Reduced bone mineral density (BMD) is frequently associated with Crohn's disease (CD). Early studies have described a high prevalence of osteopenia (a T-score of -1 or lower) and osteoporosis (a T-score of -2.5 or lower) in inflammatory bowel disease (IBD). Uncontrolled studies gave a prevalence of severe demineralisation determined by dual-energy absorp-tiometry (Z-score of lower than -2 or T-score of lower than -2.5) that ranged from 18 to 42%, while larger studies with a healthy control group showed prevalence rates of only 2-16% . It is important to notice that these studies are prone to selection bias as they are conducted in specialised IBD centres. In fact, in prospective longitudinal studies, changes in BMD in patients with IBD were similar to those of the general population . The most relevant clinical question is to determine whether alterations in BMD can affect the fracture risk. There have been four large population-based studies describing fracture risk in patients with IBD. A survey was mailed to members of the Danish Crohn's/Colitis Association regarding fractures . The authors concluded that patients with UC had similar overall fracture rates compared with control subjects. Crohn's disease patients had a relative risk of 1.7 for all fractures (RR for female patients 2.5, 2.9 among premenopausal females, 1.8 among postmenopausal women and 0.6 among men) compared to the control group. A family fracture history (RR 2.4) especially paternal (RR 3.6) increased the risk of fracture among patients with CD. Among UC patients, maternal fracture history (RR 2.4) and smoking (RR 3.8) were additional risk factors. There was no correlation between fracture risk and steroid use in both CD and UC. It is important to notice that the control subjects were not matched to patients by age and gender and were more likely to be older and male, and less likely to be current smokers or on hormone replacement therapy than patients with Crohn's disease. Furthermore, there may have been a bias in the nature of patients who returned the questionnaire, as those who were at higher risk may have been more likely to respond. In population-based studies, the same authors observed that the relative risk of sustaining a fracture requiring hospitalisation in CD was 1.9, whereas at 1.08 in UC it had not significantly increased .
There have been two North American population-based studies of fracture risk in IBD [91,92]. The first study, published by Bernstein et al., identified hospital and out-patient fractures by collecting the data via administrative databases for the Canadian province of Manitoba. The overall fracture rate for patients with IBD was found to be approximately 1 per 100 patient-years and this increased to a relative risk of 1.41 compared with an age-gender- and geographical residence-matched control group. There was an increased fracture risk of the hip and of the spine, which was evidenced in patients over 60 years of age. No differences were observed between men and women and between CD and UC patients. However, there was a significantly increased fracture risk for UC male patients compared with females. The other North American study used the Olmsted County population-based database of 243 CD patients. Compared with controls, the overall risk ratio for any fracture was 0.9, whereas the relative risk for an osteoporotic fracture was 1.4. The risk ratio for thoracolumbar vertebral fracture was 2.2. Thus, the risk of fracture was not greater than in the general popu lation, except in the elderly. The last study was a primary care-based nested-case control study which used a General Practice Research Database in the UK that included 683 patients . The overall odds ratio for IBD patients compared with a matched control group was 1.21 without differences between males and females. After accounting for a measure of disease severity, there were no significant differences in the fracture risk between patients with CD and UC; the risk of fracture correlated with the number of symptoms and with age.
The collective messages of these studies are the following: (1) patients with IBD may have increased fracture rates but the magnitude of the excess risk is small and most evident in the elderly; (2) fracture risk is generally similar in CD and UC; (3) osteoporosis is gender neutral among patients with IBD.
The mechanisms underlying bone loss in IBD are still unclear. Several factors that also contribute to osteoporosis in the general population are implicated: physical inactivity, hypogonadism, underweight, calcium and vitamin D deficiency, malnutrition, smoking (most commonly in CD), treatment with steroids and the effects of inflammatory cytokines related to the disease activity. As noted before, among patients with IBD, fracture risk, which is similar in CD and UC, is gender neutral and most evident in adults. In the following, we will briefly discuss the other main risk factors.
Onset of inflammatory bowel disease. A recent analysis of premenopausal adult women with early onset IBD did not provide evidence that an early onset of disease is a major risk factor for early onset osteoporosis .
Steroid use. Systemic steroid therapy is associated with rapid bone loss, particularly in the trabecular bone of the lumbar spine. Steroid use is a major factor in IBD-associated bone loss. Nevertheless, it is difficult to separate the effects of corticosteroid use from those of disease activity. Bernestein et al. observed that corticosteroid use in the 2-year period preceding fracture was more frequently in patients experiencing fracture compared with those not experiencing fractures . Few studies have examined BMD in newly diagnosed patients. Gosh et al. observed reduced BMD in patients with CD, but not with UC . This could be explained by the relative lower age and hence higher BMD of the UC patients and by the high preponderance of proctitis with less deleterious systemic consequences. BMD was unaffected by the subsequent use of steroids over a 1-year period. Schoon et al.  found BMD to be normal at diagnosis. It has been suggested that the high prevalence of oral contraceptives used in this study (92% of the women) may have provided protection against bone loss. Lamb et al.  observed a reduced BMD at diagnosis, prior to corticosteroid treatment in 34 IBD patients.
Calcium intake, vitamin D deficiency, malabsorption, intestinal resection, body mass index. Adequate calcium-intake has been suggested as being an important determinant of optimal bone mass. Bernstein et al. observed, in a cohort of premenopausal women prior to 20 years of age, that the average BMD was not different than in controls and only 3% had BMD in the osteoporotic range . Therefore, IBD children achieve normal BMD as adults and it is possible that during remission periods or steroid-free periods there is a sufficient opportunity to achieve normal bone mineralisation. In this same study, oral calcium and vitamin D intake were measured by a 4-day food record and no correlation was observed between the intake of these nutrients and BMD ; this is similar to a previous report in 168 CD patients . Hence, a 4-day record can be beneficial in determining the quantity of calcium supplementation required. One variable often cited as being important in CD is the relationship between osteomalacia, the skeletal hallmark of vitamin D deficiency, and reduced vitamin D intake and/or absorption. Factors contributing to vitamin D deficiency in CD include malabsorption of dietary vitamin D and 25-hydroxy vitamin D undergoing enterohepatic circulation, lack of adequate sun exposure, a low dietary vitamin D intake and the ingestion of drugs interacting with the intestinal absorption of vitamin D. The majority of the studies suggest that low dietary intake of vitamin D is not an important determinant of BMD in IBD patients . Cholestyramine is often used to control postresectional diarrhoea due to bile acid malabsorption. Both resection of the terminal ileum and cholestyramine therapy lead to the depletion of bile acids, which are essential for vitamin D absorption; ensuring adequate intake of vitamin D is highly recommended especially in patients with small-bowel resection. Most of the studies on the importance of vitamin D deficiency come from literature in the early 1980s that specifically addressed BMD in a selected group of CD patients with decreased serum 25-OHD. A recent study showed that vitamin D absorption in CD patients is normal . Some studies have shown no relationship between BMD and measured serum 25-OHD [102-104]. Two studies have found that serum 25-OHD levels are actually lower in UC than in CD [105,106]. Relative malnutrition and low body weight are important risk factors. In the general population, body mass index is strongly correlated with BMD  and meta-analysis has concluded that a low body weight is a significant and consistent risk factor for fracture in the general population, although the 51 studies used were dominated by older women . The same appears true for CD patients. In a population-based study of 60 CD patients, 60 UC patients and 60 healthy controls, those with CD had both a lower BMD as well as lower lean mass . This effect was only seen in those with current or past systemic steroid use, which is consistent with the known adverse drug effects on both bone and muscle tissue. Among 168 CD patients, the BMI was significantly correlated with BMD (p<0.0001) .
Inflammation-mediated bone loss. The link between inflammation and bone loss may be of particular interest in IBD-associated osteopenia. The recently discovered receptor activator of nuclear factor kB (RANK) ligand (RANKL) osteoprotegerin (OPG), may be the important link between systemic inflammation and osteoporosis. The OPG molecule binds to the receptor activator of nuclear factor kB (RANK). The effect of this ligation is to regulate T cell-dendritic cell communications, dendritic cell survival and lymph node organogenesis. The interaction of RANK on the surface of the osteoclasts with its ligand RANKL induces osteoclastogenesis. Osteo-protegerin (OPG) can be secreted by osteoblasts and serves as a decoy receptor that prevents the ligation of RANKL, which can interfere with osteoclastogene-sis. The balance between RANKL and OPG is of major importance for the regulation of osteoclasto-genesis. The way in which compounds stimulate RANK ligand or OPG will affect whether they inhibit or induce osteoclastogenesis. Certain pro-inflammatory cytokines such as IL-1 and TNF alfa, induce RANKL and displace the balance of bone formation and bone reabsorption in favour of bone reabsorption causing bone loss. Corticosteroids partially exert their toxic effects on bone by the same mechanism and they also inhibit OPG production.
Genetic risk factors of rapid bone loss. An interesting report linked potential fracture risk as a measure of bone mineral density by DXA with the presence or absence of specific alleles for certain proinflammatory cytokines . Eighty-three patients with IBD were enrolled and went through a follow-up with BMD measurements over 1.6±0.3 years: 17% had a T-score below -2.5 at the spine and 11% had a T-score below -2.5 at the hip. They observed that the extent of bone loss was not correlated to clinical severity of disease or administration of steroids. Non-carriage of the 240-base pair allele of the IL-1ra gene and carriage of the 130-base pair allele of IL-6 were independently associated with increased bone loss, and their combined presence was significantly associated with increased bone loss. Todhunter et al. 
investigated the influence of IL-6, collagen type 1a1 (COL1A1 ) and vitamin D receptor gene (VDR) single nucleotide polymorphisms (SNP) on BMD in a cohort of 245 patient's with CD. They observed that lumbar spine and total hip BMD was higher in patients with CC genotype compared to GG (p=0.041 and p=0.014 respectively). In patients genotyped for COL1A1, (hip, but not lumbar spine), BMD was higher in the homozygous wild type GG than in the heterozygous GT. No differences were observed either between BMD VDR Taq 1 and Fok 1 genotypes or between BMD and CARD 15 genotypes. The authors observed that in CD, a condition characterised by increased levels of IL-6, the genotype CC is protective against IL-6 mediated bone reabsorption. Furthermore, COL1A1 gene polymorphisms at the Sp1 binding sites are thought to influence the properties of bone by altering the level of transcription and production of collagen. It has been observed that bone strength is reduced in heterozygous compared to wild type subjects .
Clinical Trials on Prevention and Therapy of IBD-Associated Bone Disease
Therapeutic intervention studies focussing on IBD are sparse and no clinical trials with the aim of fracture prevention are available. Extrapolating results from fracture prevention trials in osteoporotic and steroid-induced osteoporosis may be tricky for several reasons: (1) orally administered agents, especially biphosphonates whose absorption is only 1-5% even in healthy subjects, may not be adequately absorbed in those with intestinal disease (in patients with active disease, especially of the upper gastrointestinal tract, parenteral administration of biphos-phonates may be appropriate); (2) IBD is under-represented in the larger intervention trials on steroid-induced osteoporosis, making the conclusions arguable; (3) younger men and premenopausal women—patients of special interest with regard to IBD-associated bone disease—have not been subjected to therapeutic intervention trials outside the context of steroid-induced osteoporosis. Taking all these drawbacks as a whole, review articles on the therapy of IBD-associated bone disease should be considered with caution. Experts emphasise lifestyle modifications (physical exercise, no smoking and alcohol excess), vitamin D (400-800 IE daily) and calcium (1 000-1 500 mg/day) supplementation and hormone replacement therapy (oestrogens or selective oestrogens receptor modulators in women; testosterone in hypogonadal men). However, these recommendations are far from fully evaluated. The factors that are known at the present are discussed in the following.
Firstly, vitamin D supplementation is relatively inexpensive and does not necessitate control of calcium levels at regular intervals. It should be considered for all older patients (>60 years) because of the known high prevalence of vitamin D deficiency. In contrast, active vitamin D metabolites are expensive, necessitate control of calcium serum levels and have not been shown to be effective for fracture reduction. Secondly, calcium supplementation does not appear to be essential in patients who are being supplemented with genuine vitamin D. In addition, calcium is not well tolerated. Thirdly, early menopause or male hypogonadism should be corrected with hormone replacement therapy and fourthly, the dose of corti-costeroids should be kept to a minimum and non-systemic or controlled-release formulations should be advised .
Previous short-term studies have indicated that biphosphonates and slow release sodium fluoride can improve BMD. No effects were seen after 1 year in a randomised study of corticosteroid-using patients with IBD with the administration of calcium and vitamin D alone . One small, randomised placebo-controlled study of 32 CD patients addressed the changes in BMD after a year-long therapy with the oral bisphosphonate alendronate 10 mg/day . After one year, the bone mineral density had increased significantly at the spine in the alen-dronate-treated group compared with the control group and showed a trend for recovery at the femoral neck. However, several issues have to be considered when interpreting the data of this study. First of all, the patients were selected for disease quiescence, and patients with active disease, whose bone microenvironment may be more exposed to bone-resorbing cytokines or whose ability to absorb oral biphospho-nates may be compromised, were excluded. Additionally, although the study was randomised, the alendronate-treated group had significantly higher levels of biochemical markers of bone reabsorption at baseline, which may have improved the response to anti-reabsorptive therapy. There are, however, some encouraging aspects: the favourable response of CD patients to oral and the good tolerability of the drug in these patients. In a more recent randomised controlled study, Von Tirpitz et al. randomised 84 CD patients with reduced BMD to receive calcium citrate (800 mg/day plus vitamin D 1 000 IU/day) alone (n=13) or with either slow release sodium fluoride (25 mg twice daily; n=36) or ibandronate (1 mg intravenously every 3 months; n=35) . The randomisation was unbalanced as patients with osteoporosis were assigned either to the fluoride group or to the ibandronate group. Other problems were the shorter average disease duration in the fluoride group and incomplete follow-up. At 27 months, lum bar bone density increased by 2.6% (p=0.066) for the group given only calcium and vitamin D, 5.7% (p=0.003) for those given fluoride and 5.4% (p=0.003) for those given ibandronate; this effect was particularly evident during the first year. Femoral BMD did not change in any group and no participant suffered a new vertebral fracture. Thirty-five patients who received steroids at least once during the study showed a mean increase in BMD similar to that observed in those who did not receive steroids. A significant correlation was observed between BMI and the BMD during the observational period and improved nutrition may alone contribute to the improvement of BMD (p<0.001), emphasising that treatment of underlying bowel disease and associated improvement of body weight may be important factors in the management of osteoporosis. Bernstein et al.  measured the BMD in 46 CD patients treated with infliximab for 1 year. At baseline, reduced BMD occurred in 43% of patients at the lumbar spine and 46% at the left femur; after 1 year of therapy, BMD was significantly increased. BMD gain between the groups with and without osteopenia was not different. Changes in BMD were not correlated to concurrent steroid therapy, calcium supplementation or changes in C-reactive proteins.
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