title: Impact of therapeutic strategies on linear growth and bone health in children with Crohn's Disease
Creators: name: Altowati, Mabrouka M.A.
Publisher: name: University of Glasgow
Year: 2017
Subjects: subject: Linear growth, bone health, children with Crohn's Disease, therapeutic strategies.

description: Growth retardation and impaired bone health are common complications of paediatric inflammatory bowel disease (IBD), especially Crohn's disease (CD). Aetiology may include undernutrition, inflammatory impact on the hormonal growth axis, delayed puberty, the effect of drugs such as glucocorticoids (GC) and low muscle mass. Despite an increase in our knowledge of its pathogenesis, growth retardation and impaired bone health remain common problems for children with CD. Control of disease activity and minimizing the need for GC therapy are necessary measures to facilitate normal growth. However, in many cases these strategies are not sufficient and data on the role of adjuvant therapy with recombinant human growth hormone (rhGH) remain scarce. Moreover, currently there is conflicting evidence on the benefit of anti-tumour necrosis factor-α (anti-TNF-α) on bone health and there are no reports on the effect of rhGH therapy on bone health in children with CD. To address this knowledge gap, this thesis studied the hypothesis that successful treatment of inflammation with anti-TNF-α would improve linear growth and bone health in children with CD. Additionally, a further objective was to examine the role of adjuvant therapy with rhGH on linear growth and bone health in children with quiescent CD. A prospective study was first carried out to assess the effect of 12-months anti-TNF-α therapy on linear growth, the growth hormone (GH)-insulin like growth factor (IGF) axis, and bone turnover. The results showed that other than depressed acid label subunit (ALS), markers of GH axis were not particularly abnormal in the majority. Bone turnover markers were also low at baseline. With therapy and improvement in disease, patient height was modestly improved in those with growth potential, and this was associated with increased bone formation but no clear change in markers of the GH-IGF axis. These findings suggest that if growth is of concern then adjuvant therapy combined with other forms of growth-promoting therapy during critical periods of growth warrants further exploration. Further prospective analyses were conducted in this cohort to examine the effects of anti-TNF-α therapy on bone density and structure, at the time of, and 12 months after initiation of treatment and also to explore the association of IGF-1 axis, cytokines and muscle with bone density in children with CD. These results indicated that although anti-TNF-α therapy was associated with an improvement in disease activity and bone formation, there was insufficient evidence, as assessed by imaging, to show a change in bone health. The observed persistent bone impairment could be related to two possible factors. Firstly, there is a potential lag between growth and bone formation, and secondly, persistent muscle deficit may partly explain the poor bone health seen in CD. These findings suggest that the anti-TNF-α therapy may not be sufficient for improving musculoskeletal development in children with CD and the role of adjuvant therapy such as nutrition, exercise or manipulation of the GH/IGF axis requires further investigation. A subsequent analysis was conducted to investigate the effects of 24-months rhGH (67mg/kg/day) therapy on linear growth and insulin sensitivity in 14 children with CD, compared to an equal number of historical controls, matched for age, gender and duration of disease. The results of this analysis demonstrated that the growth-promoting effect of rhGH in children with CD, that were previously observed over a period of 6 months, is sustained over a longer period without a deleterious effect on glucose homeostasis. Improved growth with rhGH therapy was sustained over a two-year period, justifying the need for a randomised clinical trial (RCT) of this therapy. Close monitoring of glucose homeostasis is still recommended with the use of rhGH in children with CD and growth retardation. Chapter 5 explores a preliminary analysis of the effect of adjuvant therapy with high dose rhGH therapy for 24 months on bone health and body composition by DXA in 8 children with inactive/quiescent CD. The results showed that despite increases in the biomarkers of bone turnover with most children having completed pubertal growth, deficiency in bone mineral density persists. This finding may be explained by partial recovery of the GH-IGF-1 axis and/or decreased muscle mass. These results also underscore the importance of muscle mass for bone health in CD children. A final set of analyses were performed in a survey conducted to examine the feasibility of a RCT of injectable forms of growth-promoting therapy; and to survey the attitudes of children with CD and their parents to it. The results of this survey showed that by approaching shorter children with CD, as well as alleviating their fears about injections, a future trial would be more likely to achieve higher recruitment rates. In summary, the body of work presented in this thesis depicted that anti-TNF-α therapy is associated with a modest clinical improvement in height but no observable beneficial effect on musculoskeletal health. The use of high dose rhGH therapy for 24 months was associated with growth-promoting effects but with no discernible influence on bone and body composition. Muscle deficit may partly explain the poor bone health seen in CD.