Low bone mineral density (BMD) is recognized as a potential problem in children with inflammatory bowel disease (IBD) (1,2); however, the few longitudinal studies that have been conducted have produced diverging results (3–5). The presence of IBD during childhood and adolescence may interfere with the attainment of peak bone mass. In turn, lower peak bone mass in young adulthood may predispose patients to the development of osteoporosis later in life, which may lead to osteoporosis-related fractures (6).
The pathogenesis of disturbed bone mineralization in childhood IBD is regarded as multifactorial. The most important factors are treatment with corticosteroids (7), low body weight (8), vitamin D deficiency (9), physical activity (10), genetics (11) and cytokines released from the inflamed bowel due to chronic inflammation (12).
In a previous cross-sectional study, we described the occurrence of low BMD in a Swedish population of children and adolescents with IBD (13). The primary aim of the present study was to follow up and reexamine this population after a 2-year period to describe the longitudinal development of BMD. Second, we aimed to identify possible factors leading to changes in BMD during this time.
Patients and Study Design
The present study was designed as a prospective, longitudinal population-based study with patients from 2 pediatric centers in western Sweden: the Queen Silvia Children's Hospital at Sahlgrenska University Hospital, Gothenburg, and the Department of Pediatrics at Borås Central Hospital. These are the only facilities in the region responsible for the diagnostic workup, treatment, and follow-up of pediatric patients with IBD.
At baseline, we identified 166 eligible patients, 144 of which were included in the study during a 2-year period from January 1, 2003 to January 1, 2005 (Fig. 1). Inclusion criteria were an established diagnosis of IBD during the inclusion period and age between 6 and 19 years. The diagnosis of IBD was made on the basis of the Porto criteria (14). According to these criteria, a diagnosis of IBD, including Crohn disease (CD), ulcerative colitis (UC), and indeterminate colitis (IC), is based on clinical signs and symptoms, endoscopy, histology, and radiology.
Of the 144 patients who were enrolled at baseline, 126 agreed to participate in the follow-up study. The follow-up period lasted from January 1, 2005 to January 1, 2007.
In a later survey, we were able to identify 11 additional patients in late adolescence who were followed up by adult gastroenterologist services in the catchment area. Of these 11 patients, 7 were boys and 4 girls; 8 had a diagnosis of UC and 3 of CD. All of the patients with CD were boys. These 11 patients were not asked to participate in the study because they were identified retrospectively.
Clinical data, such as age, sex, disease subcategory (UC, CD, or IC), disease duration, and treatment (corticosteroids, azathioprine), were registered. We recorded whether the patient had ever taken corticosteroids or azathioprine regardless of the daily or cumulative dose. Data on disease location and behavior were categorized according to the Paris classification (15). Additionally, we collected data on body weight, body height, and Tanner stage. Growth charts were obtained.
Venous blood samples (vitamin D, intact parathyroid hormone [iPTH], calcium, phosphate, albumin, creatinine) were taken during nonfasting at regular visits at the outpatient clinic. These visits were scheduled close to the dual-energy x-ray absorptiometry (DXA) measurements. The blood was centrifuged, and the serum was stored frozen at −70°C before processing.
To evaluate BMD, the patients underwent DXA of the total body less head (TBLH) and the lumbar spine (LS) at the time of inclusion in the study and 2 years later at follow-up. All of the patients’ measurements during the study period were performed on the same densitometer at Sahlgrenska University Hospital in Gothenburg using a Lunar densitometer (DPX-IQ version 4.7e, General Electric Medical Systems, Lunar, Madison, WI), software version 4.7. BMD values were expressed as z scores using pediatric sex-specific and age-matched reference data from Lunar (16). These z scores were additionally adjusted for height z score according to the pediatric recommendations of the International Society for Clinical Densitometry (17). Patients with a BMD z score for the LS <−1 SD at baseline were supplemented daily with 1000 mg of calcium and 800 IE of vitamin D not to withhold a potentially beneficial treatment from our patients.
Vitamin D and iPTH Measurements
The vitamin D status was assessed based on serum 25-hydroxyvitamin D (25-OHD) levels using a competitive radioimmunoassay (DiaSorin, Stillwater, MN). This assay measures the sum of 25-OHD3 and 25-OHD2. All of the analyses were conducted at the Hormone Laboratory at Aker University Hospital (Oslo, Norway), where the described method is certified by the Norwegian Accreditation Board (NS-EN ISO/IEC 17025). The samples were measured singly. The intra- and interassay coefficients of variation were 6% and 13% to 16%, respectively. There is no consensus on optimal levels of 25-OHD in serum; however, vitamin D deficiency is defined by most experts as a value <50 nmol/L (18), and we used this definition.
The serum levels of iPTH were measured using a noncompetitive immunoluminometric assay (Immulite 2500, Siemens Healthcare Diagnostics, Los Angeles, CA). These analyses were also conducted at the Hormone Laboratory at Aker University Hospital (Oslo, Norway), where the reference range for iPTH is given as 1.5 to 7.0 pmol/L for individuals between 18 and 65 years. Pediatric reference values were provided by Coffi et al (19). The samples were measured singly. The intra- and interassay coefficients of variation were 3% to 5% and 7% to 11%, respectively. This method was also accredited by the Norwegian Accreditation Board (NS-EN ISO/IEC 17025).
Statistical analysis was performed with SPSS versions 15 and 16 (SPSS Inc, Chicago, IL). The analyses included descriptive statistics, the χ2 test, independent samples t tests, 1-sample t tests, Pearson correlation, and linear regression analysis.
To investigate possible factors related to changes in BMD during the observation period, we performed a multiple linear regression analysis with the change of BMD in the total body and in the LS (L2–L4) between baseline and follow-up as the dependent variable. Independent variables in this model were the age at the first BMD measurement, sex, the change in height z score between baseline and follow-up, treatment with azathioprine or corticosteroids, disease duration, disease subcategory, and supplementation with vitamin D and calcium. Baseline BMD was included as another independent variable to take into account a possible regression-toward-the-mean effect. Statistical significance was defined as a P value <0.05.
We obtained parental permission for all of the participants as well as assent from the younger children and informed consent from the adolescents. The study was approved by the ethical committee of the University of Gothenburg (Sweden).
A total of 166 patients were eligible during the inclusion period (Figure 1). Of the 144 patients with IBD who were enrolled at baseline (93 boys and 51 girls, mean age 14.2 years, range 6–19 years), 83 had a diagnosis of UC, 45 had CD, and 16 had IC. Additional information on disease duration, location, and behavior is given in Table 1(15). The baseline characteristics of the participating and nonparticipating group were previously described (13). There were no differences regarding sex, disease subcategories, treatment, or disease duration between these 2 groups at baseline.
At follow-up 2 years later (mean time for follow-up 24.6 months, range 15–33 months), 126 of the initial 144 patients (81 boys and 45 girls, mean age 16.6 years, range 8–22 years) were reexamined: 75 had UC, 37 had CD, and 14 had IC. The 18 nonparticipating patients at follow-up did not differ from the participating group with regard to diagnosis, sex, or BMD z score for the LS at the first DXA measurement, but they used corticosteroids less frequently (42.0% vs 80.6%, P < 0.001).
Significantly lower BMD values were seen in the LS of our patients compared with healthy references at both baseline and follow-up (Table 2). Values in the same range as in the references were observed in BMD TBLH (Table 3); thus, all of the further analyses were carried out for BMD in the LS exclusively.
Changes in BMD During the Study Period
The longitudinal changes in absolute BMD in the LS (L2–L4) are shown in Figure 2. Between baseline and follow-up, a positive significant mean change in absolute BMD occurred in all of the age groups in both sexes (Fig. 3). Because BMD is the ratio of bone mineral content and bone area, the mean change for these variables is shown in the same figure. The rate of increment in BMD was particularly pronounced in boys ages 12 to 16 years. At 17 years, the increment rate dropped but was still significant. Female BMD increased the most between the ages of 12 and 14 years, but the increment rate remained significant in the following years as well.
In the next step, we performed an analysis of the BMD z score for the LS. At baseline, we observed a significantly lower BMD mean z score for the LS in patients with CD and UC, but there was no significant difference between these 2 groups (13). Patients with IC showed normal values compared with healthy references (data not shown). During the study period, neither patients with CD nor UC improved their z score as a group (Table 2). Furthermore, significantly lower BMD z scores for the LS were found in boys, whereas in girls, z scores around 0 were seen (Table 2). This finding remained almost unchanged during follow-up.
Subsequently, subanalyses for the different age groups of IBD with respect to sex (Table 4) were conducted. Boys presented the lowest BMD mean z score for the LS in the age group from 17 to 19 years (−1.59 SD, ±3.1 SD). In contrast to the results for the entire male group and for the younger age groups, the boys in the group 17 to 19 years showed a significant increase in their BMD at follow-up (mean change in z score 1.0 SD, 95% CI 0.40–1.60).
In the group of girls (Table 4), normal BMD mean z scores for the LS were present in the age groups until age 16 at baseline, whereas for the age group from 17 to 19 years, a lower BMD z score was seen (−3.40 SD, ±3.1 SD). At follow-up, the BMD mean z score of the oldest girls showed a significant increase compared with baseline (mean change in z score 1.90 SD, 95% CI 0.60–3.20).
For a further analysis of the data, we evaluated those patients who presented as Tanner stage 5 at baseline and who had also completed their height growth (growth velocity <1.5 cm during the last year). Boys fulfilling these criteria showed a significant improvement in the BMD z score for the LS with approximately 1.2 SD (P < 0.01) during the study period (Table 5). There was also an improvement in the female group, but it was not statistically significant (P = 0.075).
Possible Factors Influencing the Change of BMD Over Time
In a multiple regression model (as described in the Statistical Analysis section), positive changes in the height z score (P < 0.001) and longer disease duration (P < 0.05) were significantly related to greater positive changes in BMD in the LS. Age showed a nonlinear effect, and the highest increase was observed in the age group from 12 to 14 years (P < 0.01). Furthermore, there was a significant difference in the change of BMD between boys and girls (P < 0.001) with a more pronounced increase in BMD in boys. Disease subcategory and treatment with azathioprine or corticosteroids were not significantly associated with a lower change in BMD. Supplementation with vitamin D and calcium did not significantly affect the change in BMD in this model.
Calcium and vitamin D were administered to the patients with BMD z scores for the LS <−1 SD at baseline; however, BMD in these patients remained low at follow-up (mean BMD z score for the LS −1.9 SD, ±1.0 SD). Of the 53 patients with BMD z score <−1 SD at baseline, 46 of them still had a z score <−1 SD (86.8%) at follow-up.
iPTH and Vitamin D Status
Increased iPTH levels were found both at baseline and at follow-up in the age groups younger than 16 years. The iPTH values for the different age groups and normal values are shown in Table 6(19). No statistically significant differences in iPTH were found with respect to season, sex, disease subcategory, disease duration, or treatment.
The mean vitamin D level was 74.9 nmol/L (range 15–235 nmol/L) at baseline and 66.4 nmol/L (range 17–153 nmol/L) at follow-up. Using a cutoff level of 50 nmol/L, 22.7% of the patients at baseline and 28.6% at follow-up were vitamin D deficient. Only 3 of the patients at baseline (2.3%) and 5 at follow-up (4.2%) presented with vitamin D levels <25 nmol/L. Furthermore, we found a significant seasonal variation in the vitamin D levels. Levels were significantly lower (P < 0.001) in the winter (November–April) than in the summer both at baseline and at follow-up. There were no statistically significant differences in vitamin D with regard to age, sex, or disease subcategory.
Additional analysis of serum calcium, phosphate, albumin, and creatinine revealed mean values within normal ranges both at baseline and at follow-up.
Relation Among Vitamin D, iPTH, and BMD
We found a significant inverse correlation between vitamin D and iPTH at follow-up (r = −0.34, 95% CI −0.18 to −0.50%, P < 0.001). At baseline, this correlation was somewhat weaker (r = −0.101, 95% CI −0.29 to −0.06). Furthermore, neither vitamin D levels and BMD nor iPTH and BMD correlated significantly with each other.
In the present longitudinal study, we found a decreased but stable BMD z score for the LS in patients with CD as well as UC over time, whereas BMD of the TBLH was in the normal range for both patient groups.
The few pediatric longitudinal studies have shown varying results (3–5). In accordance with our findings, Gupta et al (3) observed significantly lower BMD z scores for the LS in both patients with CD and UC in a group that was similar in size to ours, but no statistically significant changes in the BMD z score for the LS were observed during the follow-up period, varying from 1.7 to 8.7 years. In a study by Sylvester et al (4), the LS and total body BMD z scores were low and stable during a 2-year period in newly diagnosed children with CD; however, in patients with UC, the BMD z score was low and at the same level as the patients with CD, but it increased significantly between 1 and 2 years of follow-up. In a small study by Boot et al (5), BMD was significantly decreased at baseline. After 1-year follow-up, no improvement was observed in the entire group of patients with IBD, but after 2 years, a significant improvement in the BMD z score was seen in LS as well as in the total body. Using peripheral quantitative computed tomography (pQCT), a more recent longitudinal study found significant deficits in trabecular volumetric BMD at diagnosis in incident patients with CD ages 5 to 18 years (20). At follow-up 2 years later, trabecular volumetric BMD had improved significantly but was still significantly decreased compared with controls. The divergent results from these studies may be explained by differences in patient selection or sample size. Because our study is population based, it contains the entire clinical spectrum of pediatric IBD.
Notably, in contrast to the decreased BMD levels in the LS, BMD z scores for TBLH were in the normal range in our group of patients with IBD. Whereas BMD LS mainly represents the trabecular bone of the vertebrae, BMD TBLH reflects to a large extent the cortical bone. In accordance, previous studies using pQCT have reported decreased trabecular BMD but normal or even increased cortical BMD in children and adolescents with IBD (20,21). These findings may be explained by altered bone metabolism and bone geometry in pediatric patients with IBD, expressed by low trabecular BMD, low cortical thickness, and increased cortical BMD (20,21).
Our data indicate that gains in BMD may continue even beyond late adolescence in patients with IBD and that there may be potential for recovery of BMD in boys and girls into early adulthood. Thus, analyzing the group of patients who had completed their pubertal development and height growth at baseline, we could show that these patients continued gaining BMD in the LS. This resulted in improved BMD z scores for the LS at the end of the study period. This contrasts to our reference group from LUNAR, where boys and girls had only slight gains of BMD in the LS after 16 years of age (16). Furthermore, a study from the same area where our study was conducted showed that peak bone mass in the LS of healthy boys is achieved by ages 18 to 20 years (22). Van der Sluis et al (23), who collected Dutch reference data for BMD in healthy children and young adults, described a peak of BMD at the end of adolescence with only a slight increase thereafter. The results of the study of Bernstein et al (24) more indirectly indicate the potential of recovery of BMD in patients with IBD. The authors investigated a population-based cohort of premenopausal women with the onset of IBD before 20 years of age and compared a group of 12 women with a prepubertal onset of the disease with a group of 58 women with postpubertal onset. It was concluded that regardless of whether IBD presented before or after puberty, it had little effect on the ultimate peak bone mass achieved in adulthood.
In our investigation of the factors that may affect gains in BMD using multiple linear regression analysis, we found that longer disease duration and positive changes in height z score were associated with a significantly greater positive change in BMD. Neither disease subcategory nor treatment with azathioprine or corticosteroids played a significant role. The previously published findings concerning the influence of treatment with corticosteroids somewhat conflict. Boot et al (5) reported that the cumulative dose of corticosteroids between the DXA measurements correlated negatively with the change in LS and total body BMD. In contrast, Sylvester et al (4) found that the use of corticosteroids was not associated with BMD z score <−1 SD. A study by Issenman et al (25) showed that male pediatric patients with CD receiving long-term alternate-day prednisone therapy maintained bone mineralization at a level similar to those who did not receive this kind of treatment.
Vitamin D deficiency has been reported to play an important role in bone metabolism (26). In adults and children with IBD, both normal (2,27) and decreased (1,9) vitamin D levels have been reported; however, there exists no consensus regarding the optimal level of 25-OHD in serum. Some studies have defined vitamin D deficiency as a level <25 nmol/L (28), whereas others have proposed that a level <50 nmol/L constitutes deficiency (18). Using a level of 50 nmol/L as a cutoff, 25% of our patients were vitamin D deficient. Furthermore, we observed a significant seasonal variation with lower levels during winter. This seasonal variation has been described elsewhere (29). The lower levels during winter can be explained by the fact that the area of Gothenburg where our study was conducted is situated at latitude 57.7°N. The production of vitamin D in the skin is regarded as insufficient during winter between latitudes 30° and 60°N.
Due to ethical considerations, we decided to supplement patients with BMD z scores <−1 SD with vitamin D and calcium. At the time the present study was planned (before 2003), no pediatric recommendations existed regarding this issue. The guidelines available at that time for adults with IBD provided no BMD treatment threshold but mentioned a possible threshold at a z score <1 SD (30). Furthermore, we did not want to withhold a potentially beneficial treatment from our patients; however, the supplementation of our patients did not improve their BMD. Accordingly, Benchimol et al (31) found, in an open-label prospective study conducted during a 12-month period, that pediatric patients with IBD supplemented with vitamin D and calcium did not have an accelerated increase in LS BMD. Furthermore, we found no significant correlation between vitamin D levels and BMD either at baseline or at follow-up, which corresponds with the findings of Sylvester et al (4).
Additionally, we observed that the vitamin D and iPTH levels were inversely related in our patients. This has been described previously in healthy adolescents (32), but as far as we know, it has not been reported in pediatric patients with IBD. Furthermore, we found elevated iPTH levels in the patients younger than 16 years. Abrams et al (32) have reported increased rates of iPTH in healthy adolescents ages 10 to 14 years and suggested that in adolescents, especially in the presence of vitamin D insufficiency, PTH secretion increases to adapt to the higher rates of bone formation associated with growth. Vitamin D deficiency occurred to some extent in our patients, but a functional vitamin D insufficiency in patients with IBD has also been proposed (33). Tumor necrosis factor-α is a key player in inflammation in IBD and has been shown to decrease the vitamin D receptor number and also vitamin D–stimulated receptor transactivation in osteoblastic cells (34,35). As a result, PTH is upregulated. In summary, PTH may be elevated in puberty without indicating an insufficient supply of vitamin D or calcium. An elevated PTH concentration is regarded as a physiological response to meet the increased demands for calcium and phosphorus that parallel the increased growth velocity and calcium accretion during puberty.
Considering weaknesses of our study, a methodological issue lies in the nature of DXA. DXA does not reflect a real density but the ratio of bone mineral content over an area. A consequence of this may be an underestimation of BMD in pediatric subjects who are growth stunted, as is the case in some patients with IBD. As an attempt to overcome these difficulties, the areal BMD was mathematically transformed into volumetric BMD in some studies (2). Furthermore, the new technique pQCT allows measuring the “true” volumetric BMD, but this method was not available at the time the present study was conducted. Another limitation of DXA is that it does not allow for the characterization of the differences in deficits between trabecular and cortical bone, nor does it assess bone–muscle interaction; however, pQCT may resolve these questions.
As previously mentioned, we used the pediatric Lunar reference data and did not recruit our own control group. The Lunar reference material provides age- and sex-matched references. This material was regarded as sufficient because it encompasses a large number of measurements from white volunteers from different countries, including European (36–41). Moreover, the relevance of the Lunar reference data has been demonstrated by Eriksson et al (42) in a Swedish population from the area of Gothenburg, where our study took place.
Notably, in our population from western Sweden, UC is predominant. Hildebrandt et al (43) reported similar figures from approximately the same area 20 years ago. Lindberg et al (44) made the same observation in a study including patients from all over Sweden. These findings are in contrast to what has been found in populations in countries where the diagnosis of CD is prevalent, for example, in the United States (45).
The strength of our study is that it is population based with patients from 2 hospitals in western Sweden and a well-defined catchment area. The participation rate was high, with 87% of the original population at baseline and 76% at follow-up. Another strength is that we were able to follow a number of patients beyond the pediatric age group, which gave us new insight into the changes in BMD that occur in patients with IBD into early adulthood.
In conclusion, this longitudinal population-based study shows that low BMD LS is prevalent in Swedish pediatric patients with IBD both at baseline and at follow-up 2 years later. No improvement of BMD z score was observed in the groups of patients with CD and UC or in boys or girls; however, there may be some evidence that afflicted children, both boys and girls, have the potential to improve their BMD by the time they reach early adulthood.
We are grateful to our patients for participating in the present study. Helene Lindfred (RN, PhD) and the staff of the pediatric departments in Gothenburg and Borås are thanked for support during the study period, Senada Catic (RN) for technical performance of the DXA measurements, Birgitta Hillvärn and Josefin Karlsson for help with the database and office work, and Marie Krantz (MD, PhD) for advice during planning and design of the study. Furthermore, we thank Prof Emeritus Egil Haug and Kari Julien from the hormone laboratory at Aker University Hospital Oslo (Norway) for the excellent support in the analysis of the vitamin D and iPTH samples.
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