of fracture. Did any BMD recover after the budesonide or prednisolone was stopped? This information also is not available. It is known that corticosteroid-induced bone loss can be partially reversible. Thus, if subjects can withdraw from corticosteroids within 3–6 months, will it matter whether the short-term treatment of active disease is with budesonide or prednisolone? In the study by Schoon et al, those starting out with BMD T scores less than −1.5 (considered to be at higher risk for fracture) had no difference in BMD outcome whether they were on budesonide or prednisolone. The only corticosteroid-naïve subjects whose BMD decreased more on prednisolone than on budesonide were those starting out with BMD in the normal range (T scores greater than −1.5). However, the clinical implications of a decrease in the BMD that remained within the normal range are unclear. Is the observed difference simply a statistical finding of no clinical consequence?Another approach to limiting fracture risk in corticosteroid users is to administer additional therapy that will prevent bone loss. Siffledeen et al2Siffledeen J.S. Fedorak R.N. Siminoski K. et al.Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 122-132Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar should be congratulated for conducting one of the few randomized trials of a bisphosphonate in patients with inflammatory bowel disease. This group enrolled a convenience sample of 154 subjects with Crohn’s disease and BMD T scores less than −1.5 presenting to specialty clinics at 2 Canadian centers. Subjects were randomized to receive etidronate 400 mg orally for 14 days or nothing followed by calcium 500 mg and vitamin D 400 IU for 76 days. This cycle was repeated every 3 months for 2 years. BMD was measured at 6, 12, and 24 months. Both groups had significantly increased BMD at 24 months; however, there was no difference between the groups, and hence the etidronate provided no additional benefit over the calcium and vitamin D supplementation. The study design has some flaws that warrant comment, but overall there are a number of important messages from this study.First, the study was non-blinded. There was no placebo-treated group but rather a control group who were aware they were not receiving the study drug etidronate, which might be beneficial to their bones. It is plausible that this group might have enhanced their intake of calcium and vitamin D to improve their bone status because they knew they were not getting the other treatment.Second, the investigators did not review food records on a regular basis. It is unknown whether at baseline the study population was ingesting suboptimal calcium and vitamin D, although predictably, they might have been.3Bernstein C.N. Seeger L.L. Anton P.A. et al.A randomized, placebo-controlled trial of calcium supplementation for decreased bone density in corticosteroid-using patients with inflammatory bowel disease a pilot study.Aliment Pharmacol Ther. 1996; 10: 777-786Crossref PubMed Scopus (129) Google Scholar, 4Bernstein C.N. Bector S. Leslie W.D. Lack of relationship of calcium and vitamin D intake to bone mineral density in premenopausal women with inflammatory bowel disease.Am J Gastroenterol. 2003; 98: 2468-2473Crossref PubMed Scopus (41) Google Scholar, 5Reed C.A. Nichols D.L. Bonnick S.L. et al.Bone mineral density and dietary intake in patients with Crohn’s disease.J Clin Densitom. 1998; 1: 33-40Abstract Full Text PDF PubMed Scopus (15) Google Scholar More importantly, it is also unknown whether their calcium and vitamin D intake remained stable over time. Recording dietary and other supplemental calcium and vitamin D intake might have allowed a clearer assessment as to whether etidronate enhanced bone health.Third, the study by Siffledeen et al2Siffledeen J.S. Fedorak R.N. Siminoski K. et al.Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 122-132Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar enrolled predominantly subjects with BMD in the osteopenic (T scores between −1.5 and −2.5) rather than osteoporotic (T scores less than −2.5) range. An important message from this study is that the results support the suggestion by the AGA Technical Review on osteoporosis in gastrointestinal diseases that because T scores of −1.5 to −2.5 overlap with BMD of normal healthy subjects, treatment of such patients with anything more than calcium (and in this study low dose calcium) and vitamin D is unwarranted, unless the patients are chronically on corticosteroids or there is a documented history of fragility fractures.6Bernstein C.N. Leslie W.D. Leboff M. AGA Technical Review osteoporosis in gastrointestinal diseases.Gastroenterology. 2003; 124: 795-841Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar In the article by Siffledeen et al, more than 50% of subjects were using corticosteroids. Their BMD did not worsen, but it improved significantly at multiple sites and substantially at 24 months in those patients with BMD T scores less than −2.5.Another important message of this article is that young patients with IBD generally preserve BMD well. In this study 35% of subjects were younger than age 35 years. Our group has previously shown that young female patients diagnosed with IBD before age 20 years had on average normal BMD when assessed in young adulthood before menopause.7Bernstein C.N. Leslie W.D. Taback S. Bone density in a population based cohort of premenopausal adult women with early-onset inflammatory bowel disease.Am J Gastroenterol. 2003; 98: 1094-1100Crossref PubMed Scopus (53) Google Scholar Although there is a concern that children who have active inflammatory disease during critical bone mass forming years and who might receive corticosteroids are going to have long-term ill effects on their BMD, this did not prove to be the case.Four fractures occurred during the study,2Siffledeen J.S. Fedorak R.N. Siminoski K. et al.Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 122-132Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar two in each group (Siffledeen and Fedorak, personal communication, 2004). In a 2-year study of 200 subjects, only 4 fractures might be expected.8Bernstein C.N. Blanchard J.F. Leslie W.D. et al.The incidence of fractures among patients with IBD a population-based study.Ann Intern Med. 2000; 133: 795-799Crossref PubMed Scopus (402) Google Scholar Hence such studies must be conducted for longer periods to accrue more fractures and in much larger samples, or surrogate end points such as BMD must be used as an end point. Although enhancing BMD, or at least limiting its diminution over time, is of benefit for bone health, BMD does not wholly account for fracture risk.In a study of 293 patients with Crohn’s disease from a specialty clinic, subjects with BMD T scores less than −1 (n = 156) underwent thoracolumbar spine x-rays with combined visual and quantitative vertebral morphometry to identify compression fractures.9Klaus J. Armbrecht G. Steinkamp M. et al.High prevalence of osteoporotic vertebral fractures in patients with Crohn’s disease.Gut. 2002; 51: 654-658Crossref PubMed Scopus (172) Google Scholar Of these, 34 (22%) had 63 osteoporotic vertebral fractures, the vast majority of which (88%) were asymptomatic. Only 38% of the fracture cases actually had spine BMD that was in the osteoporotic range.These findings are consistent with a large prospective cohort study of 9704 postmenopausal women followed for 8.5 years after baseline BMD measurement. In this study, the proportion of fractures attributable to osteoporosis (based on a T score less than −2.5) was only 25%–39% for spine fractures, 21%–28% for hip fractures, and 16%–26% for wrist fractures.10Espallargues M. Sampietro-Colom L. Estrada M.D. et al.Identifying bone-mass-related risk factors for fracture to guide bone densitometry measurements a systematic review of the literature.Osteoporos Int. 2001; 12: 811-822Crossref PubMed Scopus (237) Google Scholar A T-score cutoff of −1.5 was only marginally better in defining attributable risk (31%–51%) for these same sites.Although BMD might be an important predictor of fractures, it is clear that other risk factors are involved10Espallargues M. Sampietro-Colom L. Estrada M.D. et al.Identifying bone-mass-related risk factors for fracture to guide bone densitometry measurements a systematic review of the literature.Osteoporos Int. 2001; 12: 811-822Crossref PubMed Scopus (237) Google Scholar and can be combined to form a fracture risk index.11Black D.M. Steinbuch M. Palermo L. et al.An assessment tool for predicting fracture risk in postmenopausal women.Osteoporos Int. 2001; 12: 519-528Crossref PubMed Scopus (419) Google Scholar Prior vertebral fracture is the strongest risk factor for future vertebral fractures (relative risk, 4.4; 95% confidence interval, 3.6–5.4), and risk is high even when BMD is normal.12Klotzenbuecher C.M. Ross P.D. Landsman P.B. et al.Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. Meta-analysis of therapies for postmenopausal osteoporosis. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis.J Bone Miner Res. 2000; 15: 721-739Crossref PubMed Scopus (1580) Google Scholar, 13Ross P.D. Davis J.W. Epstein R.S. et al.Pre-existing fractures and bone mass predict vertebral fracture incidence in women.Ann Intern Med. 1991; 114: 919-923Crossref PubMed Scopus (973) Google Scholar Vertebral fractures also predict non-vertebral fractures (including hip fractures with relative risk of 2.3, 95% confidence interval, 2.0–2.8).In another recent bisphosphonate study in 74 patients with Crohn’s disease and BMD T scores less than −1.5, a comparison was undertaken of calcium 500 mg/day plus vitamin D 400 IU/day with and without intravenous pamidronate every 3 months.14Bartram S.A. Peaston R.T. Rawkings D.J. et al.A randomized controlled trial of calcium and vitamin D, alone or in combination with intravenous pamidronate, for the treatment of low bone mineral density associated with Crohn’s disease.Aliment Pharmacol Ther. 2003; 18: 1121-1127Crossref PubMed Scopus (67) Google Scholar Both groups increased BMD at 1 year, and there were no statistically significant differences in changes in BMD between the 2 groups.The study by Siffledeen et al2Siffledeen J.S. Fedorak R.N. Siminoski K. et al.Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 122-132Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar concludes: “future studies will need to assess the therapeutic effect of more potent next generation bisphosphonates in patients with IBD.” It is not clear why this is necessary, given that subjects did well on old generation bisphosphonate or no bisphosphonate, with significant improvement in their BMD and few fractures during a period of 2 years. The study by Siffledeen et al is reassuring us that bisphosphonates are rarely needed in IBD patients, most of whom have T score greater than −2.5, and many of whom are using corticosteroids to some extent.So are calcium and vitamin D sufficient to enhance BMD in IBD patients? In a small pilot study in subjects using corticosteroid, calcium 1000 mg and vitamin D 250 IU were not better than placebo, but in both these treatment groups, BMD did not decrease during a period of 1 year.3Bernstein C.N. Seeger L.L. Anton P.A. et al.A randomized, placebo-controlled trial of calcium supplementation for decreased bone density in corticosteroid-using patients with inflammatory bowel disease a pilot study.Aliment Pharmacol Ther. 1996; 10: 777-786Crossref PubMed Scopus (129) Google Scholar Unfortunately, the study by Siffledeen et al2Siffledeen J.S. Fedorak R.N. Siminoski K. et al.Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 122-132Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar did not include a placebo arm, so it is uncertain whether the calcium and vitamin D alone enhanced BMD, or whether this was simply a group of patients whose bone mass was at low risk. Nonetheless, these supplements are generally easy to use and inexpensive and make good sense for subjects with either borderline BMD (T score −1.5 to −2.5) or with osteoporosis (T score less than −2.5) and for any subjects using corticosteroids.Although budesonide offers several advantages over prednisolone in terms of corticosteroid adverse events,1Schoon E.J. Bollani S. Mills P.R. et al.Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 113-121Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar it might be more cost-effective to prescribe prednisolone plus calcium and vitamin D than budesonide, if a primary concern is protecting bone mass. If subjects are chronically on corticosteroids and/or have other significant risk factors such as past fragility fractures, they might require treatment in addition to calcium and vitamin D.Finally, it is important to comment on studies that use BMD as the singular bone outcome as opposed to fracture. BMD measurements are convenient because studies of 2 years’ duration are typically insufficient to observe a substantial number of fractures. The study by Schoon et al1Schoon E.J. Bollani S. Mills P.R. et al.Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 113-121Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar included 38 subjects (14.2%) with asymptomatic vertebral fractures. This is an important group because it might reflect the situation in postmenopausal women in whom up to 38% of fractures occur with normal BMD. However, in the study by Schoon et al we are not informed whether the corticosteroid-naïve group included any with asymptomatic fractures or of the BMD in this group with asymptomatic fractures. Others have shown previously that subjects with IBD who stop using corticosteroids can have reversal of previous bone mass loss.15Laan 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 (409) Google Scholar Hence the optimal approach for avoiding bone loss that might lead to fractures with corticosteroid treatment in IBD would be to minimize corticosteroid use or at least reduce and withdraw corticosteroids as soon as possible. However, for those who have used corticosteroids in the past or concurrently, using budesonide will be unlikely to prevent BMD reduction. The authors’ data showing that the fracture rate in Crohn’s disease was independent of cumulative corticosteroid dosing and BMD reinforce the limited utility of using BMD to predict fractures in IBD.16Stockbrugger 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 (91) Google Scholar A September 21, 2004 press release from a panel of World Health Organization-supported experts noted that BMD is only one component of fracture risk. The panel recommended that accurate assessment of fracture risk should ideally take into account other readily measured indices or aspects of fracture risk through the development of a composite fracture risk score,17Assessment of fracture risk. http://osteofound.org/health_professionals/fracture_risk_assessment/index.html. Accessed November 1, 2004.Google Scholar, 18Kanis J.A. Gluer C.C. the Committee of Scientific Advisors, International Osteoporosis FondationAn update on the diagnosis and assessment of osteoporosis with densitometry.Osteoporos Int. 2000; 11: 192-202Crossref PubMed Scopus (763) Google Scholar, 19Kanis J.A. Black D. Cooper C. et al.A new approach to the development of assessment guidelines for osteoporosis.Osteoporos Int. 2002; 13: 527-536Crossref PubMed Scopus (259) Google Scholar and that intervention should not be guided solely by BMD.17Assessment of fracture risk. http://osteofound.org/health_professionals/fracture_risk_assessment/index.html. Accessed November 1, 2004.Google Scholar The implication for gastroenterologists is that the algorithm for assessing and managing osteoporosis risks in IBD patients will not be as simple as getting the BMD results and using them alone to decide on interventions. In fact, assessing composite risk on the basis of several factors should direct gastroenterologists away from measuring BMD on all patients. Some might require intervention regardless of BMD, and some have such a low probability of an osteoporotic fracture on the basis of clinical probability that the measured BMD will not sufficiently justify the need for treatment.20Johansson H. Oden A. Johnell O. et al.Optimisation of BMD measurements to identify high risk groups for treatment-A test analysis.J Bone Miner Res. 2004; 19: 906-913Crossref PubMed Scopus (110) Google Scholar This view also supports the recommendations in the recent AGA Technical Review on Osteoporosis in Gastrointestinal Diseases.6Bernstein C.N. Leslie W.D. Leboff M. AGA Technical Review osteoporosis in gastrointestinal diseases.Gastroenterology. 2003; 124: 795-841Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar In this issue of the journal, fracture risk in Crohn’s disease is addressed from the perspectives of limiting corticosteroid-induced bone loss with an alternative corticosteroid (budesonide)1Schoon E.J. Bollani S. Mills P.R. et al.Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 113-121Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar and enhancing bone mass with a bisphosphonate.2Siffledeen J.S. Fedorak R.N. Siminoski K. et al.Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 122-132Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Neither of these studies prove that the specific interventions prevent fractures, but they do address 2 issues that continue to be unresolved in practice. Schoon et al1Schoon E.J. Bollani S. Mills P.R. et al.Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 113-121Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar reported the outcome of a multicenter study comparing budesonide, a topically acting corticosteroid with high first pass metabolism, and prednisolone in the treatment of active Crohn’s disease. Changes in bone mineral density (BMD) over time were a secondary end point in the study. There were no differences in BMD among patients who were corticosteroid dependent, or corticosteroid-exposed in the past. For those who never received corticosteroids in the past (corticosteroid-naïve), there was less BMD loss at 24 months among those randomized to budesonide versus prednisolone. However, these data do not prove that budesonide has tangible effect on preventing fractures, the one bone-related outcome that matters. For corticosteroid-naïve patients, the reductions in BMD were 1.04% and 3.35% in the budesonide and prednisolone groups, respectively (P = .0084). By per protocol analysis there was no significant difference in BMD reduction for either treatment group; the lack of difference was attributed to the small numbers of subjects remaining in the study by 24 months. What is the clinical relevance of this diminution of BMD loss afforded by budesonide? Did any of these subjects whose BMD values reduced actually sustain fractures? This information is not provided in the article, although the implication is that if corticosteroids were continued during a longer period of time, there would be a greater risk of fracture. Did any BMD recover after the budesonide or prednisolone was stopped? This information also is not available. It is known that corticosteroid-induced bone loss can be partially reversible. Thus, if subjects can withdraw from corticosteroids within 3–6 months, will it matter whether the short-term treatment of active disease is with budesonide or prednisolone? In the study by Schoon et al, those starting out with BMD T scores less than −1.5 (considered to be at higher risk for fracture) had no difference in BMD outcome whether they were on budesonide or prednisolone. The only corticosteroid-naïve subjects whose BMD decreased more on prednisolone than on budesonide were those starting out with BMD in the normal range (T scores greater than −1.5). However, the clinical implications of a decrease in the BMD that remained within the normal range are unclear. Is the observed difference simply a statistical finding of no clinical consequence? Another approach to limiting fracture risk in corticosteroid users is to administer additional therapy that will prevent bone loss. Siffledeen et al2Siffledeen J.S. Fedorak R.N. Siminoski K. et al.Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 122-132Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar should be congratulated for conducting one of the few randomized trials of a bisphosphonate in patients with inflammatory bowel disease. This group enrolled a convenience sample of 154 subjects with Crohn’s disease and BMD T scores less than −1.5 presenting to specialty clinics at 2 Canadian centers. Subjects were randomized to receive etidronate 400 mg orally for 14 days or nothing followed by calcium 500 mg and vitamin D 400 IU for 76 days. This cycle was repeated every 3 months for 2 years. BMD was measured at 6, 12, and 24 months. Both groups had significantly increased BMD at 24 months; however, there was no difference between the groups, and hence the etidronate provided no additional benefit over the calcium and vitamin D supplementation. The study design has some flaws that warrant comment, but overall there are a number of important messages from this study. First, the study was non-blinded. There was no placebo-treated group but rather a control group who were aware they were not receiving the study drug etidronate, which might be beneficial to their bones. It is plausible that this group might have enhanced their intake of calcium and vitamin D to improve their bone status because they knew they were not getting the other treatment. Second, the investigators did not review food records on a regular basis. It is unknown whether at baseline the study population was ingesting suboptimal calcium and vitamin D, although predictably, they might have been.3Bernstein C.N. Seeger L.L. Anton P.A. et al.A randomized, placebo-controlled trial of calcium supplementation for decreased bone density in corticosteroid-using patients with inflammatory bowel disease a pilot study.Aliment Pharmacol Ther. 1996; 10: 777-786Crossref PubMed Scopus (129) Google Scholar, 4Bernstein C.N. Bector S. Leslie W.D. Lack of relationship of calcium and vitamin D intake to bone mineral density in premenopausal women with inflammatory bowel disease.Am J Gastroenterol. 2003; 98: 2468-2473Crossref PubMed Scopus (41) Google Scholar, 5Reed C.A. Nichols D.L. Bonnick S.L. et al.Bone mineral density and dietary intake in patients with Crohn’s disease.J Clin Densitom. 1998; 1: 33-40Abstract Full Text PDF PubMed Scopus (15) Google Scholar More importantly, it is also unknown whether their calcium and vitamin D intake remained stable over time. Recording dietary and other supplemental calcium and vitamin D intake might have allowed a clearer assessment as to whether etidronate enhanced bone health. Third, the study by Siffledeen et al2Siffledeen J.S. Fedorak R.N. Siminoski K. et al.Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 122-132Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar enrolled predominantly subjects with BMD in the osteopenic (T scores between −1.5 and −2.5) rather than osteoporotic (T scores less than −2.5) range. An important message from this study is that the results support the suggestion by the AGA Technical Review on osteoporosis in gastrointestinal diseases that because T scores of −1.5 to −2.5 overlap with BMD of normal healthy subjects, treatment of such patients with anything more than calcium (and in this study low dose calcium) and vitamin D is unwarranted, unless the patients are chronically on corticosteroids or there is a documented history of fragility fractures.6Bernstein C.N. Leslie W.D. Leboff M. AGA Technical Review osteoporosis in gastrointestinal diseases.Gastroenterology. 2003; 124: 795-841Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar In the article by Siffledeen et al, more than 50% of subjects were using corticosteroids. Their BMD did not worsen, but it improved significantly at multiple sites and substantially at 24 months in those patients with BMD T scores less than −2.5. Another important message of this article is that young patients with IBD generally preserve BMD well. In this study 35% of subjects were younger than age 35 years. Our group has previously shown that young female patients diagnosed with IBD before age 20 years had on average normal BMD when assessed in young adulthood before menopause.7Bernstein C.N. Leslie W.D. Taback S. Bone density in a population based cohort of premenopausal adult women with early-onset inflammatory bowel disease.Am J Gastroenterol. 2003; 98: 1094-1100Crossref PubMed Scopus (53) Google Scholar Although there is a concern that children who have active inflammatory disease during critical bone mass forming years and who might receive corticosteroids are going to have long-term ill effects on their BMD, this did not prove to be the case. Four fractures occurred during the study,2Siffledeen J.S. Fedorak R.N. Siminoski K. et al.Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 122-132Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar two in each group (Siffledeen and Fedorak, personal communication, 2004). In a 2-year study of 200 subjects, only 4 fractures might be expected.8Bernstein C.N. Blanchard J.F. Leslie W.D. et al.The incidence of fractures among patients with IBD a population-based study.Ann Intern Med. 2000; 133: 795-799Crossref PubMed Scopus (402) Google Scholar Hence such studies must be conducted for longer periods to accrue more fractures and in much larger samples, or surrogate end points such as BMD must be used as an end point. Although enhancing BMD, or at least limiting its diminution over time, is of benefit for bone health, BMD does not wholly account for fracture risk. In a study of 293 patients with Crohn’s disease from a specialty clinic, subjects with BMD T scores less than −1 (n = 156) underwent thoracolumbar spine x-rays with combined visual and quantitative vertebral morphometry to identify compression fractures.9Klaus J. Armbrecht G. Steinkamp M. et al.High prevalence of osteoporotic vertebral fractures in patients with Crohn’s disease.Gut. 2002; 51: 654-658Crossref PubMed Scopus (172) Google Scholar Of these, 34 (22%) had 63 osteoporotic vertebral fractures, the vast majority of which (88%) were asymptomatic. Only 38% of the fracture cases actually had spine BMD that was in the osteoporotic range. These findings are consistent with a large prospective cohort study of 9704 postmenopausal women followed for 8.5 years after baseline BMD measurement. In this study, the proportion of fractures attributable to osteoporosis (based on a T score less than −2.5) was only 25%–39% for spine fractures, 21%–28% for hip fractures, and 16%–26% for wrist fractures.10Espallargues M. Sampietro-Colom L. Estrada M.D. et al.Identifying bone-mass-related risk factors for fracture to guide bone densitometry measurements a systematic review of the literature.Osteoporos Int. 2001; 12: 811-822Crossref PubMed Scopus (237) Google Scholar A T-score cutoff of −1.5 was only marginally better in defining attributable risk (31%–51%) for these same sites. Although BMD might be an important predictor of fractures, it is clear that other risk factors are involved10Espallargues M. Sampietro-Colom L. Estrada M.D. et al.Identifying bone-mass-related risk factors for fracture to guide bone densitometry measurements a systematic review of the literature.Osteoporos Int. 2001; 12: 811-822Crossref PubMed Scopus (237) Google Scholar and can be combined to form a fracture risk index.11Black D.M. Steinbuch M. Palermo L. et al.An assessment tool for predicting fracture risk in postmenopausal women.Osteoporos Int. 2001; 12: 519-528Crossref PubMed Scopus (419) Google Scholar Prior vertebral fracture is the strongest risk factor for future vertebral fractures (relative risk, 4.4; 95% confidence interval, 3.6–5.4), and risk is high even when BMD is normal.12Klotzenbuecher C.M. Ross P.D. Landsman P.B. et al.Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. Meta-analysis of therapies for postmenopausal osteoporosis. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis.J Bone Miner Res. 2000; 15: 721-739Crossref PubMed Scopus (1580) Google Scholar, 13Ross P.D. Davis J.W. Epstein R.S. et al.Pre-existing fractures and bone mass predict vertebral fracture incidence in women.Ann Intern Med. 1991; 114: 919-923Crossref PubMed Scopus (973) Google Scholar Vertebral fractures also predict non-vertebral fractures (including hip fractures with relative risk of 2.3, 95% confidence interval, 2.0–2.8). In another recent bisphosphonate study in 74 patients with Crohn’s disease and BMD T scores less than −1.5, a comparison was undertaken of calcium 500 mg/day plus vitamin D 400 IU/day with and without intravenous pamidronate every 3 months.14Bartram S.A. Peaston R.T. Rawkings D.J. et al.A randomized controlled trial of calcium and vitamin D, alone or in combination with intravenous pamidronate, for the treatment of low bone mineral density associated with Crohn’s disease.Aliment Pharmacol Ther. 2003; 18: 1121-1127Crossref PubMed Scopus (67) Google Scholar Both groups increased BMD at 1 year, and there were no statistically significant differences in changes in BMD between the 2 groups. The study by Siffledeen et al2Siffledeen J.S. Fedorak R.N. Siminoski K. et al.Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 122-132Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar concludes: “future studies will need to assess the therapeutic effect of more potent next generation bisphosphonates in patients with IBD.” It is not clear why this is necessary, given that subjects did well on old generation bisphosphonate or no bisphosphonate, with significant improvement in their BMD and few fractures during a period of 2 years. The study by Siffledeen et al is reassuring us that bisphosphonates are rarely needed in IBD patients, most of whom have T score greater than −2.5, and many of whom are using corticosteroids to some extent. So are calcium and vitamin D sufficient to enhance BMD in IBD patients? In a small pilot study in subjects using corticosteroid, calcium 1000 mg and vitamin D 250 IU were not better than placebo, but in both these treatment groups, BMD did not decrease during a period of 1 year.3Bernstein C.N. Seeger L.L. Anton P.A. et al.A randomized, placebo-controlled trial of calcium supplementation for decreased bone density in corticosteroid-using patients with inflammatory bowel disease a pilot study.Aliment Pharmacol Ther. 1996; 10: 777-786Crossref PubMed Scopus (129) Google Scholar Unfortunately, the study by Siffledeen et al2Siffledeen J.S. Fedorak R.N. Siminoski K. et al.Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 122-132Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar did not include a placebo arm, so it is uncertain whether the calcium and vitamin D alone enhanced BMD, or whether this was simply a group of patients whose bone mass was at low risk. Nonetheless, these supplements are generally easy to use and inexpensive and make good sense for subjects with either borderline BMD (T score −1.5 to −2.5) or with osteoporosis (T score less than −2.5) and for any subjects using corticosteroids. Although budesonide offers several advantages over prednisolone in terms of corticosteroid adverse events,1Schoon E.J. Bollani S. Mills P.R. et al.Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 113-121Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar it might be more cost-effective to prescribe prednisolone plus calcium and vitamin D than budesonide, if a primary concern is protecting bone mass. If subjects are chronically on corticosteroids and/or have other significant risk factors such as past fragility fractures, they might require treatment in addition to calcium and vitamin D. Finally, it is important to comment on studies that use BMD as the singular bone outcome as opposed to fracture. BMD measurements are convenient because studies of 2 years’ duration are typically insufficient to observe a substantial number of fractures. The study by Schoon et al1Schoon E.J. Bollani S. Mills P.R. et al.Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn’s disease.Clin Gastroenterol Hepatol. 2005; 3: 113-121Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar included 38 subjects (14.2%) with asymptomatic vertebral fractures. This is an important group because it might reflect the situation in postmenopausal women in whom up to 38% of fractures occur with normal BMD. However, in the study by Schoon et al we are not informed whether the corticosteroid-naïve group included any with asymptomatic fractures or of the BMD in this group with asymptomatic fractures. Others have shown previously that subjects with IBD who stop using corticosteroids can have reversal of previous bone mass loss.15Laan 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 (409) Google Scholar Hence the optimal approach for avoiding bone loss that might lead to fractures with corticosteroid treatment in IBD would be to minimize corticosteroid use or at least reduce and withdraw corticosteroids as soon as possible. However, for those who have used corticosteroids in the past or concurrently, using budesonide will be unlikely to prevent BMD reduction. The authors’ data showing that the fracture rate in Crohn’s disease was independent of cumulative corticosteroid dosing and BMD reinforce the limited utility of using BMD to predict fractures in IBD.16Stockbrugger 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 (91) Google Scholar A September 21, 2004 press release from a panel of World Health Organization-supported experts noted that BMD is only one component of fracture risk. The panel recommended that accurate assessment of fracture risk should ideally take into account other readily measured indices or aspects of fracture risk through the development of a composite fracture risk score,17Assessment of fracture risk. http://osteofound.org/health_professionals/fracture_risk_assessment/index.html. Accessed November 1, 2004.Google Scholar, 18Kanis J.A. Gluer C.C. the Committee of Scientific Advisors, International Osteoporosis FondationAn update on the diagnosis and assessment of osteoporosis with densitometry.Osteoporos Int. 2000; 11: 192-202Crossref PubMed Scopus (763) Google Scholar, 19Kanis J.A. Black D. Cooper C. et al.A new approach to the development of assessment guidelines for osteoporosis.Osteoporos Int. 2002; 13: 527-536Crossref PubMed Scopus (259) Google Scholar and that intervention should not be guided solely by BMD.17Assessment of fracture risk. http://osteofound.org/health_professionals/fracture_risk_assessment/index.html. Accessed November 1, 2004.Google Scholar The implication for gastroenterologists is that the algorithm for assessing and managing osteoporosis risks in IBD patients will not be as simple as getting the BMD results and using them alone to decide on interventions. In fact, assessing composite risk on the basis of several factors should direct gastroenterologists away from measuring BMD on all patients. Some might require intervention regardless of BMD, and some have such a low probability of an osteoporotic fracture on the basis of clinical probability that the measured BMD will not sufficiently justify the need for treatment.20Johansson H. Oden A. Johnell O. et al.Optimisation of BMD measurements to identify high risk groups for treatment-A test analysis.J Bone Miner Res. 2004; 19: 906-913Crossref PubMed Scopus (110) Google Scholar This view also supports the recommendations in the recent AGA Technical Review on Osteoporosis in Gastrointestinal Diseases.6Bernstein C.N. Leslie W.D. Leboff M. AGA Technical Review osteoporosis in gastrointestinal diseases.Gastroenterology. 2003; 124: 795-841Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar