From the AGA Journals

Bisphosphonate safe, effective in IBD

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Bisphosphonate findings are 'reassuring'

Dr. Stephen B. Hanauer

My colleague, Atsushi Sakuraba, is the senior author of the meta-analysis evaluating the efficacy and safety of medical therapies to prevent or treat osteoporosis in a wide spectrum of inflammatory bowel disorder patients. Both ulcerative colitis and Crohn's disease have numerous risk factors for the development of osteoporosis and the younger ages of IBD patients create a longer duration of risk such that the AGA considers monitoring of bone mineral density and treatment with calcium and vitamin D in patients exposed to corticosteroids for greater than 3 months as important indicators of quality care. Active inflammation, malabsorption, vitamin D deficiency, and treatment with glucocorticoids all contribute to the risk of decreased bone density and fractures. Because of the heterogeneity of risk factors and many small, individual clinical trials, a meta-analytic approach was required to substantiate benefits in the diverse patient subpopulations (active vs. quiescent ulcerative colitis or Crohn's disease) and in patients taking glucocorticoids. The most significant finding is that bisphosphonates, whether oral or parenteral, were the singular therapeutic drug class that provided benefits across the disease states; calcium plus vitamin D alone in very small patient samples, fluoride, or calcitonin were not effective. It is reassuring that, even in the presence of IBD, these agents were well tolerated. Of course, while bisphosphonates may be the "mortar," adequate replacement of calcium and vitamin D, are the necessary "bricks" in the wall.

Dr. Stephen B. Hanauer is the Joseph B. Kirsner Professor of Medicine and Clinical Pharmacology, University of Chicago. He has no relevant conflicts of interest.


Bisphosphonates are safe and effective for treating low bone mineral density in inflammatory bowel disease, according to a meta-analysis of 19 randomized controlled studies published in the January issue of Clinical Gastroenterology and Hepatology.

On the other hand, alternative therapies such as calcium plus vitamin D, calcitonin, and low-impact exercise demonstrated questionable efficacy, leading the authors to conclude that bisphosphonates alone "should be more aggressively considered" in this population.

Dr. John Melek of Mercy Hospital and Medical Center, Chicago, and Dr. Atsushi Sakuraba of the Inflammatory Bowel Disease Center at the University of Chicago Medicine, searched the MEDLINE and EMBASE databases as well as Google scholar, the UMIN Clinical Trials Registry, and the Cochrane Central Register for randomized controlled trials conducted between 1981 and 2011 assessing treatment for low BMD in IBD.

Overall, 11 of the 19 included studies evaluated bisphosphonates versus placebo or no treatment, while 4 looked at sodium fluoride versus placebo/no treatment, and 2 assessed calcium plus vitamin D versus placebo/no treatment.

The remaining analyses tested calcitonin versus placebo (1); low-impact exercise versus habitual physical activity (1); and bisphosphonates versus vitamin D (1) and fluoride (1). (Three studies compared multiple arms within the same study.)

Among all data on bisphosphonate efficacy, the authors found that the pooled overall effect by mixed-effect analysis revealed bisphosphonates to be significantly superior to control therapies in improving lumbar spine BMD, with a standard difference in means (SDm) of 0.51 (95% confidence interval [CI], 0.29-0.72; P less than .01).

Indeed, among the seven studies that reported improvements in the hip BMD, for example, a pooled overall effect by mixed-effect analysis showed that bisphosphonates were significantly superior to controls (both other treatments and no treatment; SDm, 0.26; 95% CI, 0.04-0.49; P = .02).

Moreover, among studies which reported the incidences of nonvertebral and vertebral fractures, the pooled ORs were 0.35 (95% CI, 0.06-1.95; P = .23) and 0.38 (95% CI, 0.15-0.96; P = .04), respectively.

Looking at adverse effects, meanwhile, the pooled odds ratio of adverse effects was a nonsignificant 1.24 (95% CI, 0.83-1.85; P = .29), "demonstrating that bisphosphonate treatment was not associated with an increased incidence of adverse effects."

Sodium fluoride, meanwhile, showed some efficacy: The four studies that assessed this treatment showed it was superior to placebo/no treatment in improving lumbar spine BMD (SDm, 1.18; 95% CI, 0.10-2.26; P = .03).

Fluoride did not, however, significantly improve hip BMD, compared with placebo, nor did it reduce the incidence of vertebral or nonvertebral fractures.

Similarly, the one study that looked at calcitonin (and assessed only children and adolescents with active or quiescent Crohn’s disease or ulcerative colitis, plus osteopenia or osteoporosis) found that this treatment was not superior to placebo in improving BMD at the lumbar spine. It did not find changes in hip BMD or the incidence of fractures.

Nor was low-impact exercise superior to control (habitual physical activity) in improving BMD at the hip or lumbar spine; fracture incidence was not assessed.

The authors conceded several limitations, the greatest of which was the presence of marked heterogeneity among studies, which necessitated use of the random-effects model or mixed-effect analysis. Indeed, much of this heterogeneity was due to the fact that some studies aimed to prevent bone loss, whereas others treated established osteopenia, they wrote.

Additionally, although many IBD patients are today treated with biologic therapies, few studies evaluated BMD regimens in IBD patients who underwent biologic treatment.

The authors disclosed no conflicts of interest related to this analysis. Dr. Sakuraba was supported by the Foreign Clinical Pharmacology Training Program of the Japanese Society of Clinical Pharmacology and Therapeutics.

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