Crohn's disease and growth deficiency in children and adolescents

Table 2 Summary of the main studies that were reviewed on growth issues and bone health in pediatric Crohn’s disease

Ref.	Type of study	Patients	Results	Conclusion
Abraham et al[21] J Clin Gastroenterol 2012	Systematic review	3505 CD, 2071 UC, and 461 IBD-U (age at onset < 18 yr)	Growth failure was reported in CD (10% and 56%) more often than UC (0%-10%) or non-IBD controls; Improvements in growth occurred after surgical resection in CD pts; Increase in disease reclassification over time from UC and IBD-U Dg to CD; CD pts had higher number of hospitalizations and hospital days per year vs UC pts in most studies; The reported surgery rates in CD ranged between 10% and 72%; the colectomy rates in UC ranged between 0% and 50%	Childhood-onset IBD pts had growth failure reported in pts with CD more often than those with UC, and had a reclassification of disease type to CD over time; Higher rates of surgery and hospitalizations were found with CD than with UC
Kim et al[45] Clin Endosc 2013	Prospective cohort study	44 IBD (21 aged < 30 yr; 23 aged > 30 yr)	Significant bone mass reduction at the LS in IBD patients aged < 30 yr vs patients aged > 30 yr (BMD P < 0.01; T-score P < 0.01; Z-score P < 0.01); Multivariate analysis: risk factor of bone mass reduction for patients < 30 yr → HR = 3.96, P = 0.06	Bone mass reduction is more severe in patients diagnosed with IBD before the age of 30 yr
Schmidt et al[51] J Pediatr Gastroenterol Nutr 2012	Longitudinal cohort study	144 IBD pts 83 UC, 45 CD	Children with UC and CD had significantly lower mean BMD Z-scores for the LS at baseline and after 2 yr; The reduction in BMD was equally pronounced in patients with UC and CD; Neither group improved their Z-score during the follow-up period; Significantly lower mean BMD Z-scores for the LS were found at baseline in M (P  <  0.001), but not in F; Lowest BMD values in the group of patients ages 17 to 19 yr in M and in F	The entire group of pediatric patients with IBD showed permanent decreases in their BMD Z-scores for the LS; however, afflicted children have the potential to improve their BMD by the time they reach early adulthood
Tsampalieros et al[53] J Clin Endocrinol Metab 2013	Prospective cohort study	CD (age 5-21)	Disease activity improved over the study interval (P < 0.001); Trabecular BMD-Z improved over the first 6 mo; Increases associated with improved disease activity (P < 0.001), younger age (P = 0.005), and increases in vitamin D levels (P = 0.02); Greater increases in tibia length associated with greater increases in cortical area-Z (P < 0.001); Greater glucocorticoid doses and disease activity significantly associated with failure to accrue cortical area, and more pronounced with greater linear growth (interaction P < 0.05); Mean ± SD trabecular BMD and cortical area Z-scores significantly reduced at the final visit	CD was associated with persistent deficits in trabecular BMD; Younger participants demonstrated greater potential for recovery; Greater linear growth associated with greater recovery of cortical dimensions, especially among participants with lesser glucocorticoid exposure and inflammation; Younger age and concurrent growth provide a window of opportunity for skeletal recovery
Malik et al[54] J Crohns Colitis 2012	Prospective cohort study	36 children with CD (Male 22)	28 (78%) CD children treated with adalimumab went into remission; Overall 42% of children showed catch-up growth, which was more likely in: Pts who achieved remission (P = 0.007); Pts who were on immunosuppression (P = 0.03); Pts whose indication for adalimumab was an allergic reaction to infliximab (P = 0.02); Pts who were on prednisolone when starting adalimumab, (P = 0.04)	Clinical response to adalimumab is associated with an improvement in linear growth in a proportion of children with CD; Improved growth is more likely in patients entering remission and on immunosuppression but is not solely due to a steroid sparing effect
Malik et al[55] Arch Dis Child 2012	Retrospective cohort study	116 CD children; 68 M; Mean age at diagnosis 10.8 yr (range 4.9-15.5); Mean age at maximum follow-up of 15.4 yr (9.4-19.3)	At T0, mean height SD score was -0.5 (-3.3-2.6) compared to a mid-parental mean height SD score of 0.2 (-2.0-1.4) (P = 0.002); At T1, T2, T3, and maximum follow-up, mean height SD score was -0.6 (-4.8-7.8), -0.6 (-2.9-2.2), -0.7 (-3.6- 2.5) and -0.5 (-3.5-2.9), respectively; Mean Ht velocity SDS at T1, T2, T3 and maximum follow-up was -1.4 (-7.4-7.4), -0.6 (-7.5-6.1), -0.1 (-6.6 -7.6) and 0.6 (-4.8-7.8), respectively (P < 0.05)	In final models: Mean Ht velocity SDS was associated negatively with the use of prednisolone (P = 0.0001), azathioprine (P = 0.0001), methotrexate (P = 0.0001), and weight SDS (WtSDS) P = 0.0001); Mean Ht velocity SDS was associated positively with age (P = 0.0001) and Wt SDS (P = 0.01); ΔHt SDS was associated negatively with use of prednisolone (P < 0.02)
Laakso et al[56] Calcif Tissue Int 2012	Cross-sectional Cohort Study	80 IBD pts (median age 14.9 yr, range 5-20), median disease duration 3.4 yr; 51 UC, 26 CD, and 3 IBD-U	IBD pts had lower bone age-adjusted LS and whole-body areal BMD (P < 0.001 for both) and whole-body composition adjusted for Ht (P = 0.02) than controls; Lean mass and fat mass Z-scores did not differ between the groups, but IBD patients had lower whole-body composition relative to muscle mass (P = 0.006); Vitamin D deficiency in 48%, despite vitamin D supplementation; In IBD cumulative weight-adjusted prednisolone dose > 150 mg/kg for the preceding 3 yr increased the risk for low whole-body areal BMD (OR = 5.5, 95 %CI: 1.3-23.3, P = 0.02). Vertebral fractures found in 11% of patients and in 3% of controls (P = 0.02)	IBD in childhood was associated with low areal BMD and reduced bone mass accrual relative to muscle mass; The risk for subclinical vertebral fractures may be increased; Careful follow-up and active preventive measures are needed
Ahmed et al[60] J Pediatr Gastroenterol Nutr 2004	Prospective cohort study	47 CD and 26 UC (median age of 13.5 yr - range, 5.5-18.2 yr)	Pts with CD were shorter than those with UC (P < 0.05); Median ppBone Area for LS and total body for the whole group was 85% and 81%, respectively; ppBone Area at both sites was directly related to height SDS and BMI SDS (r > 0.5; P < 0.005); Median BMD SDS for LS and total body was -1.6 and -0.9, respectively; Median ppBMC for LS and total bone was 98% and 101%, respectively; ppBMC showed no relationship to ppBone Area (r = 0.1, NS); Children with osteopenia 22% after adjustment for bone area	Children with IBD often have small bones for age because they have growth retardation; When DXA data are interpreted with adjustment for bone size, most children have adequate bone mass; Correct interpretation of DXA is important for identifying children who may be at a real risk of osteoporosis
Burnham et al[61] J Bone Miner Res 2004	Prospective cohort study	104 children and young adults with CD 233 healthy controls (age 4-26)	CD pts had significantly lower Ht Z-score, BMI Z-score, and lean mass relative to Ht compared with controls (all P < 0.0001); After adjustment for group differences in age, Ht, and race, the ratio of BMC in CD relative to controls was significantly reduced in M (0.86; 95%CI: 0.83-0.94) and F (0.91; 95%CI: 0.85-0.98) with CD; Adjustment for pubertal maturation did not alter the estimate; addition of lean mass to the model eliminated the bone deficit; Steroid exposure was associated with short stature but not bone deficits	Importance of considering differences in body size and composition when interpreting DXA data in children with chronic inflammatory conditions; Association between deficits in muscle mass and bone in pediatric CD
Boot et al[62] Gut 1998	Prospective cohort study	55 pts (34 M 21 F, age range 4-18 yr) 22 CD, 33 UC	Mean SDS of LS BMD and total body BMD were significantly lower than normal (-0.75 and -0.95, both P < 0.001); Height SDS and BMI SDS were decreased. The decrease in BMD SDS could not be explained by delay in bone maturation; The cumulative dose of prednisolone correlated negatively with LS BMD SDS (r = -0.32, P < 0.02); BMI SDS correlated positively with total body BMD SDS (r = 0.36, P < 0.02); CD pts had significantly lower LS and total BMD SDS than UC pts, even after adjustment for cumulative dose of prednisolone; In the longitudinal data cumulative dose of prednisolone between the measurements correlated negatively with the change in LS and total BMD SDS; Lean tissue mass measured by dual X-ray absorptiometry had a strong correlation with lean body mass measured by bioelectrical impedance analysis (r = 0.98)	IBD children have a decreased BMD; CD children have a higher risk of developing osteopenia than UC children; Corticosteroid therapy and nutritional status are important determinants of BMD in IBD pts

Dg: Diagnosis; pt/pts: Patient/patients; CD: Crohn’s disease; UC: Ulcerative colitis; IBD-U: Unclassified IBD; rhGH: Recombinant growth factor; ESR: Erythrocyte sedimentation rate; BMC: Body cell mass; BMI: Body mass index; Ht: Height; Wt: Weight; BMD: Bone mineral density; DXA: Dual-energy X-ray absorptiometry; EEN: Exclusive enteral nutrition; GH: Growth hormone; (P)CDAI: (Pediatric) Crohn’s disease activity index; PUCAI: Pediatric ulcerative colitis activity index; M: Male; F: Female.