Original article—alimentary tract
Improvement in Biomarkers of Bone Formation During Infliximab Therapy in Pediatric Crohn's Disease: Results of the REACH Study

https://doi.org/10.1016/j.cgh.2008.07.010Get rights and content

Background & Aims

Crohn's disease (CD) is associated with altered bone metabolism. This study examined changes in bone formation and resorption after infliximab induction and associations between bone biomarkers, linear growth, and disease activity (Pediatric Crohn's Disease Activity Index [PCDAI]) after 54 weeks of infliximab therapy.

Methods

One hundred twelve subjects ages 6–17 years with moderate to severe CD received infliximab induction (5 mg/kg/dose) at weeks 0, 2, and 6; week-10 responders were randomized to infliximab every 8 or every 12 weeks maintenance therapy. Serum bone-specific alkaline phosphatase (BSAP), N-terminal propeptide of type 1 collagen (P1NP), urine C-telopeptide of collagen cross-links (CTX-1), and deoxypyrodinoline (DPD) were collected at baseline and 10 weeks. PCDAI and height z-scores were assessed at baseline and at 10 and 54 weeks.

Results

Models were adjusted for bone age, gender, height, and steroid use. Baseline BSAP and P1NP levels were negatively associated with PCDAI (both P = .01). BSAP and P1NP increased during induction (both P < .001) and were associated with 54-week increases in height z-score (P < .05 and P < .001, respectively). Improvements in P1NP were associated with 54-week decreases in PCDAI (P = .01). CTX-1 and DPD also increased during induction (P < .001 and P = .01, respectively) but were not associated with changes in PCDAI. Changes in CTX-1 were associated with improvements in height z-score (P < .002).

Conclusions

Infliximab therapy is associated with dramatic increases in BSAP and P1NP, consistent with inhibition of tumor necrosis factor–α effects on osteoblasts. The increases in CTX-1 and DPD likely reflect coupling of bone formation and resorption and increases in linear growth.

Section snippets

REACH: Study Subjects and Design

The REACH international multicenter, randomized, open-label study enrolled 112 subjects from February 2003 through March 2004. The institutional review boards at participating sites approved the protocol. Written informed consent was obtained from all parents/legal guardians, and assent was obtained from children on the basis of individual institutional review board guidelines.

The details of the study protocol were previously described.27 Briefly, subjects were 6–17 years of age, with

Subject Characteristics

Table 1 summarizes baseline subject characteristics. The baseline deficits in height and BMI z-scores reflect the growth and nutritional status in subjects with moderate to severe CD. On average, the baseline chronologic age was 0.77 ± 1.43 years greater than the bone age. Baseline PCDAI scores, bone age deficits, and height z-scores did not differ in the 36 subjects concurrently treated with corticosteroids, compared with the remaining 77 subjects. There were no gender differences in growth

Discussion

This prospective multicenter study is the first to examine changes in bone biomarkers during infliximab induction therapy in children and adolescents with CD. These data demonstrated marked increases in bone formation biomarkers and moderate increases in bone resorption markers. On average, BSAP increased 109% and P1NP increased 208% (P < .001). The magnitude of these increases is substantially greater than the 15%–26% increases in bone formation markers in adult studies, as detailed below. In

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    The authors would like to acknowledge Karen Hayden and Harry Walton for their technical support and Grace Lang and Stephen Xu for statistical support.

    The authors disclose the following: Centocor, Inc, Malvern, PA provided support for this study.

    Allan Olson is currently employed at Robert Wood Johnson Pharmaceutical Research and Development and is a former employee of Centocor, Inc. Jewel Johanns, and Colleen Marano are employees of Centocor Inc. Jeffrey Hyams received research funding in conjunction with the conduct of this study and other studies sponsored by Centocor and served as a consultant to Centocor. Wallace Crandal and Subra Kugathasan received research funding in conjunction with the conduct of this study, served as a consultant to Centocor, and received an honorarium from Centocor. Robert Heuschkel received research funding in conjunction with the conduct of this study and also received a grant from Schering-Plough. Anthony Otley, Gigi Veereman-Wauters, Anne Griffiths, and Robert Baldassano received research funding in conjunction with the conduct of this study.

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