Bones in Crohn's: Cytokines, a Missing Link?

The pathophysiology of osteoporosis in Crohn's disease ^(1-3) has been attributed to malabsorption of calcium and vitamin D by inflamed bowel, compounded by the use of corticosteroids ⁽⁴⁾. However, there is conflicting evidence supporting these factors as the primary cause of osteoporosis in Crohn's disease in the absence of prior surgery ^(5-6).

Crohn's disease most often involves the distal ileum and proximal colon ⁽⁷⁾. Even though low levels of vitamin D and hypercalciuria can be found at diagnosis, it is difficult to identify malabsorption as the cause ⁽⁸⁾. Nutrient deficiencies have been attributed more frequently to anorexia, poor intake, and impaired utilization ⁽⁹⁾. Dietary repletion alone does not always correct severe osteoporosis. Paradoxically, circulating calcitriol levels rise and hypercalciuria resolves with anti-inflammatory treatment, which may include steriods ⁽³⁾.

Studies in both adults and children have consistently documented one further puzzling observation: patients with ulcerative colitis have much less bone demineralization than patients with Crohn's ⁽¹⁰⁾. This parallels the observations that growth failure is more likely in children with Crohn's than in children with ulcerative colitis, ⁽¹¹⁾ and that mineralization of the radius is often normal if corrected for height age ⁽³⁾. It is of major significance that the growth impairment seen in Crohn's disease may precede the onset of clinical symptoms ⁽¹²⁾. Furthermore, growth failure may continue in a subset of patients despite correction of nutritional deficiencies and clincial remission ⁽¹³⁾. All of these observations suggest that some factor(s) other than malabsorption might be responsible for the growth failure as well as the bone demineralization documented in this disease.

In this issue of the Journal, Hyams and colleagues implicate a serum factor possibly a cytokine produced as a result of the transmural intestinal inflammation characteristic of Crohn's disease ⁽¹⁴⁾. Mucosal immunologists have defined a host of cytokines that circulate in increased amounts in patients with inflammatory bowel diseases ^(15-16) These cytokine studies have evoked interest and provoked controversy. While some investigators contend that cytokines directly cause complications, others suggest that these factors are epiphenomena that result from the inflammatory response. Nevertheless, there is increasing evidence that proinflammatory cytokines appear to influence bone formation and resorption ⁽¹⁷⁾.

The article by Hyams et al. describes studies that used in vitro techniques to explore the differing clinical observations seen in patients with Crohn's disease and those with ulcerative colitis. The investigators examined the effects of serum from patients with Crohn's disease, ulcerative colitis, and controls in an established rat calvarium organ culture model. They studied bone formation, calcium content, collagen synthesis, DNA content, and calcium release. The cultured bone specimens were also examined by light microscopy. The authors demonstrated a powerful effect of serum from the Crohn's disease patients' serum on bone formation, even at 1:100 dilution. Expected increases in dry weight and calcium content were inhibited 31% and 60% respectively, as compared to incubations with serum from healthy controls. Serum from patients with ulcerative colitis had no significant effect on either measurement. However, serum from patients with ulcerative colitis interfered with non-collagen protein synthesis, an effect not seen with serum from control patients and those with Crohn's disease.

Histologic evaluation of bone culture innoculated with serum from Crohn's disease patients demonstrated disorganized mineral and osteoid. Misshapen and distended osteoblasts had fallen out of their normal alignment to the bone. Differing results were seen with serum from patients with ulcerative colitis. There was no effect demonstrated on bone resorption by any of the patient or control serums from either diseases or control group.

Based on these studies, the authors speculated that clinical demineralization might be a direct effect of a serum factor such as a cytokine resulting in impaired bone mineralization rather than decreased collagen synthesis or osteoclast bone resorption. These findings are tantalizing. Potentially, a serum factor might also be shown to play a major role in the larger issue of growth failure seen in some patients beyond apparent remission.

It is noteworthy that even though serum levels of IL-6 and ESR were significantly higher in patients with Crohn's disease, they failed to correlate with parameters of bone formation and resorption. Scores on the pediatric Crohn's Disease Index also failed to correlate. It might be argued that like glycosylated hemoglobin in diabetes, osteoporosis and growth failure provide a better summative measure of disease activity than the current Crohn's Disease Activity Index whose scores seem to lose sensitivity in the lower range of smouldering disease ⁽¹⁸⁾.

The lack of correlation of aberrations in mineralization with levels of IL-6 prompt the question of what other factor circulating in the serum of young patients with Crohn's disease might interfere with organization and calcification of rat calvarial bones? Will the factor turn out to be a cytokine-or some other element? Despite this unanswered question, this study effectively focuses attention upon the production side of bone mineralization as a problem in Crohn's disease. The authors report the results of an effective collaboration between clinicians and basic researchers who have joined interests and techniques to describe a phenomenon whose implications go far beyond the issue of bones in Crohn's.