Department of Medicine, Guy's, King's, St Thomas' Medical School, Bessemer Road, London SE5 9PJ, UK
Patients with inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis) are no more immune to the development of osteoporosis than the general population [1]. Initial estimates suggested that ~30% of patients with severe Crohn's disease and somewhat fewer patients with ulcerative colitis had metabolic bone disease, either osteoporosis or osteomalacia [13]. The pathogenesis was thought to relate to ileal and small intestinal involvement of disease, or surgical resections, causing vitamin D and/or calcium malabsorption, oestrogen deficiency, malnutrition or treatment with cholestyramine in Crohn's disease [1, 2, 47] and corticosteroids in ulcerative colitis.
With the introduction of dual X-ray absorptiometry (DXA) to quantitate bone mineral density (BMD) reliably, reproducibly and with ease, and its application to patients with IBD, the above prevalence rates and mechanisms of reduced BMD have been reviewed. Pigot et al. [8] showed that 60% of patients with Crohn's disease and ulcerative colitis had BMD (vertebra and/or hip Z scores) below -1 S.D. Ghosh et al. [9] expanded on these observations and showed that newly diagnosed patients with Crohn's disease had significantly reduced BMD as compared with newly diagnosed patients with ulcerative colitis, six of 15 whom nevertheless had spinal Z scores of -1 or less. With minor discrepancies, these observations have been confirmed [1013] (see Table 1).
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There are indications from the above studies that the reduced BMD in patients with IBD differs from many other diseases associated with reduced BMD. For instance, the hip appears to be more severely affected than the vertebra [10, 13, 20], which is contrary to what is to be expected with corticosteroid treatment, but does resemble that found in rheumatoid arthritis [22, 23].
It is intriguing that reduced BMD is found at the time of diagnosis of Crohn's disease and most studies suggest that reduced BMD in patients with IBD may occur independently of corticosteroid treatment and alterations in calcium homeostasis [10, 14, 15, 18, 24], although not all agree [11, 13, 16]. Nevertheless, as a compromise, corticosteroids can at least be seen to accelerate the rate of loss of BMD as the most severely affected patients (osteoporosis=with Z or T scores less than -2.5) have a high lifetime corticosteroid intake [1, 10]. Again, the resemblance with rheumatoid arthritis is striking [22, 23].
The possible pathogenesis of reduced BMD in IBD is clearly as multifactorial and varied as that seen in the general population relating to the effect of oestrogen deficiency, alterations in calcium homeostasis, corticosteroid treatment, nutritional and dietary factors (wasting and low body mass index), smoking, alcohol, immobility, etc. It has not been worked out whether and/or how these factors interact in patients with IBD. Such studies can be made as complex as it takes to keep epidemiologists and statisticians busy for years, but early indications are that these effects and associations are weak and overshadowed by the effect of the IBD itself [11, 15, 16, 2426]. Support for this idea comes from a study in a selected group of IBD patients who did not have significant conventional risk factors for reduced BMD [10] and since confirmed in a relatively unselected group of patients with IBD [13, 18, 20]. These studies show a consistent and characteristic change in metabolic bone marker profiles [10] in patients with IBD, distinguishing them from some other, mainly non-inflammatory, diseases that are also associated with reduced BMD. Accordingly, a significant increase in resorption markers is found in these patients without a compensatory increase in formation markers [10, 18, 20, 21]. In patients on corticosteroids, there may be a concomitant reduction in bone formation [15, 18]. These bone marker profiles differ from that of post-menopausal women (associated with a reduction in formation markers) [27, 28] or that associated with tobacco use (no changes in formation or resorption markers) [29].
Considering the above, and in particular the fact that newly diagnosed patients with untreated Crohn's disease have reduced BMD, there is a strong case for suggesting that demineralization in patients with IBD occurs primarily as a consequence of the intestinal inflammation. One possibility is that cytokines, or other inflammatory mediators, spill over from the inflamed intestine into the circulation and that this somehow leads to osteoclast activation. In the absence of osteoblast activation, this would then account for the low BMD. An analogy can be drawn to the reduced BMD in patients with rheumatoid arthritis where it was suggested that the synovium was the source of inflammatory mediators that affected bone [23].
The clinical implications of reduced BMD in patients with IBD are, as with other demineralizing bone disease, that it might lead to significant morbidity due to spine, hip and radial fractures [30, 31]. As yet, no study has addressed this directly in patients with IBD, although an enhanced risk of fractures has been described in children with Crohn's disease [32]. In adults, a conservative estimate, based on X-rays in patients with clinical symptoms, showed that 27% of patients with IBD had sustained a fracture [16]. These had significantly lower BMD (mean Z scores -1.47 and -0.73 for Crohn's and ulcerative colitis) than those who did not have a history of fracture (Z scores -0.62 and 0.03, Crohn's and ulcerative colitis, respectively). Of note was that the BMDs in those with fractures were mainly within the osteopenia, rather than the osteoporosis, definition range of the bone disease. Furthermore, there were no significant differences in the prevalence of fractures in patients with Crohn's disease and ulcerative colitis. A similar conclusion was reached by Abitol et al. [15] who reported a 7% prevalence rate of vertebral bone fractures as assessed by standard dorsal and lumbar spine radiography. Silvennoinen et al. [11], who report one of the lowest prevalence rates of reduced BMD in patients with IBD, state that none of their patients had a history of osteoporotic or pathological fractures. The overall impression at present is that fracture risk is probably increased in patients with IBD and that this relates in part to the severity of the bone changes, but studies specifically designed to address these issues are needed.
Prevention and treatment of established decrease in BMD may be indicated in patients with IBD, provided that it is shown that reduced BMD places patients in a significant risk group for fractures, with their attendant morbidity. However, avoidance of fractures in patients with IBD may be more pressing than in some other diseases. If patients with IBD require analgesia for relief of the pain associated with fractures, they are commonly prescribed conventional non-steroidal anti-inflammatory drugs. However, non-steroidal anti-inflammatory drugs may cause severe clinical relapse of the intestinal disease and indeed very few patients can take these drugs without some increase in disease activity [3335].
Extrapolation of results from treatment trials in patients with conventional osteoporosis over to patients with IBD is not acceptable as the pathogenesis of the bone disease may differ. Most treatment trials for reduced BMD in IBD have been carried out with adequate controls and blinding, but the number of patients treated in each study is relatively small (which does not pose a problem if the treatment is effective and clinically meaningful). Successful treatment of low BMD in patients with IBD was described in a single open study in post-menopausal women treated with conventional hormone replacement doses of oestrogens [36]. This treatment is unsuitable for the majority of patients with IBD; 50% are male and many of the females are pre-menopausal. A randomized controlled trial showed that low-impact exercise had, at best, a modest beneficial effect on BMD in patients with Crohn's disease [26]. The effect of calcium and vitamin D supplementation is somewhat controversial [37, 38].
Based on the observations that resorption is significantly and selectively enhanced in patients with IBD, targeted treatment to inhibit osteoclast function becomes an option. Bisphosphonates are strong candidates for this purpose. I suspect that it will be particularly important to use one of the i.v. administered preparations as it is exceedingly difficult to convince these patients to take yet another daily oral medication, in particular if the drugs have significant gastrointestinal side-effects. There is additionally the problem that patients' well-being is not improved in the short term.
A more adventurous treatment option is to control the primary disease itself. If the reduced BMD in IBD is related to inflammatory mediator spill-over from the bowel to the circulation, it would be desirable to treat the intestinal disease aggressively. Prompt and appropriate treatment is probably achieved for the vast majority of clinical relapses of the disease. However, when clinical remission of disease is achieved, most gastroenterologists withdraw active treatment and focus on measures to prevent relapse of disease, which include fixed doses of the 5-aminosalicylic acid preparations, azathioprine and perhaps poorly absorbed corticosteroids such as budesonide. However, clinically quiescent disease is nevertheless characterized by substantial inflammatory activity [39,40] and it is probable that this is sufficiently severe in many cases to contribute significantly to the reduced BMD. Intestinal inflammation in clinically quiescent disease therefore becomes a logical target for treatment, in particular now that intestinal inflammation can be quantitated accurately, objectively and with ease (J. Tibble et al., in preparation). Drug doses and length of treatment need to be worked out, but can now be titrated according to the intensity of this, asymptomatic, inflammatory phase of IBD. Gastroenterologists are unfortunately often slow to react to new ideas. For instance, the gastroenterological concept of second-line treatment (note that this is not directed against the acute and asymptomatic inflammatory component of the disease) to alter the natural history of IBD lags far behind that of most other similar chronic relapsing diseases, such as rheumatoid arthritis. IBD is not a common disease, research funding is sparse and the pharmaceutical companies probably do not see IBD or the bone disease associated with it as a major therapeutic growth area. Progress is, therefore, likely to be slow on all fronts, but then again, what is new?
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