The Journal of Pediatrics
Volume 148, Issue 4 , Pages 429-432, April 2006

Bone loss in children with Crohn disease: Evidence of “osteoimmune” alterations

  • Catherine M. Gordon, MD, MSc

      Affiliations

    • Corresponding Author InformationReprint requests: Catherine M. Gordon, MD, MSc, Division of Endocrinology, Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115.

Director, Children’s Hospital Bone Health Program, Staff Physician, Divisions of Adolescent Medicine and Endocrinology, Children’s Hospital Boston, Assistant Professor of Pediatrics, Harvard Medical School, Boston MA 02115

Article Outline

Abbreviations: BMD, Bone mineral density, CD, Crohn disease, DXA, Dual-energy x-ray absorptiometry, IFN, Interferon, OPG, Osteoprotegerin, RANKL, Receptor activator of nuclear factor-κB ligand

 

“Osteoimmunology” is a recently coined term that encompasses the cross-talk that exists between the skeletal and immune systems.1 The bone marrow serves as a reservoir for both bone and blood cells, including progenitors of the bone-forming osteoblasts, bone-resorbing osteoclasts, and lymphocytes that constitute the immune system. Interplay between these systems is further illustrated by the pathological bone resorption seen in rheumatoid arthritis, an inflammatory disease in which bone destruction is mediated by interactions between activated T cells and osteoclasts.2, 3 An understanding of how the “osteoimmune system” functions in both healthy and ill individuals will have important therapeutic implications for individuals afflicted with inflammatory diseases that weaken the skeleton through dysregulation of bone remodeling. A knowledge of this system is particularly important for health providers of young patients given the importance of childhood and adolescence for the achievement of peak bone mass.4, 5

Osteoporosis prevention is an area of increasing concern for pediatric providers because an increasing number of children are being identified as at risk for low bone mass.4, 5 Included in this group are children with inflammatory bowel disease, as examined by Sylvester et al in this issue of The Journal.6 Caveats arise in the interpretation of measurements of bone density in children, because the most commonly accepted method of measuring bone density, dual-energy x-ray absorptiometry (DXA) provides only a 2-dimensional measurement of bone rather than capturing its true 3-dimensional structure.4, 5 Therefore, as was done by Sylvester et al, rigorous attention to detail is needed, including the use of conservative measures to ensure that bone mineral density (BMD) data are interpreted correctly.

To completely understand the current findings, an explanation of new terminology is needed, including molecular pathways that underlie the osteoimmune system. As part of the normal immune response, activated T cells can synthesize receptor activator of nuclear factor-κB ligand (RANKL), an essential factor in normal osteoclast formation and activity.7 RANKL is also critical to the development of the immune system; results from animal studies have shown that mice lacking RANKL exhibit defects in early T-cell and B-cell differentiation and lack lymph tissue.8 Osteoprotegerin (OPG) is a soluble neutralizing receptor that regulates the activity of RANKL by blocking its effects.9 Another cytokine, interferon (INF)-γ, produced by activated T cells, is also a potent inhibitor of RANKL. A noteworthy feature of INF-γ is that it inhibits both osteoclast formation and osteoblast function,10 thereby altering both bone resorption and bone formation.11, 12, 13

In a translational research protocol including both measurements from a clinical protocol and T-cell activation studies performed in a basic laboratory, Sylvester et al examined whether circulating T cells release cytokines that decrease bone turnover in children with Crohn disease (CD).6 The role of T cells as regulators of bone remodeling and bone mass in children with CD is unclear, and this study provides some important new insights. The authors compared 23 children with CD with 40 healthy control subjects, including measurements of BMD, circulating cytokines, hormones, and bone turnover markers. A unique aspect of this study’s protocol is that data were obtained in newly diagnosed children before they received glucocorticoids or other therapies that can affect the immune response or skeletal metabolism. In vitro T-cell production of RANKL, INF-γ, and OPG was also studied, with T lymphocytes harvested from the participants’ blood samples. The authors introduce a novel terminology, suggesting that circulating T cells in patients with CD serve as “inflammation shuttles” between bone and the digestive tract and, as such, affect the metabolic activity of bone through the release of cytokines into the systemic circulation.

Sylvester et al appropriately used conservative measures to interpret BMD measurements, correcting for bone age and height age. The fact that BMD was normal in this report but subnormal in previous reports of children and adolescents with CD14, 15, 16, 17 may be explained by the different correction methods used to interpret BMD, as well as receipt of glucocorticoids by participants and other disease- or patient-specific factors. Sylvester et al did not interpret BMD with respect to body composition as was done in previous studies of children with CD,16, 17 which would have been informative. In those earlier studies, BMD was found to be proportional to lean body mass.16, 17 Preservation of both weight and lean body mass through nutritional and anti-inflammatory measures may ultimately preserve bone mass in these patients. Future protocols should examine predictors of body composition and BMD in these patients, because the interdependence between muscle and bone (ie, “muscle–bone unit”) is an area of increased interest and investigation.18

At least 3 important findings can be derived from the study of Sylvester et al. First, in these newly diagnosed patients, the BMD Z-scores were, surprisingly, normal. As mentioned earlier, bone loss has been reported in children and adolescents with CD, but those previous studies enrolled patients in later stages of the disease.14, 15, 16, 17 In addition, because there is no standard method for correcting pediatric DXA measurements, heterogeneity is introduced as results are compared among studies,4, 5 and the reference database used for interpreting BMD can vary. The duration of disease may also explain why many adults exhibit bone loss.19, 20, 21, 22 Second, Sylvester et al found significantly decreased bone resorption in patients with CD compared with controls, in contrast to studies of adults that found increased bone resorption.19, 20, 21, 22 Increased bone resorption may not be as common in children, especially at the time of diagnosis. This finding is noteworthy because it adds to accumulating data indicating that the pediatric skeleton responds differently to a given disease state or intervention than the adult skeleton.23, 24 Leonard et al 23 reported that the skeleton is relatively resistant to high-dose glucocorticoid therapy in children with glucocorticoid-sensitive nephrotic syndome. Finally, the in vitro results afford insight into mechanisms behind the decreased bone remodeling observed in these newly diagnosed children. Activated T cells from the patients with CD produced higher INF-γ concentrations, accompanied by significantly higher circulating OPG concentrations. Thus, increased secretion of INF-γ by T cells would explain the decrease in both bone formation and resorption reported by the authors, evidenced by significantly lower serum bone turnover markers in the patients than in control subjects. OPG secreted by an inflamed intestine and possibly other sources likely decrease the number and activity of osteoclasts, reducing bone resorption even more profoundly.

If these findings can be replicated in a larger sample of patients, they will have important clinical implications. First, the data suggest that bone density may be normal at the time of diagnosis in children with CD. This provides hope: full delineation of disease-specific mechanisms may provide an opportunity for preventing bone loss. Skeletal deficits may also be preventable if the disease is identified early before the inflammatory response is activated and weight loss ensues. In this study, body mass index was comparable in the children with CD and the control group. Children with chronic disease of multiple etiologies often lose bone as they lose weight. Because the diagnosis of CD in these children apparently was made early, before significant weight loss occurred, their bone density may have been preserved. Because bone resorption was not increased, anabolic strategies to prevent bone loss as opposed to antiresorptive agents may be the most appropriate first line of defense to prevent bone loss in these children. Finally, the in vitro findings, most notably alterations of OPG and INF-γ, are important because they may provide therapeutic targets for future pharmacologic interventions.

Some limitations of this study must be considered. Due to the small sample size, the findings cannot be generalized to all newly diagnosed patients with CD. In addition, results need to be replicated in patients who present with weight loss. Although the differences in serum concentrations of OPG, RANKL, and T-cell-produced INF-γ were statistically significant, the biological significance requires further exploration. Moreover, although serum concentrations of RANKL were measured, membrane-bound levels within activated T cells were not evaluated. As the authors acknowledge, T cells may influence the function of bone cells through intimate contact within the marrow space. Therefore, measurements of membrane-bound RANKL may prove more informative. The source of the increased OPG in these patients (inflamed colonic cells vs osteoblasts vs other tissues) is also not yet known and merits investigation. Finally, these data were obtained in patients naïve to medications known to affect bone metabolism. This aspect of the protocol represents both a strength and weakness. Insight is afforded into the effect of the disease process itself on the skeleton independent of these therapies; however, how the immune and skeletal systems are altered after receipt of glucocorticoids or various anti-inflammatory agents in children with CD would also be an important future research endeavor, especially given how often these agents are prescribed.

In summary, this translational research study provides new insights into mechanisms that mediate bone loss in children with CD. The authors’ title poses the question: “Are activated T-cells regulators of bone metabolism in children with Crohn disease?” Data from this sample of newly diagnosed patients suggest that the answer is “yes.” Clinical findings from this study, including patients exhibiting a normal BMD at diagnosis of CD accompanied by suppressed bone resorption, provide yet another example of a disease process affecting the pediatric skeleton differently than an adult skeleton that is fully grown and developed.23, 24 As has been stated previously with respect to bone density issues in pediatrics, the data of Sylvester et al support the view that “children are not small adults.”24

See related article, p 461

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References 

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PII: S0022-3476(06)00062-X

doi:10.1016/j.jpeds.2006.01.036

Refers to article:

  • Are activated T cells regulators of bone metabolism in children with Crohn disease?

    Francisco A. Sylvester, Patricia M. Davis, Nancy Wyzga, Jeffrey S. Hyams, Trudy Lerer
    The Journal of Pediatrics April 2006 (Vol. 148, Issue 4, Pages 461-466)

The Journal of Pediatrics
Volume 148, Issue 4 , Pages 429-432, April 2006

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