Children with IBD are at risk for inadequate intake of calories as well as micronutrients including calcium, vitamin D, and zinc secondary to anorexia due to upper tract inflammation, malabsorption, increased metabolic demands, lactose intolerance, abdominal pain, or depression. Even in the setting of adequate caloric intake, malabsorption can cause deficiency states of the above micronutrients depending on location and severity of disease. Diarrhea can result in zinc deficiency, which has the potential to impact growth. Vitamin D deficiency may result from malabsorption as well as decreased exposure to sunlight due to disease flares. Vitamin K deficiency may result from malabsorption and altered bowel flora due to antibiotic use and IBD-associated dysbiosis, which may result in increased concentrations of undercarboxylated osteocalcin, which is associated with decreased bone turnover and fractures [37]. Nutrients that may contribute to impaired bone acquisition in pediatric IBD include calcium, vitamin D, vitamin K, and magnesium [38].

Multiple studies have reported that vitamin D deficiency frequently complicates pediatric IBD [39–42]. For example, Pappa et al. examined vitamin D levels in 130 children and young adults with IBD, 94 with Crohn disease, and 36 with ulcerative colitis. The prevalence of vitamin D deficiency (serum 25 (OH) vitamin D concentration ≤ 15 ng/mL) was 34.6%, and the mean serum 25 (OH) vitamin D concentration was similar in patients with Crohn disease and ulcerative colitis, 52.6% lower among patients with dark skin complexion, 33.4% lower during the winter months (December 22 to March 21), and 31.5% higher among patients who were taking vitamin D supplements. Patients with Crohn disease and upper gastrointestinal tract involvement were more likely to be vitamin D deficient than those without it. A similar study reported that 45% of children with IBD had vitamin D levels less than 20 ng/mL [39]. Of note, none of these studies detected a relation between vitamin D levels and spine BMD, as measured by dual energy x-ray absorptiometry (DXA) [39–41]. A recent study by Augustine et al. demonstrated an association between greater inflammatory burden and lower serum 1, 25 (OH) vitamin D concentration and higher PTH levels associated with higher 1, 25 (OH) vitamin D concentrations [43]. The authors suggest that inflammation may lower PTH and thereby decrease renal conversion of 25 (OH) vitamin D to 1,25 (OH) vitamin D.

Bone adapts its strength in response to the magnitude and direction of the forces to which it is subjected. Mechanical forces on the skeleton arise primarily from muscle contraction. This capacity of bone to respond to mechanical loading with increased bone size and strength is greatest during growth, especially during adolescence [44]. Numerous studies have documented the beneficial effect of physical activity and biomechanical loading on bone geometry in healthy children [45–50]. These relationships dictate that studies of bone health in chronic childhood diseases consider the effects of alterations in muscle mass and strength.

Weight-bearing physical activity and biomechanical loading of bone are critical determinants of bone mass in growing normal children [51]. The influence of skeletal loading on bone accretion is illustrated in two exercise trials in healthy children. An easily implemented school-based jumping intervention augmented cortical thickness in the femoral neck of healthy children [52]. A randomized clinical trial of physical activity and calcium supplementation in prepubertal children resulted in a significant, positive interaction between calcium supplements and physical activity in both cortical thickness and cortical area [53]. Harpavat et al. reported that none of the subjects in a small series of children with IBD were participating in weight-bearing physical activities [54]. Werkstetter et al. compared 39 children with quiescent or mild IBD to 39 healthy controls and found decreased physical activity and lean mass in the children with IBD despite no differences in the measurements in quality of life or energy intake [55]. We recently reported that in children with incident Crohn disease, both muscle cross-sectional area and muscle strength are independently associated with cortical section modulus, a summary measure of cortical bone dimension and strength [56]. The reports of decreased lean mass and muscle strength in pediatric IBD suggest that decreased biomechanical loading of the skeleton may contribute to impaired bone accrual in this disorder, but additional studies are needed.

The relations between bone and muscle mass have been demonstrated in multiple studies in children and adolescents with Crohn disease. Burnham et al. reported that Crohn disease was associated with a 0.50 SD deficit (p = 0.006 compared with controls) in whole-body bone mineral content (BMC) relative to height in males, adjusted for age, race, and Tanner stage [8]. Adjustment for whole body lean mass attenuated this deficit to 0.19 SD (p = 0.13 compared with controls). The authors noted that the absence of a bone deficit after statistical adjustment for lean mass does not imply that the bones are normal or adequate. In a similar study, deficits in DXA estimates of femoral neck subperiosteal width were not statistically significant after adjustment for lean mass [57]. Our study of children with newly diagnosed Crohn disease found that cortical section modulus was 6.8% greater than predicted compared to healthy controls, given muscle cross-sectional area and strength deficits [56]. A prospective cohort study using tibia peripheral QCT in children with newly diagnosed Crohn disease reported that muscle mass improved significantly over 1 year following diagnosis, but cortical section modulus worsened significantly [58]. This apparent disconnect between changes in bone and muscle mass over time illustrates the limitations of the functional muscle bone unit paradigm in chronic inflammatory disease. In addition to lean mass and muscle strength, the role of inflammatory cytokines, physical activity, and therapeutic agents on bone outcomes must be further studied.

Glucocorticoids are widely used in the treatment of IBD and impact bone formation and resorption. Decreased bone formation is the primary mechanism for bone loss in glucocorticoid-induced osteopenia [59]. Mesenchymal stems cells, which also give rise to adipocytes, myoblasts and chondrocytes, differentiate into osteoblasts. Glucocorticoids shift the cellular differentiation away from osteoblasts and towards adipocytes, and prevent the termination differentiation of osteoblasts [60]. Osteoblast numbers are decreased further by glucocorticoid-induced increases in osteoblast apoptosis [61]. In addition, glucocorticoids inhibit osteoblast production of bone matrix components [62]. Finally, glucocorticoids suppress the synthesis of insulin-like growth factor-I (IGF-1), a hormone important in bone formation [63]. The cellular response to glucocorticoids also includes an early phase of increased bone resorption, probably a result of the increased expression of receptor activator of nuclear factor-κ-B ligand (RANKL) and decreased osteoprotegerin (OPG) – increased RANKL and decreased OPG both promote osteoclastogenesis, as detailed below [64]. However, typically a more chronic state of decreased bone resorption develops due to loss of cell signaling to osteoclast progenitors and apoptosis [65].

Patients treated with glucocorticoids have an underlying disease, which frequently also carries a risk of osteoporosis. Therefore, the independent effects of glucocorticoids on bone turnover and bone structure during growth are not readily apparent from clinical studies. However, recent animal models demonstrate that glucocorticoid administration during growth resulted in decreased bone formation, decreased bone resorption, reductions in the age dependent increases in trabecular thickness, and reductions in linear growth and accrual of cortical thickness in the femur [66, 67]. These deficits were associated with decreased bone strength in the vertebrae and femur in mechanical testing [66, 67]. Of note, it is unclear if the reductions in femoral cortical thickness were proportionate to the significant reductions in bone length. That is, did the bones have normal cortical thickness and strength relative to the shorter length?

Cellular inflammatory pathways in Crohn disease activate the protean transcriptional regulatory factor nuclear factor-κB with increased production of a variety of cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) [68]. Three groups of cytokines are particularly important in bone physiology: interleukin-6 (IL-6), TNF-α, and IL-1 [64]. Inflammatory cytokines promote osteoclastogenesis and accelerated bone resorption. TNF-α induces the expression of receptor activator of NF-κB ligand (RANKL). RANKL stimulates osteoclast differentiation and activation and inhibits osteoclast apoptosis, thereby dramatically prolonging osteoclast survival and increasing bone resorption [69, 70]. Additionally, TNF-α decreases expression of osteoprotegerin (OPG), a decoy receptor that blocks RANKL [71, 72]. Inflammatory mediators, including IL-1 and IL-6, also increase RANKL secretion and contribute to bone loss [73]. TNF-α also has direct effects on bone formation; it inhibits osteoblast differentiation, inhibits osteoblast collagen secretion, causes increased resorption by inducing osteoblasts secretion of IL-6, and induces osteoblast apoptosis [74, 75]. These effects on bone formation are strikingly similar to the effects of glucocorticoids [59, 60].

DXA is widely accepted as a quantitative measurement technique for assessing skeletal status. DXA scans involve the use of two x-ray beams and measurement of x-ray penetration through bone. The radiation exposure from a conventional DXA examination is less than 10 microsieverts (μSv), while a two-view chest x-ray would be 60 μSv, and a CT exam of the pelvis 5000 μSv [76]. In elderly adults, DXA BMD is a sufficiently robust predictor of osteoporotic fractures that it can be used to define the disease. The World Health Organization criteria for the diagnosis of osteoporosis in adults is based on a T-score, the comparison of a measured BMD result with the average BMD of young adults at the time of peak bone mass [77]. A T-score ≤−2.5 SD below the mean peak bone mass is used for the diagnosis of osteoporosis, and a T-score ≤ −2.5 SD with a history of a low-impact fracture is classified as severe osteoporosis. While the T-score is a standard component of DXA BMD results, it is clearly inappropriate to assess skeletal health in children through comparison with peak adult bone mass. Rather, children are assessed relative to age or body size, expressed as a Z-score. In adults, low impact fractures are defined as fractures that occur after a fall from standing height or less. This definition is often difficult to apply to fractures in children that occur during play or sports activities.

While there are no clear evidence-based guidelines for the definition of osteoporosis in children. The International Society for Clinical Densitometry has suggested that the diagnosis of osteoporosis in children and adolescents should include a history of clinically significant fracture and bone mineral content or density Z-score ≤ 2.0 (adjusted for age, sex, and bone size) [78]. Fractures occur commonly in otherwise healthy children with a peak incidence during early adolescence around the time of the pubertal growth spurt [21]. Faulkner et al. recently reported that peak gains in bone area preceded peak gains in BMC in a longitudinal sample of boys and girls, supporting the theory that the dissociation between skeletal expansion and skeletal mineralization results in a period of relative bone weakness [79]. This may be due to increased calcium demands during maximal skeletal growth.

Several studies have compared the DXA BMD of normal children and adolescents with forearm fractures to that of age-matched controls without fractures. Most [80–84], but not all [85, 86] found that mean DXA BMD was significantly lower in children with forearm fractures than in controls. One study reported that 69% of fractures in healthy children were due to low-energy falls at home [85]; illustrating the difficulties defining low-energy fractures in children. Studies using QCT or metacarpal morphometry to characterize cortical geometry showed that decreased cortical thickness was associated with significantly increased fracture risk [84, 87]. Finally, television, computer, and video viewing had a dose-dependent association with wrist and forearm fractures [88]. A recent prospective cohort study in over 6200 children in the United Kingdom reported a weak inverse relationship between whole body (less head) BMD at 9.9 years of age and subsequent fracture risk [odds ratio (OR) per SD decrease = 1.12; 95% CI, 1.02–1.25] [89]. The association between fracture risk and BMD was much stronger when adjusted for bone and body size; fracture risk was inversely related to BMC adjusted for bone area, height, and weight (OR = 1.89; 95% CI, 1.18–3.04).

These data suggest that low DXA BMD can be a contributing factor for pediatric fracture in healthy children; however, bone geometry and nonskeletal factors such as sports participation, body size, and sedentary activities may have an independent contribution to fracture risk. Importantly, the relationships between DXA BMD, bone geometry, and fracture risk in children with chronic diseases, such as IBD, may be different than those observed in healthy children.

DXA is, by far, the most commonly employed method for the assessment of bone health in children. However, DXA has several limitations that are pronounced in the assessment of children (Table 24.1). A study highlighting the importance of these limitations evaluated children referred for enrollment in a childhood osteoporosis protocol based on low DXA spine BMD and found 80% had at least one error in interpretation of the DXA scan [112]. The most common error was the use of T-scores, and ultimately, only 26% retained the diagnosis of low BMD.

The significant limitation of DXA is the reliance on measurement of areal rather than volumetric BMD. DXA provides an estimate of bone mineral density expressed as grams per anatomical region (e.g., individual vertebrae, whole body, or hip). Dividing the BMC within the defined anatomical region (g) by the projected area of the bone (cm²) then derives “areal-BMD” (g/cm²). This BMD is not a measure of volumetric density (g/cm³) because it provides no information about the depth of bone. Bones of larger width and height also tend to be thicker. Since bone thickness is not factored into DXA estimates of BMD, reliance on areal-BMD inherently underestimates the bone density in individuals with short stature. Despite identical volumetric bone density, the child with smaller bones appears to have a mineralization disorder (decreased areal-BMD). This is clearly an important artifact in children with chronic diseases, such as IBD, that are associated with growth delay and short stature [113]. An analysis by Zemel et al. found that adjustment of age-specific BMC and BMD z-scores for age-specific height Z-scores were the least biased methods to correct for the confounding effect of height [114].

The confounding effect of skeletal geometry on DXA measures is now well recognized and multiple analytic strategies have been proposed to express DXA bone mass in a form that is less sensitive to differences in skeletal size [95, 96, 115–117]. The technique developed by Carter et al. is based on the observation that vertebral BMC scaled proportionate to the projected bone area to the 1.5 power [115]. Therefore, vertebral volume is estimated as (area)^1.5 and bone mineral apparent density (BMAD) is defined as BMC/(area)^1.5. Kroger et al. proposed an alternative estimate of vertebral volume: the lumbar body is assumed to have a cylindrical shape and volume of the cylinder is calculated as (π)(radius²)(height), which is equivalent to (π)((width/2)²)(area/width) [118, 119]. This approach was validated by comparison with MR measures of vertebral dimensions in 32 adults [116]; DXA-derived volumetric BMD correlated moderately well with BMD based on MR-derived estimates of vertebral volume (R = 0.665). Although these methods provide estimates of vertebral volume, the BMC includes the bone content of the superimposed cortical spinous processes.

A study by Wren et al. sought to evaluate the usefulness of DXA spine correction factors based on published geometric formula and anthropometric parameters, compared with three-dimensional QCT [120]. Subject height, weight, body mass index, skeletal age, and Tanner stage were assessed in 84 healthy children. While DXA and QCT measures of BMC were highly correlated (r ² = 0.94), DXA areal BMD only moderately correlated with CT volumetric BMD (r ² = 0.39), illustrating the potential confounding effects of bone size on DXA areal BMD. The correlations between QCT volumetric BMD and DXA estimates were particularly poor for subjects in Tanner stages 1–3 (r ² = 0.02 for areal BMD), but multiple regression accounting for the anthropometric and developmental parameters greatly improved the agreement between the DXA and CT densities (r ² = 0.91). These results suggest that DXA BMC is a more accurate and reliable measure than DXA BMD for assessing bone acquisition, particularly for prepubertal children and those in the early stages of sexual development. Use of DXA BMD would be reasonable if adjustments for body size, pubertal status, and skeletal maturity are made, but these additional assessments add significant complexity to research studies, and to clinical interpretation.

An additional shortcoming of DXA is that the integrated measure of bone mass in a given projected area does not allow distinction between cortical and trabecular bone. DXA-based measures provide no information on bone architecture and are limited in their usefulness to differentiate the spectrum of bone accrual during growth.

Comparisons to appropriate pediatric reference data are essential to describe accurately the clinical impact of childhood disease on bone development, to monitor changes in bone mineralization, and to identify patients for treatment protocols. Multiple sources of pediatric DXA reference data are now available for the calculation of DXA z-scores. These include varied approaches, such as gender-specific centile curves, age- and height- specific means and standard deviations, Tanner- and weight-specific percentiles, age-, sex-, weight- and height- adjusted curves, and Z-score prediction models [95–108]. Differences in reference data have a significant impact on the diagnosis of osteopenia in children with chronic disease [109]. For example, the use of reference data that are not gender-specific results in significantly greater misclassification of males as osteopenia [109]. In addition, the use of published pediatric reference ranges has been complicated by differences in scanner manufacturers, and frequent changes in hardware and software technology, including fan-beam technology, low-density software analysis modes and specialized pediatric software. These technical changes result in clinically significant alterations in DXA results [92]. The use of adequate reference data and validated classification schemes is important in the study of bone health in children.

A three-dimensional structural analysis of trabecular architecture and cortical bone dimensions can be obtained by computed tomography (CT). This technique offers an opportunity to overcome the limitations of two-dimensional imaging with DXA and advance our understanding of bone mineralization in children. CT provides an image unobscured by overlying structures [121]. The CT attenuation of different bone tissues provides quantitative information, referred to as quantitative CT (QCT). In contrast to DXA, this technique describes authentic volumetric BMD (vBMD), accurately measures bone dimensions, and distinguishes between cortical and trabecular bone. In order to minimize radiation exposure, special high-resolution scanners were developed for the peripheral skeleton (pQCT), specifically, the radius or tibia. The distal site is largely trabecular bone, while the mid-shaft is almost entirely cortical bone. The volume of each component is calculated from the scan thickness and cross-sectional area, and the density by attenuation of the x-ray beam. Bone strength can also be estimated by pQCT from the total bone area, and cortical thickness and density [122]. QCT studies of bone mineral accretion and bone strength demonstrated gender, maturation, and ethnic-specific patterns of development of bone strength during childhood and adolescence [123]. A study longitudinal in children with Crohn disease comparing QCT measured vBMD versus DXA-derived measures of BMD demonstrated greater BMD deficits at diagnosis and greater improvements over 12 months with the PQCT vBMD approach [124].

Numerous studies have reported decreased DXA BMD in children with IBD [39]. However, as detailed above, DXA studies are frequently confounded by disease effects of growth. For example, two studies reported that DXA BMD for age Z-scores were significantly correlated with height for age Z-scores in children with IBD [39, 125]. Furthermore, expression of DXA results as BMAD (an estimate of volumetric BMD) eliminated the correlation with height Z-scores [125]. Another study addressed the confounding effect of short stature by expressing the spine DXA results as percent predicted BMC for bone area for age and gender in 73 children with Crohn disease or ulcerative colitis [126]. The percent predicted bone area for age and gender was decreased in IBD, compared with controls, consistent with shorter stature. While the median BMD for age and gender Z-score was significantly decreased in IBD (mean Z-score in spine = −1.6, in whole body = −0.9), the percent predicated BMC for bone area, age, and gender was normal. The authors concluded that children with IBD have small bones for age due to growth retardation, but adequate bone mass relative to bone size. Finally, Herzog et al. reported that BMD Z-scores were less than −2.0 in 44% of children when expressed relative to chronologic age, but were less than −2.0 in only 26–30% when expressed relative to bone age of height age [127].

The above studies illustrate the varied approached used to adjust for the confounding effects of poor growth. Leonard et al. reported that whole body BMC relative to height predicted bone strength (estimate by stress-strain index) as measured by QCT [117]. From the same group, Burnham et al. assessed whole body BMC, lean mass and fat mass (as measured by DXA) relative to height in 104 children and young adults with established Crohn disease, and 233 healthy controls, 4–26 years of age. The studies demonstrated significant bone and muscle deficits [8, 128]. Individuals with Crohn disease had significantly lower height-for-age, body mass index (BMI)-for-age, and whole body lean mass-for-height Z-scores than healthy controls (all p < 0.001). Table 24.2 summarizes four sequential models in males and females. The least adjusted models assessed whole body BMC in Crohn disease, compared with controls, adjusted for age and race, and revealed substantial deficits. Assessment of BMC without consideration of the decreased skeletal size for age in subjects with Crohn disease group may overestimate bone deficits. Accordingly, the second model was also adjusted for height. Figure 24.3 demonstrates that the marked BMC deficits relative to age (A) are less pronounced when assessed relative to height (B). Adjustment for height attenuated the Crohn disease effect in the multivariate regression model; however, significant BMC deficits persisted in males and females with Crohn disease, compared with controls. In the third model in Table 24.2 Tanner stage was added to determine if delayed pubertal maturation for age contributed to the decreased BMC in Crohn disease. Adjustment for delayed pubertal maturation did not appreciably change the estimate of BMC deficits in Crohn disease. The fourth and final model, adjusted for lean mass, eliminated significant BMC deficits in Crohn disease.

None of the glucocorticoid measures were significantly correlated with BMC-for-height Z-scores. However, height Z-score was negatively and significantly associated with duration of glucocorticoid therapy (r = −0.24, p = 0.02), and cumulative (mg/kg) glucocorticoids (r = −0.36, p < 0.001). Parenteral nutrition, isolated upper tract disease, hypoalbuminemia, nasogastric feeding, and decreased BMI Z-scores were associated with decreased BMC-for-height Z-scores, but these factors have the potential to be confounded by greater disease severity. Whereas BMC and BMD Z-scores for age may overestimate bone deficits, bone Z-scores for height have the potential to underestimate bone deficits. This can occur because children and adolescents with IBD may be of more advanced pubertal status than their comparators of similar height. As such, adjusting age-specific BMD or BMC z-scores for age-specific height Z-scores may be a more accurate approach [114].

Over 90% of the children and young adults in the prior study had a history of glucocorticoid exposure; therefore, it was not possible to distinguish between disease and glucocorticoid effects on bone. The impact of the underlying IBD process is best assessed in subjects with newly-diagnosed disease. The largest study of DXA BMD in newly diagnosed subjects was reported by Gupta et al. [129]; however, the study was complicated by the observation that BMD was markedly decreased in controls, compared with the DXA reference database. Overall, DXA spine BMD was comparable in the 41 children with ulcerative colitis and the controls, while results were significantly lower in the 82 subjects with Crohn disease. Laakso et al. reported on a longitudinal study of children and adolescents followed over a median of over 5 years and found greater lifetime glucocorticoid exposure to be associated with lower lumbar spine BMD [130]. The authors conclude that the findings may likely reflect both glucocorticoid effect and glucocorticoid exposure as a surrogate of more severe disease. In steroid-sensitive nephrotic syndrome, a condition without underlying inflammation but involving glucocorticoid therapy, no deficits in bone mineral content are seen, but this may be related to the increase in skeletal loading associated with increases in BMI [131]. This demonstrates the complex interaction between medication exposures, side effects of therapy, and underlying disease pathophysiology.

Walther et al. recently compared lumbar spine BMAD Z-scores in 34 steroid-naïve and 53 steroid-treated children with IBD in order to obtain information about the influence of non-steroidal factors [125]. Overall, 56 had Crohn disease and 30 had ulcerative colitis. Reference data were obtained in 52 controls. The mean BMAD Z-scores in the subjects with Crohn disease were −0.76 ± 1.25 in females and −0.79 ± 0.92 in males. The mean BMAD Z-scores in the subjects with ulcerative colitis were −0.30 ± 0.75 in females and −1.08 ± 1.23 in males. Among the steroid-naïve subjects, the duration of treatment ranged from 0 to 8 years, but the majority (approximately 80%) were within the first 5 weeks of therapy. Among the steroid treated subjects, the cumulative steroid exposure averaged 4600 mg (range 0.05–25,000 mg) over the treatment duration of several days to 7.6 years. The mean BMAD Z-scores were comparable in steroid-naïve (−0.74 ± 1.08) and steroid-treated (−0.66 ± 1.08) subjects. The 19 subjects that had been treated with calcium and/or vitamin D supplements were all within the steroid-treated group. The study is limited by the small number of controls and the lack of data on disease activity between the steroid-naïve and steroid-treated groups. Nonetheless, these data demonstrate bone deficits in the absence of steroid therapy. The studies listed above were all based on DXA estimates of BMC and BMD and did not distinguish between cortical and trabecular bone.

Sylvester examined DXA BMD and bone biomarkers in 23 children with newly diagnosed Crohn disease [132]. Although BMD Z-scores did not differ between Crohn disease subjects and controls in this small sample, bone biomarkers were significantly lower in Crohn disease. This may be due to reduced bone remodeling, or reduced growth velocity. Importantly, activated T cells produced greater concentrations of interferon-γ, which may contribute to lower bone turnover.

Dubner et al. performed tibia pQCT in 78 CD subjects (ages 5–18 year) at diagnosis and followed them for 12 months [58]. At diagnosis, CD subjects had significant deficits in trabecular vBMD (Z-score: −1.32 ± 1.32, p < 0.001), section modulus (a summary measure of cortical bone dimensions and strength) (−0.44 ± 1.11, p < 0.01), and muscle cross-sectional area (−0.96 ± 1.02, p < 0.001), compared with controls. Over the first 6 months, trabecular vBMD and muscle Z-scores improved significantly (both p < 0.001); however, section modulus worsened (p = 0.0001) and all three parameters remained low after 1 year. Improvements in muscle were associated with improvements in section modulus and improvements in trabecular vBMD were greater in prepubertal subjects. Werkstetter et al. in a longitudinal study using forearm pQCT of 102 pediatric IBD patients (82 CD, 30 newly diagnosed) showed similar findings at diagnosis and median follow-up interval of 2.6 (0.9–5.8) years [133]. A study from Sweden following children with IBD over 2 years. At baseline, subjects had mean disease duration of 41.3 months and mean lumbar spine BMD Z-score of −0.9 ± 2.8 and this did not change significantly over the 2 year [134]. The authors note that corticosteroid and azathioprine exposures were not significantly associated with changes in BMD. Whereas the role of anti-TNF-alpha agents was not evaluated in the study from Sweden, Griffin et al. described the changes occurring over 12 months using QCT in children and adolescents initiating therapy with anti-TFN-alpha [135]. In this study, 74 subjects with median disease duration of 2.1 years (range 0.2–9.7) had baseline trabecular BMD Z-score −1.44 ± 1.11, cortical BMD Z-score 0.19 ± 1.08, and cortical area Z-score −0.97 ± 1.35. After 12 months, trabecular BMD and cortical area increased significantly (0.45 ± 0.76 and 0.29 ± 0.65, respectively, both p < 0.001), but cortical BMD decreased. Bone biomarkers were significantly increased over the first 10 weeks of anti-TNF therapy and the authors hypothesize that the decline in cortical BMD is a consequence of rapid increase in periosteal bone formation necessary in catch-up growth. This study highlights the value of QCT distinction of cortical versus trabecular bone and also demonstrates the role of anti-TNF-alpha therapy in the bones of children with IBD.

Finally, the impact of childhood IBD on peak bone mass and risk of osteoporosis is not yet clear but has been described. Bernstein et al. assessed spine, proximal femur, and whole body BMD in 780 premenopausal adult women (age < 45 year) that were diagnosed with IBD prior to 20 years of age [136]. The mean BMD T-scores were normal in the spine (−0.14 ± 1.05), femoral neck (−0.15 ± 1.04) and whole body (0.09 ± 1.04) and results did not differ between the 12 subjects with disease onset before puberty, and the 58 subjects with disease onset after puberty. Alternatively, Azzopardi et al. recently described 83 adult subjects with Crohn disease and found that age of diagnosis <17 years was significantly associated with lower BMD (p = 0.0006) [137].

Physical activity is an important determinant of bone mass accretion during growth; simple loading exercises promote bone accretion in healthy children. Numerous studies have documented the beneficial effect of physical activity and biomechanical loading on bone geometry in healthy children [45–47, 49, 50, 138]. Bone adapts its strength in response to the magnitude and direction of the forces to which it is subjected. This capacity of bone to respond to mechanical loading with increased bone size and strength is greatest during growth, especially during adolescence [44]. Physical activity affects the skeleton via two distinct mechanisms, which function as osteogenic stimuli: (1) “muscle pull” involves the force of contracting muscles upon their bony attachments and (2) weight-bearing exercise results in the mechanical loading of the bone with compressive forces. A physical intervention trial in adults with CD utilizing a home-based program of low-impact dynamic muscle conditioning exercises did not show a statistically significant difference in bone mineral density of the lumbar spine and hip between cases and controls; however, analyses limited to those subjects achieving 100% adherence to the program did show a significant increase in trochanteric BMD [139]. A recent systematic review on the influence of physical activity on bone strength in children and adolescents concluded that physical activity has a significant positive impact on bone strength in the growing skeleton (36/37 studies) and that weight-bearing activity specifically enhances bone strength [140]. These findings were in healthy children, and the potential for physical activity to modulate the relationship between disease and bone metabolism will require further study. Based on existing evidence, a program consisting of resistance training (muscle-building) activity in addition to high-impact weight-bearing activity may result in positive impacts on skeletal health.