Pediatric providers strive for insight into both bone

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1 Boning Up: Exploring Bone Structure and Strength in Children With Crohn s Disease See Longitudinal assessment of bone density and structure in an incident cohort of children with Crohn s disease, by Dubner SE, Shults J, Baldassano RN, et al, on page 123. Pediatric providers strive for insight into both bone density and structure as they care for children with chronic disease. There are increasing numbers of young patients who belong to risk groups for poor bone health; these children are predisposed to develop a low bone mass and skeletal fragility related to an underlying disease and/or pharmacologic therapy. 1,2 The assessment tool used most commonly in clinical practice for both pediatric and adult bone density measurements is dual energy x-ray absorptiometry (DXA). 1 3 This methodology provides a 2-dimensional measurement of bone mineral density (BMD), but does not afford information on the volume of trabecular versus cortical bone (the 2 types of bone of which the skeleton is composed). DXA also does not directly yield information on bone structure, geometry, or strength. Challenges arise in the interpretation of DXA measures from a small, growing pediatric skeleton because of potential confounding by bone size. Therefore, obtaining accurate skeletal assessments is more difficult in children than adults, and there is continued debate over which adjustments (eg, height, pubertal stage, bone age) should be made in the final interpretation of DXA results. 1 3 The assessment of fracture is also more difficult in growing children or adolescents primarily owing to a lower fracture rate in the pediatric age group compared with adults. 1,4 Expert task forces were assembled in 2007 by the International Society for Clinical Density to develop position statements related to bone health assessments in children and adolescents. 5 These guidelines provide invaluable assistance, but there is still significant work to do to fill in the remaining gaps in knowledge. Children with Crohn s disease possess many risk factors for poor bone health, including growth and pubertal delay, vitamin D deficiency and other manifestations of malnutrition, decreased physical activity, ongoing inflammation from the underlying disease, and glucocorticoid therapy. 6 8 Bone turnover seems to be altered in these children, with marked suppression of bone formation seen, 9,10 even at the time of diagnosis. 11 These patients also seem to be at increased risk for fragility fractures, 12 and a continued concern is a compromise of a child s peak bone mass. Therefore, affected children and adolescents may enter adulthood at increased risk for developing osteoporosis. The majority of studies to date in children with Crohn s disease have used DXA to examine skeletal outcomes. 6,8 16 Many of these previous reports were derived from cross-sectional samples, introducing heterogeneity, and not allowing a delineation of the effects of the underlying disease from that of ongoing therapies. Four prior pediatric reports include patients with incident Crohn s disease, but each used DXA for the bone outcomes obtained. 9,15,17,18 An understanding of the structural basis for decreased skeletal strength in young patients with Crohn s disease remains elusive, and is a critically important question in our understanding of the skeletal consequences of this disease. Dubner et al 19 have carried out an elegant study reported in this month s issue of GASTROENTEROLOGY in children with new-onset Crohn s disease. Their protocol was rigorously designed to examine numerous variables, including anthropometric data, underlying disease characteristics, body composition, and glucocorticoid therapy, each a factor that may affect bone density, structure, or strength. They used the more sophisticated assessment tool peripheral quantitative computed tomography (pqct) to obtain information on volumetric (3- dimensional) BMD, lean body mass, fat mass, and polar section modulus (an engineering principle that is a function of the outer [periosteal] and inner [endosteal] dimensions of the cortical shell; Figure). Section modulus Figure 1. (A) Location of pqct measurements along the tibial metaphysis and diaphysis. (B) Cross-sectional view of the tibia, with dynamic periosteal and endosteal compartments depicted. 35

2 provides an estimate of bending and torsional bone strength. 20 An understanding of the dynamics of the periosteum (dense connective tissue lining the outer surface of bones) and endosteum (lining of inner surface or medullary cavity of bone; Figure) in specific clinical settings is critically important in the assessment of fracture risk. pqct measurements were obtained at the 3%, 38%, and 66% sites of the tibia, providing measures of trabecular, cortical, and lean/fat mass, respectively (Figure). As is illustrated, the 3% site encompasses the metaphysis of the tibia, and the 38%, the diaphysis. The investigators enrolled patients at diagnosis, and then examined changes in pqct musculoskeletal endpoints, as well as anthropometric and disease-specific variables over the subsequent year. There are many strengths of this study that merit discussion. One of the most notable is that participants were enrolled at the time of diagnosis. Therefore, the investigators were able to focus on endogenous, diseaserelated factors that directly affected the musculoskeletal outcomes. In addition, the children and adolescents were followed for 1 year, which provided some longitudinal data on how glucocorticoids and disease-related factors affected both bone and muscle acquisition. Noteworthy is the fact that this seems to be the first study to use pqct to examine bone health in either children or adults with Crohn s disease. Use of this technique over DXA enabled more accurate measurements of bone density, important here because children with Crohn s disease may exhibit both growth and pubertal delay. The authors also examined both muscle and bone outcomes rather than focusing solely on the skeleton, which broadens the clinical applications of these data. The final strength is an impressively large control group for the pqct outcomes. The authors enrolled 650 healthy controls, which provided a robust reference population for the comparison of the many musculoskeletal outcomes that were examined. Data from the baseline visit provide evidence of compromised trabecular density and cortical strength in children with Crohn s disease. Deficits in trabecular bone were observed in these children at diagnosis, with the mean trabecular BMD Z-score indicating that they were at the 10th percentile for age, gender, and race. Cytokinemediated alterations in bone turnover, most profoundly affecting bone formation during a developmental period of expected skeletal gains, likely translated into trabecular losses in these patients. One of the most concerning findings was decreased cortical bone strength (expressed as section modulus) in the children with Crohn s disease, which likely stemmed from a reduced outer (or periosteal) cortical shell, in concert with significant expansion of the inner, endosteal compartment of the diaphysis. Of note, the authors examined each of these variables with respect to both age and tibial length. These maneuvers are critically important to consider in a growing child because bones should be expanding and changing as the child gets older. This pattern of alterations in both the periosteum and endosteum could have resulted from decreased biomechanical forces associated with cachexia, decreased physical activity from the chronic illness, and/or alterations in remodeling from sustained secretion of inflammatory cytokines. This study provided important insights about bone health in children with Crohn s disease, but what did it teach us about muscle? In this incident cohort, increases in muscle mass significantly and independently attenuated decreases in both section modulus (ie, skeletal strength) and the periosteal circumference. One can speculate regarding the benefits of mechanical loading in these patients, supported by findings from previous studies of healthy children. Two studies of healthy youth have revealed that physical activity alters the periosteal and endosteal compartments in a pattern that promotes net bone accretion. 21,22 Significant body composition alterations have also been previously reported in children with Crohn s disease, the most noteworthy carried out by the current research team. 23 As was replicated in the study of Dubner et al, children with Crohn s disease exhibit significant muscle deficits that likely reflect cachexia from ongoing inflammation and malnutrition. As the current study illustrates, soft tissue evaluations, acquired in parallel with skeletal assessments, can be helpful in the care of children with chronic diseases. Growth, the chronic illness itself, and specific interventions to counter the disease may affect the skeleton, lean body mass, and fat mass simultaneously. 2,24 Two previous DXA studies of children with Crohn s disease have found BMD to be directly correlated with lean body mass. 13,16 The interdependence between muscle and bone (termed the muscle bone unit ) 25 is an area of intense research in different pediatric disease models. 2 There is debate over which algorithm should be used in children to understand most accurately the relationship between muscle mass and various skeletal outcomes in specific clinical scenarios. 26 The study by Dubner et al provides insightful new information on the muscle bone relationship in children with Crohn s disease. 19 However, there is need for continued research exploring the interactions between body composition and bone not only in Crohn s disease and other chronic pediatric conditions, but also in healthy children. How do lessons learned about muscle from this study teach us about bone density, structure, and strength? In the study by Dubner et al, use of pqct was particularly informative because it afforded an examination of both the trabecular and cortical compartments of the skeleton. 19 The skeleton is composed of approximately 80% cortical bone; 20% is trabecular bone. Trabecular bone is 36

3 more metabolically active, thereby responding more quickly to changes in the hormonal milieu, such as those that may be inflicted by a chronic disease, or altered by glucocorticoid or other therapies. pqct also enabled the authors to consider the simultaneous dynamics of the endosteum and periosteum, and to consider how these changes might alter bone strength. One of the most noteworthy and concerning findings from this study was the observation that there was a failure to expand the periosteal circumference relative to the increase in tibial length in young patients with Crohn s disease. These reductions in the periosteal circumference directly led to reductions in bone strength (expressed as section modulus Z-scores). Interestingly, cortical BMD was normal at baseline and increased significantly over the following 6 months. The significance of this finding is unclear. It is important to note that increases in bone density do not always translate into benefits. As has been shown previously in young men with stress fractures, more slender, dense cortical bones may be more brittle and susceptible to cumulative damageability. 27 This same pattern was seen among the children with Crohn s disease, which may ultimately predispose to an increased fracture risk. These findings remind us to insert caution and use clinical judgment in the interpretation of bone density data, as this may be a circumstance where normal BMD or skeletal gains do not ultimately translate into benefits for bone health. There is currently debate in the pediatric bone field regarding the skeletal effects of glucocorticoids. The pediatric skeleton seems to be more vulnerable to the deleterious effects of these agents in some clinical settings, whereas in others, it may be more resistant compared with what is seen in adults. As was recently reviewed by Leonard, 28 differences in the characteristics of the underlying disease may account for varying skeletal responses to glucocorticoid therapy. In the current study, glucocorticoids were not associated with bone loss in children with Crohn s disease. Steroid-sensitive nephrotic syndrome represents another clinical model in which this therapy has not been shown to induce significant deleterious skeletal effects; the only suggestion of an effect was a lower spinal bone mineral content compared to controls, but only after correction for body mass index. 28,29 Paradoxically, in the current study, glucocorticoid therapy was directly correlated with increases in cortical BMD Z-scores after 6 months, and the absence thereof with declines in cortical BMD in the subsequent 6 months. These results are puzzling. The authors speculate that glucocorticoids led to a reduction in bone turnover, possibly causing reduced intracortical porosity, greater secondary mineralization, and higher cortical BMD. However, it must be underscored that a higher cortical BMD, as may have been induced by glucocorticoids, may not reflect normal bone quality. This study provides some indirect evidence of deleterious skeletal effects of glucocorticoids. Mean section modulus Z-scores decreased during the 6 months after diagnosis, and remained low after adjustment for muscle cross-sectional area Z-scores. The deterioration of section modulus, even while muscle cross-sectional area improved, may reflect the effect of glucocorticoids in the suppression of bone formation, leading to an impairment of periosteal bone acquisition. The definitive explanation for these findings requires further study. Limitations of this study are few, and discussion thereof, brief. Correlations of circulating biomarkers of bone turnover, cytokines, and growth factors (eg, insulinlike growth factor I) with pqct skeletal outcomes would have been interesting to examine. Some of these factors have been reported by the authors in a previous article that examined relationships of circulating factors with musculoskeletal outcomes by DXA. 15 As the authors acknowledge, bone histomorphometric data by bone biopsy would have been needed to provide a definitive assessment of bone remodeling, noting effects of both the underlying disease and associated therapies. Surrogate markers of bone turnover would have provided some information, albeit in a much less precise way compared with biopsy. The authors used the summary measure (mg/kg per day) to quantitate glucocorticoid exposure. However, this measure may not accurately capture intermittent glucocorticoid exposure. There is debate over how to present glucocorticoid dosing data in a way that most accurately reflects the clinical significance of this therapy, especially with respect to the skeleton. Last, although glucocorticoids likely have the most profound effect on bone density, structure, and remodeling, other pharmacologic therapies are used in children with Crohn s disease, and it would have been interesting to note and explore their effects on pqct measures of bone density and structure. Many new research questions arise from this study. The authors examined the effects of glucocorticoids on bone in children with incident Crohn s disease. More information on longitudinal effects, subsequent to the first year after diagnosis, would provide additional data on the natural history of this disease with respect to the skeleton, and how specific therapies may have an impact on bone health. An informative future study would examine other therapeutic agents such as infliximab to evaluate how other therapies may mitigate or exacerbate bone loss. The muscle and bone structural findings obtained at baseline emphasize the need to test nutritional interventions in these patients, as well as the effect of anabolic agents, therapies that may both significantly impact lean muscle mass, and enhance bone strength. It would be interesting to note the effect of exercise and 37

4 other forms of mechanical stimulation on the muscle bone unit in these patients, noting the effects of both short- and long-term interventions, and whether skeletal and muscular gains are sustained. Last, longitudinal studies that correlate skeletal outcomes to fracture risk would be extremely helpful in the care of these children. In summary, the study of Dubner et al 19 adds to a growing body of knowledge regarding the relationship between muscle and bone, and deficits therein, in children with Crohn s disease. Mechanistic insights are offered as to why fracture risk is increased in these patients. The authors data suggest that these children have structural alterations that lead to an increased susceptibility to fracture. Substantial deficits in trabecular bone and a worsening section modulus were seen, and interestingly, glucocorticoids were not associated with bone loss. A recent review on pediatric bone health captures the challenges that abound in this field, Examining the developing bone: What do we measure and how do we do it? 30 For children with Crohn s disease, the study of Dubner et al represents an important step forward. CATHERINE M. GORDON, MD, MSc Divisions of Adolescent Medicine and Endocrinology Children s Hospital Boston Boston, Massachusetts References 1. Bachrach LK. Measuring bone mass in children: can we really do it? Horm Res 2006;65(suppl 2): Gordon CM, Bachrach LK, Carpenter TO, et al Dual energy X-ray absorptiometry interpretation and reporting in children and adolescents: the 2007 ISCD Pediatric Official Positions. J Clin Densitom 2008;11: Fewtrell MS; British Pediatric & Adolescent Bone Group. Bone densitometry in children assessed by dual x-ray absorptiometry: uses and pitfalls. Arch Dis Child 2003;88: Rauch F. Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2007 Pediatric Official Positions. J Clin Densitom 2008;11: Baim S, Binkley N, Bilezikian J, et al. Official Positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Position Development Conference. J Clin Densitom 2008;11: Sentongo TA, Semeao EJ, Piccoli DA, et al. Growth, body composition, and nutritional status in children and adolescents with Crohn s disease. J Pediatr Gastroenterol Nutr 2000;31: Lichtenstein GR, Sands BE, Pazianias M. Prevention and treatment of osteoporosis in inflammatory bowel disease. Inflamm Bowel Dis 2006;12: Pappa HM, Gordon CM, Saslowsky T, et al. Vitamin D status in children and young adults with inflammatory bowel disease. Pediatrics 2006;118: Sylvester FA, Wyzga N, Hyams JS, et al. Natural history of bone metabolism and bone mineral density in children with inflammatory bowel disease. Inflamm Bowel Dis 2007;13: Tuchman S, Thayu, Shults J, et al. Interpretation of biomarkers of bone metabolism in children: impact of growth velocity and body size in healthy children and chronic disease. J Pediatr 2008; 153: Sylvester FA, Davis PM, Wyzga N, et al. Are activated T cells regulators of bone metabolism in children with Crohn s disease? J Pediatr 2006;148: Semeao EJ, Stallings VA, Peck SN, et al. Vertebral compression fractures in pediatric patients with Crohn s s disease. Gastroenterology 1997;112: Boot AM, Bouquet J, Krenning EP, et al Bone mineral density and nutritional status in children with chronic inflammatory bowel disease. Gut 1998;42: Burnham JM, Shults J, Petit MA, et al. Alterations in proximal femur geometry in children treated with glucocorticoids for Crohn s disease or nephrotic syndrome: impact of the underlying disease. J Bone Miner Res 2007;22: Thayu M, Shults J, Burnham JM, et al. Gender differences in body composition deficits at diagnosis in children and adolescents with Crohn s disease. Inflamm Bowel Dis 2007;13: Burnham JM, Shults J, Semeao E, et al. Whole body BMC in pediatric Crohn s disease: independent effects of altered growth, maturation, and body composition. J Bone Miner Res 2004;19: Gupta A, Paski S, Issenman R, et al. Lumbar spine bone mineral density at diagnosis and during follow-up in children with IBD. J Clin Densitom 2004;7: Harpavat M, Greenspan SL, O Brien C, et al. Altered bone mass in children at diagnosis of Crohn s disease: a pilot study. J Pediatric Gastroenterol 2005;40: Dubner SE, Shults J, Baldassano RN, et al. Longitudinal assessment of bone density and structure in an incident cohort of children with Crohn s disease. Gastroenterology 2008;136: Liu D, Manske SL, Kontulainen SA, et al. Tibial geometry is associated with failure load ex vivo: a MRI, pqct and DXA study. Osteoporosis Int 2007;18: Petit MA, McKay HA, MacKelvie KJ, et al. A randomized schoolbased jumping intervention confers site and maturity-specific benefits on bone structural properties in girls: a hip structural analysis study. J Bone Miner Res 2002;17: Bass SL, Saxon L, Daily RM, et al. The effect of mechanical loading on the size and shape of bone in pre-, peri-, and postpubertal girls: a study in tennis players. J Bone Miner Res 2002; 17: Burnham JM, Shults J, Semeo E, et al. Body-composition alterations consistent with cachexia in children and young adults with Crohn s disease. Am J Clin Nutr 2005;82: Crabtree NJ, Kent K, Zemel B. Acquisition of DXA in children and adolescents. In: Sawyer AE, Bachrach LK, Fung EB, eds. Bone densitometry in growing patients. Totowa, NJ: Humana Press; 2007: Rauch F, Bailey DA, Baxter-Jones A, et al. The muscle-bone unit during the pubertal growth spurt. Bone 2004;34: Schoenau E, Neu CM, Beck B, et al. Bone mineral content per muscle cross-sectional area as an index of the functional musclebone unit. J Bone Miner Res 2002;17: Tommasini SM, Nasser P, Schaffler MB, et al. Relationship between bone morphology and bone quality in male tibias: implications for stress fracture risk. J Bone Miner Res 2005;20: Leonard MB. Glucocorticoid-induced osteoporosis in children: impact of the underlying disease. Pediatrics 2007;119(suppl 2):S166 S Leonard MB, Feldman HI, Shultx J, et al. Long-term, high-dose glucocorticoids and bone mineral content in childhood glucocorticoid-sensitive nephrotic syndrome. N Engl J Med 2004;351:

5 30. Petit MA, Beck TJ, Kontulainen SA. Examining the developing bone: What do we measure and how do we do it? J Musculoskelet Neuronal Interact 2005;5: Address requests for reprints to: Catherine M. Gordon, MD, MSc, Director, Bone Health Program, Divisions of Adolescent Medicine and Endocrinology, Children s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115; catherine.gordon@childrens.harvard.edu; fax: (617) The author discloses no conflicts by the AGA Institute /09/$36.00 doi: /j.gastro Hepatitis C and Hepatocellular Carcinoma: Grist for the Mill See Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease, by Lok AS, Seeff LB, Morgan TR, et al, on page 138. The Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) study is a prospective, randomized, investigator-initiated study to determine whether maintenance therapy with low-dose pegylated interferon alpha in patients with chronic hepatitis C who had failed to clear virus following a standard course of treatment would slow the progression of disease. 1 Progression of disease was determined on biopsy and by the development of the end-stage complications of progressive hepatitis C, namely development of hepatocellular carcinoma (HCC), liver failure, and the need for liver transplant. Previous reports from the HALT-C study have indicated that this treatment regimen did not halt progression of liver disease. 1 In a report in this issue of GASTROENTEROLOGY, Lok et al 2 provide evidence that the incidence of hepatocellular carcinoma is also not different in those who were on maintenance therapy versus untreated controls. These results are in contradistinction to an earlier report on 2-year maintenance therapy in nonresponders. 3 However, the sample size in this study was small and may have led to type 1 error. 3 HCC is a common complication of cirrhosis in patients with chronic hepatitis C. The reported incidence of HCC varies between 1% and 10% in some series. 4 6 The quality of the studies looking at this issue varies, with a paucity of prospective studies, and none that compare the incidence of HCC in patients with hepatitis C cirrhosis with an uninfected control group. Some factors that identify patients with hepatitis C at risk for HCC have been identified, including older age, cirrhosis, and a low platelet count. Thus far, however, there has been no attempt to use these factors to predict HCC occurrence within a defined time period, such as 3 5 years. Risk of HCC in hepatitis C cirrhosis is not fixed, but increases with time as disease progresses. Despite this, quoted incidence figures in cirrhosis assume that all patients have equal risk. This is relevant when the issue of surveillance for HCC is considered. It would be very helpful to have some means of more accurately identifying those hepatitis C cirrhotics with a higher risk of developing cancer within a short period of time. For example, if the 5-year risk of HCC were 5%, then patients might warrant surveillance; if the 5-year risk was only 0.5%, surveillance might not be recommended. There are several issues that are raised by this report from the HALT-C study. These are related to the incidence of HCC and the assessment of HCC risk, the efficacy of surveillance, and HCC staging. The incidence of HCC in noncirrhotic patients in the HALT-C study was unexpectedly high. In the cirrhotic group, the incidence of HCC was 7.0%. In the patients who were noncirrhotic, the incidence of HCC was 4.1%. In North America, until this report, HCC developing in a noncirrhotic hepatitis C patient was considered uncommon. Although the patients were not cirrhotic, they did have advanced fibrosis as a precondition for inclusion in the study. These results can be interpreted in 2 ways. One explanation, as the authors note, is that the severity of fibrosis on the initial biopsy was undercalled, because of sampling error, and these patients actually had cirrhosis. Some patients clearly progressed to cirrhosis over the course of the study, but it is unlikely that 47% of initial biopsies were underinterpreted. Others developed thrombocytopenia, suggesting that they had portal hypertension, and thus were indeed cirrhotic, even if not identified on biopsy. Alternatively, these results indicate that the cancer risk starts to increase before cirrhosis develops. There were some patients who developed HCC who did not have cirrhosis by any clinical, biochemical, or hematologic criteria. Whatever the true explanation, it is irrelevant to the clinical situation. Clinicians are faced with biopsies in patients with hepatitis C that show advanced fibrosis but not cirrhosis. These HALT-C study results 39