Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease

doi:10.1016/S1542-3565(04)00663-9

Clinical Gastroenterology and Hepatology

Volume 3, Issue 2, February 2005, Pages 122-132

https://doi.org/10.1016/S1542-3565(04)00663-9 Get rights and content

Background & Aims: Crohn’s disease causes an increase in osteopenia and osteoporosis. This study assessed the efficacy of adding etidronate to calcium and vitamin D supplementation for treatment of low bone mineral density in Crohn’s disease. Methods: One hundred fifty-four patients with Crohn’s disease with decreased bone mineral density, determined by using dual-energy x-ray absorptiometry, were randomly assigned to receive etidronate (400 mg orally) or not for 14 days; both groups were then given daily calcium (500 mg) and vitamin D (400 IU) supplementation for 76 days. This cycle was repeated 8 times during a period of 24 months. Biochemical characteristics and bone mineral densities were assessed at 6, 12, and 24 months. Results: After 24 months bone mineral density significantly increased from baseline in both the etidronate- and the non-etidronate-treated groups (both groups receiving calcium and vitamin D supplementation) at the lumbar spine (P < .001), ultradistal radius (P < .001), and trochanter (P = .004) sites, but not at the total hip. The increase in bone mineral density was similar in each treatment group. No bone mineral density differences were found when groups were analyzed according to gender, corticosteroid use, bone mineral density at baseline, or age. Conclusions: Low bone mineral density is frequently associated with Crohn’s disease. Supplementation with daily calcium and vitamin D is associated with increases in bone mineral density. The addition of oral etidronate does not further enhance bone mineral density.

Section snippets

Study participants

Two hundred twenty-four consecutively encountered patients who had either active or quiescent CD and who were attending the Inflammatory Bowel Disease Referral Clinic at the University of Alberta Hospital (Edmonton, Alberta, Canada) and 18 patients from Mount Sinai Hospital (Toronto, Ontario, Canada) were identified as possible experiment participants between September 2000 and July 2001. They completed a questionnaire documenting age, CD diagnosis date, gender, smoking status, and number of

Patient characteristics

Of the 154 patients who were initially identified as having osteoporosis or osteopenia (see Methods), 11 (7.1%) were excluded from the study before randomization because they met exclusion criteria (4 because of low 25-hydroxy vitamin D, 2 because of low testosterone, 2 because of non-attendance, and 1 each because of osteomalacia, spinal distortion, and low thyroid-stimulating hormone). One hundred forty-three patients with low BMDs thus met the criteria for randomization to the study groups (

Discussion

The objective of this longitudinal study was to assess the efficacy of etidronate treatment combined with calcium and vitamin D supplementation as compared to calcium and vitamin D supplementation alone in treating low BMD for patients who had CD. During the 2 years of the study, BMDs steadily increased in the lumbar spine, trochanter, and ultradistal radius, but not in the total hip. Improvements in BMD measurements were similar in both the etidronate treatment and non-etidronate treatment

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Impaired bone health is a common complication of chronic inflammatory intestinal diseases, such as celiac disease and inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, already at diagnosis and during follow-up. Osteopenia and osteoporosis are most frequently observed due to nutritional impairment and deficiencies, decreased overall physical health, and inflammation-associated alteration of bone metabolism. Treatment strategies for decreased bone mineral density in the course of chronic intestinal diseases have been studied sparsely and these studies are usually designed without assessment of bone fractures.
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We observed the effects of naringin on bone loss in glucocorticoid-treated inflammatory bowel disease (IBD) in a rat model. The IBD model was established in Sprague-Dawley rats by administering 5.0% dextran sodium sulfate. Dexamethasone (DEX) and naringin were given at the second week. Blood, colon and bone samples were collected for biomarker assay, histological analysis or microCT analysis. Superoxide dismutase, catalase and malonaldehyde were measured in bone. A significant decrease of procollagen type 1 N-terminal propeptide (P1NP) level was observed in DEX-treated IBD groups compared with the control (p < 0.05). P1NP levels were dose-dependently increased in the presence of naringin intervention. Bone loss and decreased bone biomechanical properties were observed in DEX-treated IBD rats compared with control rats (p < 0.01). Naringin intervention protected against bone loss and decreased bone biomechanical properties. Bone formation related gene mRNA expressions were significantly decreased in DEX-treated IBD rats compared with control rats. Naringin administration reversed the down-regulation of the expressions of those genes. Naringin treatment reduced the oxidative stress in bone from DEX-treated IBD rats. Our data indicated that naringin may have great potential for the treatment of bone loss in glucocorticoid-treated IBD patients via blocking oxidative stress and promoting bone formation.
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Osteopenia and increased risk for fractures in IBD result from several factors.
To investigate the dietary intake of calcium in IBD patients.
A 22-item quantitative validated frequency food questionnaire was used for quantifying dietary calcium in relation to gender and age, in 187 IBD patients, 420 normal- and 276 diseased controls.
Mann–Whitney, chi-square- and T-tests.
The mean calcium intake was 991.0 ± 536.0 (105.8% Recommended Daily Allowances) and 867.6 ± 562.7 SD mg/day (93.8% RDA) in healthy and diseased controls, and 837.8 ± 482.0 SD mg/day (92.7% RDA) in IBD, P < 0.001. Calcium intake was high in celiac disease (1165.7 ± 798.8 SD mg/day, 120% RDA), and non-significantly lower in ulcerative colitis than in Crohn's disease (798.7 ± 544.1 SD mg/day vs 881.9 ± 433.0). CD and UC females, but not males, had a mean calcium intake well under RDA. In all study groups the intake was lower in patients believing that consumption of lactose-containing food induced symptoms, versus those who did not (105.8% vs 114.3% RDA in normal controls; 100.4% vs 87.6% RDA in IBD).
Diet in IBD patients contained significantly less calcium than in healthy controls. Gender and age, more than diagnosis, are central in determining inadequate calcium intake, more so in IBD. Self-reported lactose intolerance, leading to dietary restrictions, is the single major determinant of low calcium intake. Inadequate calcium intake is present in one third of IBD patients and represents a reversible risk factor for osteoporosis, suggesting the need for tailored nutritional advice in IBD.
Efficacy and safety of medical therapy for low bone mineral density in patients with inflammatory bowel disease: A meta-analysis and systematic review
2014, Clinical Gastroenterology and Hepatology
Citation Excerpt :
The numbers of enrolled subjects ranged from 13–148. Seven studies targeted patients with CD,14,22–24,26,30–32 one study targeted patients with UC,13 and 5 studies included both CD and UC patients.25,27–29 Four studies used bisphosphonate as prevention and 9 studies as treatment of osteopenia/osteoporosis.
Patients with inflammatory bowel disease (IBD) are at risk for osteoporosis and fracture. However, the efficacy of medical treatments for osteoporosis in increasing bone mineral density (BMD) in patients with IBD has not been well characterized.
We conducted a meta-analysis and systematic review of controlled trials to evaluate the efficacy and safety of medical therapies used for low BMD in patients with IBD (Crohn's disease, ulcerative colitis, or indeterminate colitis). We searched MEDLINE, EMBASE, Google scholar, the University Hospital Medical Information Network (UMIN) Clinical Trials Registry, and Cochrane Central Register of Controlled Trials for studies that assessed the efficacy of medical treatment for low BMD in patients with IBD. We also manually searched abstracts from scientific meetings and bibliographies of identified articles for additional references. The primary outcome assessed was changes in BMD at the lumbar spine. We also collected data on hip BMD, numbers of new fractures, and adverse effects. Data were pooled by using random-effects models and by mixed-effects analysis for primary aims, when subgroup analysis by individual drug was possible.
We analyzed data from 19 randomized controlled studies; 2 used calcium and vitamin D as therapies, 13 used bisphosphonates, 4 used fluoride, 1 used calcitonin, and 1 used low-impact exercise. The pooled effect of bisphosphonates was greater than that of controls in increasing BMD at the lumbar spine (standard difference in means, 0.51; 95% confidence interval, 0.29–0.72) and hip (standard difference in means, 0.26; 95% confidence interval, 0.04–0.49) with comparable tolerability, and the risk of vertebral fractures was reduced. Fluoride increased lumbar spine BMD, but its ability to reduce risk of fracture was unclear. There was no evidence that the other interventions increased BMD.
On the basis of a meta-analysis, bisphosphonate is effective and well tolerated for the treatment of low BMD in patients with IBD and reduces the risk of vertebral fractures. There are insufficient data to support the efficacy of calcium and vitamin D, fluoride, calcitonin, or low-impact exercise. However, the small number of randomized controlled trials limited our meta-analysis.
Increase in bone mineral density in strictly treated Crohn's disease patients with concomitant calcium and vitamin D supplementation
2013, Journal of Crohn's and Colitis
Citation Excerpt :
Observational studies in CD patients supplemented with calcium and vitamin D and more than two years follow-up, a commonly accepted minimal interval for assessment of changes in BMD, are sparse. Moreover, study design and study population differ between the several studies concerning this subject, making clinical and therapeutic interpretation complicated.9,15–19 We report about the BMD in a well defined CD population intensively treated according to Dutch and European standards (Dutch and ECCO guidelines20,21), which are in general characterized by an active monitoring of disease activity and a medical treatment step up approach.
Decreased bone mineral density (BMD) is common in Crohn's disease (CD) patients. This paper reports on the prevalence of decreased BMD in a referral cohort study of CD-patients next to the change of BMD over time in relation with CD-associated clinical characteristics.
205 CD patients of a referral hospital were enrolled between januari 1998-January 2010 when measurement of BMD by dual X-ray absorptiometry (DXA) was available. Follow-up DXA scan was performed in subjects with known risk factors besides Crohn indicative for low BMD. Treatment of CD patients was according to a protocol which is comparable to the current (inter)national guidelines. In osteopenic patients, supplemental vitamin D (800 IU) and Calcium (500–1000 mg) were prescribed.
Mean BMD at baseline was 0.97 ± 0.16 gram/cm² in lumbar spine and 0.87 ± 0.12 gram/cm² in the total hip. At baseline, higher age and low Body Mass Index (BMI), were negatively correlated with BMD. Eighty-four patients underwent a second BMD assessment with a median interval period of 4 years (IQR 3–6). A mean annual increase of + 0.76% (95%CI: − 2.63%; + 3.87%) in lumbar spine and + 0.43% (95%CI: − 2.65% ; + 1.11%) in total hip was observed.
Higher age, male sex, low BMI, and a higher age at diagnosis of CD were associated with low BMD. Follow-up of BMD in CD patients showed a contraintuitive small increase of BMD at lumbar spine and total hip in CD patients only using supplemental vitamin D and calcium next to strict treatment of CD.

View all citing articles on Scopus

: Supported by the Crohn’s and Colitis Foundation of Canada, Cecile Mactaggart Summer Student Research Fund, and Procter and Gamble Pharmaceuticals, Canada.

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Original articlesRandomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease

Section snippets

Study participants

Patient characteristics

Discussion

Am J Gastroenterol

Gastroenterology

Gastroenterology

Gastroenterology

Am J Gastroenterol

Gastroenterology

Bone

Am J Med

J Hepatol

J Clin Densitom

Risk factors for low bone density in Crohn’s disease

Inflamm Bowel Dis

Osteoporosis in patients with inflammatory bowel disease

Gut

Altered bone metabolism in inflammatory bowel diseasethere is a difference between Crohn’s disease and ulcerative colitis

J Intern Med

Femoral neck osteopenia in patients with inflammatory bowel disease

Am J Gastroenterol

Bone mineral density is reduced in patients with Crohn’s disease but not in patients with ulcerative colitisa population based study

Gut

Osteoporosis and determinants of bone density in patients with Crohn’s disease

Dig Dis Sci

Reduced bone density in patients with inflammatory bowel disease

Gut

Osteopenia and osteoporosis in Crohn’s diseaseprevalence in a Dutch population-based cohort

Scand J Gastroenterol

Reduced bone mineral density and unbalanced bone metabolism in patients with inflammatory bowel disease

Inflamm Bowel Dis

Bones and Crohn’sanalysis of risk factors associated with low bone mineral density in patients with Crohn’s disease

Inflamm Bowel Dis

Prevention of bone mineral loss in patients with Crohn’s disease by long-term oral vitamin D supplementation

Eur J Gastroenterol Hepatol

Effect of Crohn’s disease on bone metabolism in vitroa role for Interleukin 6

J Bone Miner Res

Sex hormone status and bone metabolism in men with Crohn’s disease

Aliment Pharmacol Ther

Decreased bone density in inflammatory bowel disease is related to corticosteroid use and not disease diagnosis

J Bone Miner Res

Association of dehydroepiandrosterone sulfate deficiency with bone turnover in men with inflammatory bowel disease

Int J Colorectal Dis

Longitudinal study of cortical bone loss in patients with inflammatory bowel disease

Scand J Gastroenterol

Increased bone resorption in patients with Crohn’s disease

Aliment Pharmacol Ther

Altered bone metabolism in inflammatory bowel disease

Am J Gastroenterol

Increased degradation of type I collagen in patients with inflammatory bowel disease

Gut

Original articles
Randomized trial of etidronate plus calcium and vitamin D for treatment of low bone mineral density in Crohn’s disease