INVITED REVIEW

Endocrine and metabolic manifestations
in inflammatory bowel disease

Stelios Tigas, Agathocles Tsatsoulis

University of Ioannina, Greece

Department of Endocrinology, University of Ioannina, Greece

Conflict of Interest: None

Correspondence to: Stelios Tigas, MD, PhD, MRCP,
Dept of Endocrinology, University of Ioannina,
Ioannina 45110, Greece,
Tel: +30 26510 08089, Fax: +30 26510 08098,
e-mail: stigas@cc.uoi.gr

Received 7 September 2011; accepted 5 December 2011

Abstract

Extraintestinal manifestations from nearly every organ system are common in inflammatory bowel disease (IBD). This review article describes the epidemiology, pathogenesis, diagnosis and management of the main endocrine and metabolic manifestations in IBD, including metabolic bone disease, growth retardation, hypogonadism, pubertal delay, lipid abnormalities and insulin resistance. These clinical problems are commonly interrelated and they share a common basis, influenced by disease-related inflammation and nutritional status. In addition to nutritional support, every effort should be made to achieve and maintain disease remission, thus correcting the underlying chronic inflammation. The criteria for screening and diagnosing osteoporosis are described and treatment options are discussed (lifestyle advice, vitamin D and calcium supplementation, use of bisphosphonates or other specific antiosteoporotic agents, correction of hypogonadism). Chronic glucocorticoid therapy may affect growth as well as predispose to osteoporosis. The diagnosis and management of growth failure, pubertal delay and hypogonadism in IBD are discussed.

Keywords Inflammatory bowel disease, osteoporosis, growth failure, hypogonadism, lipids, insulin resistance

Ann Gastroenterol 2012; 25 (1): 37-44

Introduction

The two main forms of inflammatory bowel disease (IBD) are ulcerative colitis (UC) and Crohn’s disease (CD). These disorders are characterized by chronic inflammation of the gastrointestinal (GI) tract and are defined by clinical, endoscopic, pathological and radiographic features [1]. UC and CD commonly follow a relapsing and remitting course and share a number of clinical features such as diarrhea, rectal bleeding and abdominal pain. Accumulating evidence shows that IBD results from an inappropriate inflammatory response to intestinal microbes in genetically susceptible individuals [2]. The inflammation in UC is limited to the mucosa of the large intestine, typically beginning in the rectum and occasionally extending proximally to the sigmoid colon in a continuous fashion or, less commonly, to the entire colon (pancolitis). In contrast, the inflammation in CD involves all layers of the bowel wall and although the disease most commonly affects the terminal ileum and the large bowel, any part of the GI tract from mouth to anus may be affected, not necessarily in a continuous way [1].

Extraintestinal manifestations from nearly every organ system are frequent in IBD, occurring in 20-40% of patients [3,4]. Systems commonly involved are the skin, musculoskeletal system and eyes, but the hepatopancreatobiliary, nervous, cardiovascular, renal and respiratory systems may also be affected [4-8]. This article reviews the endocrine and metabolic manifestations of IBD focusing on their epidemiology, pathogenesis, as well as their diagnosis and management by the practicing physician.

Metabolic bone disease

Epidemiology and pathogenesis

The reported prevalence of osteoporosis (defined as T-score <-2.5) in patients with established IBD varies widely from 17 to 41% [9-11] with an overall prevalence of 15% [10]. The prevalence of osteopenia (T-score -1 to -2.5) varies from 22 to 67% [9]. The variation in prevalence rates is a result of differences in population characteristics, age, disease duration, dual energy x-ray absorptiometry (DXA) methodology and study design. Patients with IBD have an estimated 40% higher risk of fracture compared to the general population that increases further with age [10], or if asymptomatic vertebral fractures are taken into account [12].

The causes of reduced bone mineral density (BMD) in IBD are multifactorial; apart from the common risk factors such as age, smoking and low body mass index (BMI), other factors are glucocorticoid (GC) use, nutritional deficiencies including vitamin D and K, malabsorption of calcium, hypogonadism and finally, disease-related chronic inflammation (Table 1) [13]. In addition to reducing bone formation and increasing bone resorption, GCs have been shown to reduce absorption of calcium in the small intestine and increase excretion of calcium by the kidneys. Vertebral fractures (often asymptomatic) may affect 30-50% of patients on chronic GC therapy; the risk of bone loss and fractures is already considerable in the first few months of therapy due to a phase of early accelerated bone resorption which is then followed by a more progressive phase of impaired osteoblastogenesis. Although fracture risk increases with larger doses and prolonged length of GC treatment, fractures may occur at prednisone equivalent doses as low as 2.5 – 7.5 mg daily [14,15]. Since patients with more severe or active disease are more likely to receive GC treatment, it is difficult to estimate the relative contribution of (a) GC therapy or (b) disease-related inflammation, on BMD.

Vitamin D levels are lower than those of healthy individuals in adult and pediatric patients with IBD [16]. The prevalence of vitamin D deficiency (defined as serum 25-OH vitamin D concentration of ≤15 ng/mL) ranges from 22 to 70% for CD, and up to 45% for UC [16]. The reasons for the reduced vitamin D levels include impaired absorption (especially in CD patients who had small bowel resection) [17], reduced intake [18], lack of exposure to sunlight, altered metabolism [19] and loss through the GI tract when protein-losing enteropathy develops [16]. Serum and bone levels of vitamin K (a cofactor in the carboxylation of osteocalcin, a protein essential for calcium binding to bone) are reduced in patients with IBD and are inversely related to the rate of bone resorption in CD [20,21]. Vitamin K deficiency in IBD may be due to malabsorption or alterations in vitamin K-producing bacterial flora. Finally, calcium absorption may be impaired in IBD patients with steatorrhea, because of calcium binding to intraluminal fat. As a result, patients are predisposed to hyperoxaluria and renal stones, since calcium normally binds oxalate in the lumen facilitating oxalate extraction. When free intraluminal calcium is decreased as a result of steatorrhea, oxalate absorption increases [22].

Although it is clear that all factors described above contribute to osteoporosis in IBD, there are a number of patients with reduced BMD or osteoporosis who have adequate vitamin D levels and were never treated with GCs [23]. These observations, together with evidence from studies in experimental animals [24] suggest that disease-related chronic inflammation may play a role in the development of osteopenia or osteoporosis in adult and pediatric [25] IBD patients. It is possible that cytokines such as interleukin (IL)-6, IL-1 and tumor necrosis factor alpha (TNF–α), directly impair bone metabolism by increasing bone resorption. Interestingly, treatment with infliximab, an anti-TNF agent, has been shown to improve markers of bone metabolism and BMD in IBD patients [26].

Recent evidence suggests that alterations in the RANKL (receptor activator of nuclear factor kappa-B ligand): OPG (osteoprotegerin) ratios may be implicated in IBD-related bone loss [9,27].

Diagnosis and evaluation

Osteoporosis can be diagnosed either when there is a history or evidence of fragility fractures (regardless of BMD), or according to the BMD as measured by DXA. The American Gastroenterological Association recommends DXA screening of IBD patients with one or more risk factors for osteoporosis and fracture: history of previous fragility fracture, postmenopausal, male >50 years, corticosteroid therapy for more than 3 months, or hypogonadism [10]. The British Society of Gastroenterology (BSG) recommends DXA screening of IBD patients with continuing active disease, weight loss >10%, body mass index <20 kg/m2, age >70 years, and those <65 years requiring corticosteroids for >3 months [28]. BMD can be expressed as the number of standard deviations (SD) above or below either the mean BMD for young adults (T-score) or the mean BMD for age-matched controls (Z-score). According to the World Health Organization (WHO), osteoporosis in peri- and post-menopausal women or men >50 years of age can be defined as a T-score at the spine or hip of <-2.5 SD [29]. A T-score of between -1 and -2.5 is defined as osteopenia. For premenopausal women or men <50 however, Z-scores, not T-scores should be used; a Z-score ≤-2.0 should be interpreted as “below the expected range for age” [30]. If BMD is within the normal range, DXA should be repeated in 2-3 years’ time. In patients with abnormal BMD measurements, further clinical and laboratory evaluation is required to exclude secondary causes of osteoporosis (such as primary hyperparathyroidism, hyperthyroidism, hypogonadism or Cushing’s syndrome) and to guide treatment. Investigations should include measurement of serum calcium, phosphate, albumin, total protein, creatinine, liver enzymes including alkaline phosphatase, electrolytes, 25-hydroxyvitamin D and complete blood count. When clinically indicated, thyroid stimulating hormone (TSH), free T4, testosterone (in men), estradiol (in women), prolactin, LH and FSH should also be measured. The FRAX® (Fracture Risk Assessment Model) is a web-based tool that can help physicians to assess the 10-year probability of major osteoporotic and hip fracture by calculating a score based on a number of clinical risk factors, and may therefore assist in making treatment decisions [31,32].

Treatment

The main treatment aim is prevention of fractures. All patients should receive lifestyle-advice on: prevention of falls, adequate calcium and vitamin D intake, avoidance of excess alcohol intake and smoking cessation, regular weight-bearing exercise. An attempt should be made to control the underlying disease and maintain remission. If necessary, calcium and vitamin D supplements should be prescribed to ensure a daily calcium intake of 1000 mg in younger patients and 1200 - 1500 mg in postmenopausal women and men >55 and a daily vitamin D intake of 400 - 800 IU. Larger amounts of vitamin and calcium may be necessary in CD patients with extensive small bowel disease. Hypogonadal patients should receive hormone replacement. Premenopausal women with IBD and amenorrhea are usually treated with combined estrogen-progestin replacement (an oral contraceptive pill or transdermal estradiol plus oral progestin administered cyclically). Because GCs may cause hypogonadism by suppressing gonadotrophins, men who are on long-term GC treatment should have periodic assessments of their morning serum testosterone (and gonadotrophins) and be put on testosterone replacement should they become hypogonadal [33]. GC use should be minimized when possible by using alternative therapies (appropriate/early use of immunomodulators, budesonide [15], elemental or polymeric diet, surgery for resistant disease). All IBD patients receiving GCs should be given calcium and vitamin D supplements. Bisphosphonate prophylaxis should be used (a) for those >65 years at commencement of GC, or (b) for those <65 who are due to receive GCs for more than three months and their T score is <-1.5 [28]. Specific antiosteoporotic treatment is indicated for IBD patients with: (a) fragility fractures or a T-score of <-2.5 (b) T-scores of -2.5 to -1.0 plus long-term GC therapy or presence of other additional risk factors (Fig. 1) [10,28]. Most of the evidence regarding treatment options comes from studies conducted in postmenopausal women who did not have IBD or patients on GC-induced osteoporosis. Patients may be treated with an oral bisphosphonate (e.g. weekly alendronate or risedronate) or with 3-monthly intravenous ibandronate or yearly intravenous zolendronic acid for those unable to take oral bisphosphonates or if compliance is an issue. If bisphosphonates are poorly tolerated or ineffective, alternative agents are strontium ranelate, raloxifene in postmenopausal women, teriparatide (by daily subcutaneous injections), calcitonin by intranasal spray and denosumab [10,28]. These agents have not been specifically studied in IBD. In young men and in premenopausal women with osteoporosis (who are not hypogonadal and therefore sex hormone replacement therapy is not indicated) bisphosphonates should be used with caution as there are insufficient efficacy and safety data in this group of patients and there are potential risks during pregnancy [34] and with long-term use (osteonecrosis of the jaw, atypical femoral fractures) [35,36].

Growth failure

Pathogenesis - epidemiology

In almost 1 of 4 patients with IBD, the disease presents in childhood, mostly during puberty [37]. Only 12% of children with CD have normal height velocity at diagnosis and up to 46% have reduced height velocity before the onset of any symptoms [38]. In contrast, a significantly smaller percentage of children with UC (3-10%) have reduced height velocities at the time of diagnosis [39]. Children with IBD often present with delayed puberty, weight loss or inability to gain weight, whereas a decrease in height velocity may occur at a later stage. A significant proportion (19–37%) of patients who had CD during childhood fail to reach their expected adult height [40,41]. The pathogenesis of growth failure in children with IBD is multifactorial, the most important factors being disease-related inflammation, malnutrition, GC use and hypogonadism [42]. The growth hormone (GH) – insulin-like growth factor (IGF)-1 axis is impaired in IBD resulting in a state of relative GH resistance, manifested by low IGF-1 and IGFBP-3 levels and reduced growth [43,44]. This process may be mediated via proinflammatory cytokines such as IL-6 and IL-1β, although other factors such as under-nutrition or the use of GCs may also impair GH secretion and growth plate function [43-45]. Indirect evidence that disease-related inflammation may affect growth comes from studies in children with resistant CD who underwent complete surgical resection of affected bowel segment; following surgery there is an increase in resting energy expenditure and significant catch up growth [45,46]. Apart from surgery, significant improvements in linear growth have been observed following treatment with infliximab [47,48] or exclusive enteral nutrition [37,49]. There is no doubt that malnutrition is a major factor for growth failure and that appropriate nutritional support and management may reverse growth retardation in these children [50]. Factors contributing to malnourishment include reduced intake (cytokine induced anorexia, avoidance of food due to fear of exacerbation of symptoms), increased resting energy expenditure (REE), malabsorption of fat, protein, vitamins and micronutrients, gastritis, esophagitis. Chronic GC therapy may affect growth by impairing a number of processes essential for normal growth such as endogenous GH secretion and action, bone and collagen formation, IGF-1 binding in cartilage and nitrogen retention [41,51]. It is however difficult to estimate the GC effect on growth since disease severity/activity, anatomic location and other clinical parameters are potential confounding factors; hence, not all studies have confirmed an association between GC use and growth failure in IBD [40,52,53].

Diagnosis of growth failure /Assessment of growth and nutritional status

Monitoring at regular intervals of growth and nutritional status of children with IBD, is essential and should include a number of anthropometric and other parameters as described in Table 2 [37,54]. Additionally, in children with growth failure, measurement of IGF-1, thyroid hormones, TSH and assessment of bone age are indicated.

Management

Attempts to improve growth rate in children with IBD should focus on achieving and maintaining disease remission to minimize disease-related inflammation. Systematic assessment of growth failure is recommended, with the help of a pediatric endocrinologist. The use of long-term GC therapy should be minimized, if possible [37]. In addition, all children should receive appropriate specialist nutritional advice and support. Children with growth failure have increased energy requirements (125-150% of the recommended daily allowance for energy, and 2.4 to 3 g/kg per day of protein) and those with malabsorption may require supplementation of vitamins and minerals [54,55]. Supplemental enteral nutrition in the form of nocturnal feeding via nasogastric tube or exclusive enteral nutrition may be necessary in more severe cases, especially those children with intolerable GC-related side effects and/or growth failure [37,54,56-58]. As already mentioned, several interventions including surgery and immunomodulators such as infliximab, have been shown to have a positive effect on growth in children with IBD [45-48]. In a relatively small study in children with CD, 6-mercaptopurine (6-MP) (whose parent drug is azathioprine) was effective and reduced the need for steroids but had no effect on growth after 18 months compared with conventional prednisone treatment [59]. Growth hormone therapy should be considered in children with severe growth failure when other measures fail, as it has been shown to increase height velocity, improve BMD [60] and induce anabolic effects even in GC-dependent children with CD [61]. If GH is to be used, it is generally more effective when administered in the early rather than in the late puberty [44].

Hypogonadism, pubertal delay and fertility issues

Hypogonadism is not uncommon in both male and female patients with IBD, and may be the result of (a) a direct effect of inflammation/cytokines on the reproductive axis, ovarian and testicular function [62-64], (b) undernutrition and reduced leptin levels [65] and (c) the effect of chronic GC treatment on gonadotrophin secretion [33] (as already discussed in the paragraph discussing treatment of osteoporosis).

An association between the bone formation marker osteocalcin and testosterone levels in men with CD was reported by Robinson et al in 1998 [66]. A more recent study confirmed lower testosterone and estradiol levels in men with CD compared to controls, but failed to show any association with BMD or markers of bone metabolism [67]. Nevertheless, hormone replacement should be considered in hypogonadal IBD patients with osteoporosis, especially young men and premenopausal women. When IBD presents during childhood, hypogonadism and pubertal delay are common (in CD more often than in UC) [68]. These children have reduced linear growth and delayed accretion of lean body mass compared to their healthy peers. Because children with pubertal delay usually have delayed bone age, some catch-up growth is possible after the onset of puberty. Studies report average delays in puberty onset about 1.5 years for girls and 0.8 years for boys [69]. Management involves nutritional support and appropriate treatment of the underlying disease-related inflammation. Boys with IBD and pubertal delay may be treated with testosterone therapy; controlled studies of testosterone use in IBD are however needed [68].

Fertility is not generally impaired in men and women with IBD compared to the general population [70]. Sexual dysfunction appears to be mostly related to depression [71]. However, subfertlity may be encountered under certain circumstances such as in men who develop impotence following proctocolectomy, men with sulfasalazine-induced oligospermia (reversible, not observed with 5-ASA agents) and women who have undergone surgery [72].

Lipid abnormalities and insulin resistance

Although factors associated with atherosclerosis such as inflammation, carotid intima media thickness (cIMT), homocysteine levels and insulin resistance are commonly increased in IBD patients, low density lipoprotein cholesterol and total cholesterol levels are generally low [73]. These changes are more pronounced in CD compared to UC and they are present independently to disease activity, possibly mediated by cytokine production. LDL cholesterol is lower compared to healthy individuals, even after bowel resection. This has been attributed to malabsorption of bile acids leading to parallel stimulation of cholesterol synthesis, cholesterol degradation and LDL receptor expression in the liver, the net effect being a significant reduction in LDL cholesterol [74]. Hypocholesterolemia is a common feature of various types of acute illness such as sepsis, trauma and surgery and has been related to the severity of the illness. In addition, lipoprotein (a) levels are increased and apolipoprotein A-1 and apolipoprotein B-100 are reduced in CD, possibly predisposing CD patients to a higher risk of thrombosis [75].

In a previous study from Italy in patients with IBD during remission, indirect calorimetry was employed to assess the basal metabolic rate and substrate oxidation and the euglycemic hyperinsulinemic clamp technique was used to measure insulin sensitivity; these parameters were similar in the study group (inactive CD or UC) compared to healthy controls, whereas basal lipid oxidation was higher in patients with CD compared to both UC and healthy controls [76]. In contrast, during active CD there is increased insulin resistance as well as insulin secretion (based on the plasma insulin response during a 75 g oral glucose tolerance test) [77]. Anti-TNF-α therapy with infliximab did not alter insulin resistance in patients with active IBD whereas it increased total and HDL cholesterol levels and apo-A1 [78]. Despite the recent discovery of numerous shared susceptibility loci/genes, there is no epidemiological evidence to support an association between IBD and either type 2 or type 1 diabetes [79]. Insulin resistance, hyperglycemia, and overt diabetes may however be a consequence of GC therapy in IBD. GC-induced hyperglycemia results from an increased rate of hepatic gluconeogenesis, inhibition of glucose uptake in adipose tissue, or impairment of insulin action at the receptor and post-receptor level [80]. The risk of developing GC-induced diabetes depends on the dose used, the age, BMI and genetic predisposition. Clinically significant hyperglycemia is generally treated in the same way as it is treated in type 2 diabetes (with dietary modification, oral anti-diabetic agents and/or insulin if needed).

Conclusion

Recent evidence suggests that changes in the endocrine milieu play an important role in the pathogenesis of IBD [81-86]. Adipokines such as leptin, adiponectin and resistin are involved in a number of processes that characterize IBD including anorexia, malnutrition, altered body composition and mesenteric white adipose tissue hypertrophy [83]. Animal studies suggest that expression of peroxisome proliferator-activated receptor γ (PPAR γ) in intestinal epithelial cells as well as in macrophages and T cells of mice with experimental IBD, exhibit immunoregulatory actions and may be involved in preventing gut inflammation [84,87]. On the basis of such observations, thiazolidinediones (drugs that have been widely used to treat type 2 diabetes) have recently been tried in IBD with interesting results [85,88].

It is becoming clear that the endocrine system is involved in the pathogenesis and clinical manifestations of IBD in several ways. The main endocrine manifestations of IBD described in this brief review article (metabolic bone disease, growth failure, hypogonadism, pubertal delay and changes in lipid and carbohydrate metabolism) are interrelated and their multifactorial pathogenesis is influenced by disease-related inflammation and nutritional status. To achieve best results, interventions need to target the underlying mechanisms; it is essential that in addition to nutritional support and specific therapies for osteoporosis, growth failure and hypogonadism, a continuous effort is made to control the underlying chronic inflammation by achieving and maintaining disease remission.

References

  1. Xavier RJ, Podolsky DK. Unraveling the pathogenesis of inflammatory bowel disease. Nature 2007;448:427-434.

  2. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009;361:2066-2078.

  3. Bernstein CN, Blanchard JF, Rawsthorne P, Yu N. The prevalence of extraintestinal diseases in inflammatory bowel disease: a population-based study. Am J Gastroenterol 2001;96:1116-1122.

  4.           Levine JS, Burakoff R. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Hepatol (NY) 2011; 7:235-241.

  5. Rothfuss KS, Stange EF, Herrlinger KR. Extraintestinal manifestations and complications in inflammatory bowel diseases. World J Gastroenterol 2006;12:4819-4831.

  6. Voulgari PV. Rheumatological manifestations in inflammatory bowel disease. Ann Gastroenterol 2011;24:173-180.

  7. Katsanos KH, Tsianos EV. The kidneys in inflammatory bowel disease. Ann Gastroenterol 2002;15:41-52.

  8. Karamanolis GP. Cutaneous and ocular manifestations of IBD. Ann Gastroenterol 2006;19:181-183.

  9. Ali T, Lam D, Bronze MS, Humphrey MB. Osteoporosis in inflammatory bowel disease. Am J Med 2009;122:599-604.

10. Bernstein CN, Leslie WD, Leboff MS. AGA technical review on osteoporosis in gastrointestinal diseases. Gastroenterology 2003;124:795-841.

11. van Hogezand RA, Hamdy NA. Skeletal morbidity in inflammatory bowel disease. Scand J Gastroenterol Suppl 2006;243:59-64.

12. Siffledeen JS, Siminoski K, Jen H, Fedorak RN. Vertebral fractures and role of low bone mineral density in Crohn’s disease. Clin Gastroenterol Hepatol 2007;5:721-728.

13. Bernstein CN, Leslie WD. The pathophysiology of bone disease in gastrointestinal disease. Eur J Gastroenterol Hepatol 2003;15:857-864.

14. Mazziotti G, Angeli A, Bilezikian JP, Canalis E, Giustina A. Glucocorticoid-induced osteoporosis: an update. Trends Endocrinol Metab 2006;17:144-149.

15. Schoon EJ, Bollani S, Mills PR, et al. Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn’s disease. Clin Gastroenterol Hepatol 2005;3:113-121.

16. Pappa HM, Grand RJ, Gordon CM. Report on the vitamin D status of adult and pediatric patients with inflammatory bowel disease and its significance for bone health and disease. Inflamm Bowel Dis 2006;12:1162-1174.

17. Leichtmann GA, Bengoa JM, Bolt MJ, Sitrin MD. Intestinal absorption of cholecalciferol and 25-hydroxycholecalciferol in patients with both Crohn’s disease and intestinal resection. Am J Clin Nutr 1991;54:548-552.

18. Jowett SL, Seal CJ, Phillips E, Gregory W, Barton JR, Welfare MR. Dietary beliefs of people with ulcerative colitis and their effect on relapse and nutrient intake. Clin Nutr 2004;23:161-170.

19. Liu N, Nguyen L, Chun RF, et al. Altered endocrine and autocrine metabolism of vitamin D in a mouse model of gastrointestinal inflammation. Endocrinology 2008;149:4799-4808.

20. Schoon EJ, Müller MC, Vermeer C, Schurgers LJ, Brummer RJ, Stockbrügger RW. Low serum and bone vitamin K status in patients with longstanding Crohn’s disease: another pathogenetic factor of osteoporosis in Crohn’s disease? Gut 2001;48:473-477.

21. Duggan P, O’Brien M, Kiely M, McCarthy J, Shanahan F, Cashman KD. Vitamin K status in patients with Crohn’s disease and relationship to bone turnover. Am J Gastroenterol 2004;99:2178-2185.

22. Kappelman MD, Bousvaros A. Nutritional concerns in pediatric inflammatory bowel disease patients. Mol Nutr Food Res 2008;52:867-874.

23. Bjarnason I, Macpherson A, Mackintosh C, Buxton-Thomas M, Forgacs I, Moniz C. Reduced bone density in patients with inflammatory bowel disease. Gut 1997;40:228-233.

24. Lin CL, Moniz C, Chambers TJ, Chow JW. Colitis causes bone loss in rats through suppression of bone formation. Gastroenterology 1996;111:1263-1271.

25. Paganelli M, Albanese C, Borrelli O, et al. Inflammation is the main determinant of low bone mineral density in pediatric inflammatory bowel disease. Inflamm Bowel Dis 2007;13:416-423.

26. Veerappan SG, O’Morain CA, Daly JS, Ryan BM. Review article: the effects of antitumour necrosis factor-α on bone metabolism in inflammatory bowel disease. Aliment Pharmacol Ther 2011;33:1261-1272.

27. Moschen AR, Kaser A, Enrich B, et al. The RANKL/OPG system is activated in inflammatory bowel disease and relates to the state of bone loss. Gut 2005;54:479-487.

28. Lewis, NR, Scott, BB. Guidelines for Osteoporosis in Inflammatory Bowel Disease and Coeliac Disease. London: British Society of Gastroenterology 2007; Available at: http://www.bsg.org.uk/clinical-guidelines/ibd/guidelines-for-osteoporosis-in-inflammatory-bowel-disease-and-coeliac-disease.html

29. Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res 1994;9:1137-1141.

30. Lewiecki EM. Premenopausal bone health assessment. Curr Rheumatol Rep 2005;7:46-52.

31. Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int 2008;19:385-397.

32. Goodhand JR, Kamperidis N, Nguyen H, Wahed M, Rampton DS. Application of the WHO fracture risk assessment tool (FRAX) to predict need for DEXA scanning and treatment in patients with inflammatory bowel disease at risk of osteoporosis. Aliment Pharmacol Ther 2011;33:551-558.

33. Odell WD. Testosterone treatment of men treated with glucocorticoids. Arch Intern Med 1996;156:1133-1134.

34. Djokanovic N, Klieger-Grossmann C, Koren G. Does treatment with bisphosphonates endanger the human pregnancy? J Obstet Gynaecol Can 2008;30:1146-1148.

35. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22:1479-1491.

36. Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2010;25:2267-2294.

37. Heuschkel R, Salvestrini C, Beattie M, Hildebrand H, Walters T, Griffiths A. Guidelines for the Management of Growth Failure in Childhood Inflammatory Bowel Disease. Inflamm Bowel Dis 2008;14:839-849.

38. Kanof ME, Lake AM, Bayless TM. Decreased height velocity in children and adolescents before the diagnosis of Crohn’s disease. Gastroenterology 1988;95:1523-1527.

39. Hildebrand H, Karlberg J, Kristiansson B. Longitudinal growth in children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1994;18:165-173.

40. Sawczenko A, Ballinger AB, Savage MO, Sanderson IR. Clinical features affecting final adult height in patients with pediatric-onset Crohn’s disease. Pediatrics 2006;118:124-129.

41. Markowitz J, Grancher K, Rosa J, Aiges H, Daum F. Growth failure in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1993;16:373-380.

42. Shamir R, Phillip M, Levine A. Growth retardation in pediatric Crohn’s disease: pathogenesis and interventions. Inflamm Bowel Dis 2007;13:620-628.

43. Katsanos KH, Tsatsoulis A, Christodoulou D, Challa A, Katsaraki A, Tsianos EV. Reduced serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 levels in adults with inflammatory bowel disease. Growth Horm IGF Res 2001;11:364-367.

44. Savage MO. Growth-promoting hormone therapy in inflammatory bowel disease. JPGN 2010;51:S135-S136.

45. McLain BI, Davidson PM, Stokes KB, Beasley SW. Growth after gut resection for Crohn’s disease. Arch Dis Chil 1990;65:760-762.

46. Varille V, Cézard JP, de Lagausie P, et al. Resting energy expenditure before and after surgical resection of gut lesions in pediatric Crohn’s disease. J Pediatr Gastroenterol Nutr 1996;23:13-19.

47. Walters TD, Gilman AR, Griffiths AM. Linear growth improves during infliximab therapy in children with chronically active severe Crohn’s disease. Inflamm Bowel Dis 2007;13:424-430.

48. Malik S, Wong SC, Bishop J, et al. Improvement in growth of children with crohn disease following anti-TNF-α therapy can be independent of pubertal progress and glucocorticoid reduction. J Pediatr Gastroenterol Nutr 2011;52:31-37.

49. Newby EA, Sawczenko A, Thomas AG, Wilson D. Interventions for growth failure in childhood Crohn’s disease. Cochrane Database Syst Rev 2005;(3):CD003873.

50. Kirschner BS, Klich JR, Kalman SS, deFavaro MV, Rosenberg IH. Reversal of growth retardation in Crohn’s disease with therapy emphasizing oral nutritional restitution. Gastroenterology 1981;80:10-15.

51. Allen DB. Growth suppression by glucocorticoid therapy. Endocrinol Metab Clin North Am 1996;25:699-717.

52. Griffiths AM, Nguyen P, Smith C, MacMillan JH, Sherman PM. Growth and clinical course of children with Crohn’s disease. Gut 1993;34:939-943.

53. Motil KJ, Grand RJ, Davis-Kraft L, Ferlic LL, Smith EO. Growth failure in children with inflammatory bowel disease: a prospective study. Gastroenterology 1993;105:681-691.

54. Kleinman RE, Baldassano RN, Caplan A, et al. Nutrition support for pediatric patients with inflammatory bowel disease: a clinical report of the North American Society for Pediatric Gastroenterology, Hepatology And Nutrition. J Pediatr Gastroenterol Nutr 2004;39:15-27.

55. Oliva MM, Lake AM. Nutritional considerations and management of the child with inflammatory bowel disease. Nutrition 1996;12:151-158.

56. Wilschanski M, Sherman P, Pencharz P, Davis L, Corey M, Griffiths A. Supplementary enteral nutrition maintains remission in paediatric Crohn’s disease. Gut 1996;38:543-548.

57. Aiges H, Markowitz J, Rosa J, Daum F. Home nocturnal supplemental nasogastric feedings in growth-retarded adolescents with Crohn’s disease. Gastroenterology 1989;97:905-910.

58. Moeeni V, Day AS. Impact of inflammatory bowel disease upon growth in children and adolescents. ISRN Pediatrics 2011:365712.

59. Markowitz J, Grancher K, Kohn N, Lesser M, Daum F. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn’s disease. Gastroenterology 2000;119:895-902.

60. Heyman MB, Garnett EA, Wojcicki J, et al. Growth hormone treatment for growth failure in pediatric patients with Crohn’s disease. J Pediatr 2008;153:651-658.

61. Mauras N, George D, Evans J, et al. Growth hormone has anabolic effects in glucocorticosteroid-dependent children with inflammatory bowel disease: a pilot study. Metabolism 2002;51:127-135.

62. Azooz OG, Farthing MJ, Savage MO, Ballinger AB. Delayed puberty and response to testosterone in a rat model of colitis. Am J Physiol Regul Integr Comp Physiol 2001;281:R1483-R1491.

63. Hales DB, Diemer T, Hales KH. Role of cytokines in testicular function. Endocrine 1999;10:201-217.

64. Terranova PF, Rice VM. Review: cytokine involvement in ovarian processes. Am J Reprod Immunol 1997;37:50-63.

65. Warren MP, Voussoughian F, Geer EB, Hyle EP, Adberg CL, Ramos RH. Functional hypothalamic amenorrhea: hypoleptinemia and disordered eating. J Clin Endocrinol Metab 1999;84:873-877.

66. Robinson RJ, Iqbal SJ, Al-Azzawi F, Abrams K, Mayberry JF. Sex hormone status and bone metabolism in men with Crohn’s disease. Aliment Pharmacol Ther 1998;12:21-25.

67. Klaus J, Reinshagen M, Adler G, Boehm B, von Tirpitz C. Bones and Crohn’s: estradiol deficiency in men with Crohn’s disease is not associated with reduced bone mineral density. BMC Gastroenterol 2008;8:48.

68. Ballinger AB, Savage MO, Sanderson IR. Delayed puberty associated with inflammatory bowel disease. Pediatr Res 2003;53:205-210.

69. Brain CE, Savage MO. Growth and puberty in chronic inflammatory bowel disease. Baillieres Clin Gastroenterol 1994;8:83-100.

70. Hudson M, Flett G, Sinclair TS, Brunt PW, Templeton A, Mowat NA. Fertility and pregnancy in inflammatory bowel disease. Int J Gynaecol Obstet 1997;58:229-237.

71. Timmer A, Bauer A, Dignass A, Rogler G. Sexual function in persons with inflammatory bowel disease: a survey with matched controls. Clin Gastroenterol Hepatol 2007;5:87-94.

72. Peppercorn MA. Fertility, pregnancy, and nursing in inflammatory bowel disease. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2011.

73. Agouridis AP, Elisaf M, Milionis HJ. An overview of lipid abnormalities in patients with inflammatory bowel disease. Ann Gastroenterol 2011;24:181-187.

74. Akerlund JE, Reihner E, Angelin B, et al. Hepatic metabolism of cholesterol in Crohn’s disease. Effect of partial resection of ileum. Gastroenterology 1991;100:1046-1053.

75. Koutroubakis IE, Malliaraki N, Vardas E, et al. Increased levels of lipoprotein (a) in Crohn’s disease: a relation to thrombosis? Eur J Gastroenterol Hepatol 2001;13:1415-1419.

76. Capristo E, Mingrone G, Addolorato G, Greco AV, Gasbarrini G. Glucose metabolism and insulin sensitivity in inactive inflammatory bowel disease. Aliment Pharmacol Ther 1999;13:209-217.

77. Bregenzer N, Hartmann A, Strauch U, et al. Increased insulin resistance and beta cell activity in patients with Crohn’s disease. Inflamm Bowel Dis 2006;12:53-56.

78. Koutroubakis IE, Oustamanolakis P, Malliaraki N, et al. Effects of tumor necrosis factor alpha inhibition with infliximab on lipid levels and insulin resistance in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 2009;21:283-288.

79. Lees CW, Barrett JC, Parkes M, J Satsangi. New IBD genetics: common pathways with other diseases. Gut 2011;60:1739-1753.

80. van Raalte DH, Ouwens DM, Diamant M. Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options? Eur J Clin Invest 2009;39:81-93.

81. Peyrin-Biroulet L, Chamaillard M, Gonzalez F, et al. Mesenteric fat in Crohn’s disease: a pathogenetic hallmark or an innocent bystander? Gut 2007;56:577-583.

82. Dubuquoy L, Rousseaux C, Thuru X, et al. PPARgamma as a new therapeutic target in inflammatory bowel diseases. Gut 2006;55:1341-1349.

83. Karmiris K, Koutroubakis IE, Kouroumalis EA. Leptin, adiponectin, resistin, and ghrelin--implications for inflammatory bowel disease. Mol Nutr Food Res 2008;52:855-866.

84. Hontecillas R, Horne WT, Climent M, et al. Immunoregulatory mechanisms of macrophage PPAR-γ in mice with experimental inflammatory bowel disease. Mucosal Immunol 2011;4:304-313.

85. Lewis JD, Lichtenstein GR, Deren JJ, et al. Rosiglitazone for Ulcerative Colitis Study Group. Rosiglitazone for active ulcerative colitis: a randomized placebo-controlled trial. Gastroenterology 2008;134:688-695.

86. Valentini L, Wirth EK, Schweizer U, et al. Circulating adipokines and the protective effects of hyperinsulinemia in inflammatory bowel disease. Nutrition 2009;25:172-181.

87. Mohapatra SK, Guri AJ, Climent M, et al. Immunoregulatory actions of epithelial cell PPAR gamma at the colonic mucosa of mice with experimental inflammatory bowel disease. PLoS One 2010;5:e10215.

88. Lund JL, Stürmer T, Porter CQ, Sandler RS, Kappelman MD. Thiazolidinedione use and ulcerative colitis-related flares: an exploratory analysis of administrative data. Inflamm Bowel Dis 2011;17:787-794.