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- Patients and Methods
Previous studies have confirmed that the prevalence of decreased bone mineral density is elevated in patients with inflammatory bowel disease. The objective of the current study was to determine the prevalence of osteopenia and osteoporosis in a cross-sectional outpatient population of 242 adult patients with Crohn's disease and to determine which clinical characteristics and serum and urine biochemical factors might be predictive of bone loss. Thirty-seven percent had normal bone density, 50.0% were osteopenic, and 12.9% were osteoporotic. Among the sites used to diagnose low bone mineral density, the femoral neck demonstrated the highest prevalence of osteopenia and the ultra-distal radius the highest prevalence of osteoporosis. However, low bone mineral density at one site was always predictive of low bone mineral density at the other. Corticosteroid use during the year before assessment was found to be consistently predictive of low bone mineral density in males but not in females. In contrast, low body mass index and high platelet counts were consistently predictive of low bone mineral density in females but not in males. Disease location, smoking, and age were not predictive of changes in bone mineral density.
Several studies within the past decade have revealed that the incidence of low bone mineral density (BMD) is increased in patients with inflammatory bowel disease, with a higher prevalence in Crohn's disease (CD) than in ulcerative colitis (UC). 1–5 The mechanism underlying the lower BMD has not been clearly understood, but a number of factors have been implicated. These include disease activity, corticosteroid therapy, calcium and vitamin D deficiency, acute inflammatory cytokine action on osteoclast and osteoblast activity, sex hormone deficiency, smoking, and overall poor nutrition. 2,3,6–14 Study results have not been consistent, however, and it is likely that the cause is multifactorial.
Acute intestinal inflammation is postulated to affect bone mineral density in CD patients as a consequence of an increase in circulating proinflammatory cytokines. 10,15 These cytokines have been demonstrated to have an effect on bone metabolism in vitro, inhibiting osteoblast function and encouraging bone resorption. 10 High serum levels of IL-6, for example, have been found in osteoporotic CD patients, compared with non-osteoporotic patients. 16 In addition, acute intestinal inflammatory events can induce central hypogonadism in both males and females and can cause amenorrhea in females. 11,17 Amenorrheal states have been strongly associated with osteoporosis, and hormone replacement therapy is effective for the treatment of bone loss in postmenopausal women with CD. 18 To date, few studies have been attempted to determine whether an association between markers of inflammation and bone loss in Crohn's disease exists. Knowledge of such an association would be helpful in determining which patients with Crohn's disease are at risk for developing osteopenia and osteoporosis.
Osteopenia is defined by the World Health Organization (WHO) as a T-score between −1 and −2.5, and osteoporosis is a T-score less than −2.5, the T-score being the number of standard deviations (SD) of the patients BMD from the mean peak value for a reference population of the same sex and race. 19,20 Additionally, a low BMD measurement at an individual site will generally reflect the fracture rates at the respective site. The femoral neck and total hip measures have been identified as indicators of hip fracture, whereas the lumbar spine BMD is an indicator of vertebral fracture risk. 21,22 Similarly, the ultra-distal radius BMD indicates relative risk of Colle's fracture. 23 Indeed, the studies previously cited have reported that between 36% and 55% of CD patients are osteopenic, whereas between 6% and 58% are osteoporotic. 6,16,24–26 This high prevalence of osteopenia and osteoporosis in CD patients is likely coupled with an increased risk of fracture 2,27–29 and necessitates the development of a clinically effective approach to determining which patients with CD are at highest risk of bone loss.
To meet this objective, we must first determine what patient characteristics are associated with decreased BMD in CD patients. Characteristics such as low body mass index (BMI), age, gender, high levels of serum alkaline phosphatase and albumin, high levels of urine N-telopeptide cross-linked type I collagen (N-telopeptide), low serum magnesium, corticosteroid use, and smoking have previously been reported to correspond with low BMD. 1–4,6,7,13,14,26,30–34 Unfortunately, many of these studies presented contradictory results, likely as a consequence of small sample sizes and heterogeneous disease populations (Crohn's disease and ulcerative colitis).
The objective of the current study, thus, is to determine the prevalence of osteopenia and osteoporosis in a large cross-sectional population of adult patients with Crohn's disease and to assess what patient characteristics and serum and urine biochemical factors might be used to predict bone loss.
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- Patients and Methods
This study, the largest of its kind, confirms the previous reports of the prevalence of osteopenia and osteoporosis in patients with Crohn's disease. Our findings of 50% osteopenia and 12.9% osteoporosis within the patient population lie in the ranges of 36.4% to 55% osteopenia and 5.5% to 57.6% osteoporosis seen in previously published results. 6,16,24–26 Several reasons account for the large ranges in osteopenia and osteoporosis reported in these previous studies. Small sample populations, the inclusion of both UC and CD patients into a single analysis, the inclusion of patients with ileal resections, the use of different definitions of osteoporosis and osteopenia, the use of Z-scores instead of T-scores, and the use of varying measurement techniques all contribute to these differences.
We found osteopenia to be more prevalent in the femoral neck (46%) than in the lumbar spine (38.3%), while in contrast, osteoporosis was more common in the lumbar spine (7.9%) than in the femoral neck (5.9%). This is in agreement with Bjarnson et al, who also reported a higher prevalence of hip osteopenia (49% hip vs 36% vertebral osteopenia). 26 The same study, however, reported a much higher incidence of osteoporosis (29% hip and 18% vertebral).
Our study demonstrated that corticosteroid use in the preceding year was associated with a significant decrease in BMD at all sites measured. Interestingly, this was true only for the male patient population. Females did not exhibit differences in BMD when corticosteroid use was compared. However, the female corticosteroid use group was younger than the group that had not used corticosteroids, and this difference may have influenced the outcome. Two previous studies, one assessing BMD of the spine and femoral neck of 120 Caucasian patients in the United Kingdom and the other assessing BMD of 60 patients with CD and 60 with ulcerative colitis, also observed BMD loss in the male corticosteroid use population. 4,39 Conversely, other studies have found that being female was associated with an increased the risk of low BMD in the case of CD patients. 7,31,34 One of these female-dominant studies, however, compared the patient population to healthy controls, rather than to other female CD patients not taking corticosteroids 31; whereas the other two reported results from a small sample patient population (26 and 55 patients, respectively). 7,34 Though the current study suggests that corticosteroid use has a more deleterious effect on bone mineral density on males than on females, the reason for this is not clear. One possibility involves the fact that corticosteroid therapy can suppress gonadotropin and testosterone levels, thus interfering with the inhibitory effects of testosterone on IL-6, allowing IL-6 to stimulate osteoclast activity. 11,40 However, in this study, mean testosterone levels in the male corticosteroid group did not differ significantly from those in the male non-corticosteroid group (data not shown).
Another possible explanation for the lower BMD in the male corticosteroid using population involves the fact that corticosteroid use reflects disease activity and severity. Indeed, we found that, compared with male noncorticosteroid users, males on corticosteroid therapy exhibited higher WBC and platelet counts, and lower serum hemoglobin levels, all of which indicate active and severe disease. Disease activity is believed to lead to bone loss in CD patients by increasing circulating levels of IL-1, IL-6, and TNF-α, thus enhancing osteoclast activity and inhibiting osteoblast activity. 10,40
Taken together, our results clearly demonstrate decreased bone mineral density in patients with Crohn's disease. Several studies in non–Crohn's disease patients has identified that reduced BMD is highly predictive of fracture risk, in both men and women 28,41–44. However, the relationship between low bone mineral density and fracture rate in patients with Crohn's disease remains controversial. In a Danish cohort of Crohn's disease patients fracture risk, as determined by ICD coding, was slightly elevated with an incidence rate ratio of ˜1.15. 45 Similarly, a Canadian population-based cohort study demonstrated an incidence rate ration of ˜1.74 and 1.59 for the spine and hip, respectively. 27 In contrast, in a population-based inception cohort of patients with Crohn's disease, the risk of fracture was not elevated relative to controls. 46 The current study did not assess fracture rate and, thus, cannot comment on the ability of low BMD to predict fracture risk in Crohn's disease patients.
Regression analysis to determine predictors of low BMD identified corticosteroid use as the factor that most strongly predicted low BMD at each skeletal site in the male patient population. The predictive nature of corticosteroids use on BMD, in this study, was identified by determination of corticosteroid use in the past year and did not require determination of cumulative corticosteroid doses. Other weaker predictors of low BMD in males included BMI, older age, vitamin B12, and higher N-telopeptide excretion. In females, the most significant predictors of low BMD were BMI, platelet count, older age, corticosteroid use (only at the total hip), and N-telopeptide (only at the ultra-distal radius). There have been similar findings of an association of corticosteroid use, BMI, urine N-telopeptides, and age to low BMD 1–4,6–14,24–26,30,33,41; however, this study was the first to demonstrate that platelet count could predict low BMD in the female population. Platelets are involved in the pathogenesis of CD and contribute to it by releasing inflammatory mediators. 42 Furthermore, active CD is associated with thrombocytosis, and thus platelet count serves as a marker of disease activity. 37,38,47
The finding that urine N-telopeptide levels correlated with the lumbar spine, total hip, and ultra-distal radius T-scores of both male and female CD patients suggested that the mechanism for bone loss in patients with Crohn's disease involved increased bone resorption. Other studies have identified a strong relationship between markers of bone resorption and bone loss in patients with Crohn's disease. 33,48,49 Although high N-telopeptide levels predicted low BMD at the total hip and ultra-distal radius in males, and at the ultra-distal radius in females in our study, it failed to do so at the lumbar spine and femoral neck in both males and females with CD. This suggests that increased bone resorption is only one of many mechanisms involved in the pathogenesis of osteoporosis in Crohn's disease.
The current study did not exclude postmenopausal women. It is well-known that postmenopausal women suffer greater bone loss because of decreased estrogen production. In our study, 21.6% of the female patients were postmenopausal. However, this group's bone density distribution did not differ appreciably from that of the entire baseline group and thus did not likely influence the BMD results of the female population. Furthermore, we excluded serum LH, FSH, and estradiol from the correlation and regression analyses. It was our assertion that these variables were not linearly related to BMD, but rather increased in a stepwise fashion, according to age and menopausal status of our female patient group.
Finally, it is difficult to dissect the influence of disease activity versus corticosteroid use as the primary the causative factor for bone loss in CD patients. The reason for this is that patients with active CD are most likely to be on corticosteroid therapy, and vice versa. A longitudinal analysis assessing CD patients from the time of diagnosis, and possessing noncorticosteroid therapies for active inflammatory disease, is essential in determining the exact role of these factors in Crohn's disease-associated bone loss. Nevertheless, the results of our study are significant in that we were able to assess several clinical and biochemical factors simultaneously, with a large patient population. In addition, we separately analyzed the male and female patient populations, taking into consideration that inherent differences between the two groups may exist and can adversely affect our results if analyzed as a whole. This may explain the conflicting results reported by previous studies, as they failed to separate the patient population into female and male groups for analysis.
In conclusion, this study focused on identifying risk factors for bone loss in a cross-sectional survey of 242 patients with Crohn's disease. Clinical and biochemical characteristics were assessed to determine associations with bone mineral density at four skeletal sites. Thirty-seven percent had normal bone density, 50.0% were osteopenic, and 12.9% were osteoporotic. Among the sites used to diagnose low bone mineral density, the femoral neck demonstrated the highest prevalence of osteopenia and the ultra-distal radius the highest prevalence of osteoporsis. However, low bone mineral density at one site was always predictive of low bone mineral density at the other. Corticosteroid use during the year before assessment was found to be consistently predictive of low bone mineral density in males but not in females. In contrast, low body mass index and high platelet counts were consistently predictive low bone mineral density in females, but not in males. Disease location, smoking, and age were not predictive of changes in bone mineral density.