D. S. K. Brookes

Bone Health in Children With Inflammatory Bowel Disease: Adjusting for Bone Age

Objectives: Clinical results of bone mineral density for children with inflammatory bowel disease are commonly reported using reference data for chronological age. It is known that these children, particularly those with Crohn disease, experience delayed growth and maturation. Therefore, it is more appropriate to compare clinical results with bone age rather than chronological age. Materials and Methods: Areal bone mineral density (aBMD) was measured using dual energy x-ray absorptiometry, and bone age was assessed using the Tanner-Whitehouse 3 method from a standard hand/wrist radiograph. Results were available for 44 children ages 7.99 to 16.89 years. Areal bone mineral density measurements were converted to z scores using both chronological and bone ages for each subject. Results: Areal bone mineral density z scores calculated using bone age, as opposed to chronological age, were significantly improved for both the total body and lumbar spine regions of interest. When subjects were grouped according to diagnosis, bone age generated z scores remained significantly improved for those with Crohn disease but not for those diagnosed with ulcerative colitis. Grouping of children with Crohn disease into younger and older ages produced significantly higher z scores using bone age compared with chronological for the older age group, but not the younger age group. Conclusions: Our findings, in accordance with those presented in the literature, suggest that aBMD results in children with Crohn disease should include the consideration of bone age, rather than merely chronological age. Bone size, although not as easily available, would also be an important consideration for interpreting results in paediatric populations.

Bones in pediatric Crohn's disease: a review of fracture risk in children and adults.

&NA; There is evidence to suggest that the inflammation associated with Crohns disease (CD) impacts the bone health of patients, predisposing them to early onset osteoporosis and increasing their risk of fracture. Fractures have been documented in patients with CD, with a high proportion of these being found during young adulthood, which suggests that these patients are not simply fracturing as a result of the normal aging process but rather due to the presence of CD. In population terms, patients with CD have increased risk of fracture compared with the general population. Studies in children suggest that, irrespective of time on corticosteroid therapy, the underlying systemic inflammation associated with CD is an independent detrimental influence on the bone health of children with CD. This poses the question as to whether the onset of disease in childhood predisposes the individual to increased risk of future fractures later in life, as a result of decreased peak bone mass during the growing years. It is generally believed that dual energy x‐ray absorptiometry‐assessed areal bone mineral density is a good indicator of fracture risk; however, several studies have shown this may not be the case. New research, utilizing peripheral quantitative computed tomography, which provides a true volumetric assessment of bone, suggests altered bone geometry in patients with CD, which poses a structural threat by being more brittle and susceptible to damage accumulation. (Inflamm Bowel Dis 2010;)

Cystic fibrosis-related bone disease explored using a four step algorithm

BACKGROUND A suboptimal bone accrual in young individuals with cystic fibrosis (CF) may be related to the development of a premature CF-related bone disease. Dual energy X-ray absorptiometry (DXA) is the mainstream measure of bone health; however, the influence of body size and lean tissue mass (LTM) on bone data is poorly interpreted. METHODS Total body dual-energy X-ray absorptiometry (DXA) measurements of bone mineral content (BMC) and LTM in 53 individuals with CF (7.00-17.99years) were compared to 53 sex-matched controls. BMC, height, and LTM in relation to height and BMC Z-scores were calculated and used in a 4-step algorithm. RESULTS Pubertal females with CF had less total body BMC for age (p=0.02); pre-pubertal males (p=0.05) and pubertal females with CF (p=0.03) were shorter; and pubertal females with CF showed less total body BMC for LTM (p=0.01). CONCLUSIONS The algorithm showed the following: (1) prior to puberty lowered total body BMC was primarily due to short stature, (2) LTM was appropriate for body size, and (3) pubertal females with CF had significantly less total body BMC for their LTM. Longer controlled trials are needed to clinically interpret CF-related bone disease using DXA derived data that considers patient size and body composition.

Cystic fibrosis-related bone disease in children: Examination of peripheral quantitative computed tomography (pQCT) data

BACKGROUND The investigation of skeletal health data beyond dual X-ray absorptiometry (DXA) is limited in young individuals with CF. We assessed volumetric bone mineral densities (BMD), and bone and muscle parameters using peripheral quantitative computed tomography (pQCT) in individuals with CF and controls, 7.00-17.99 years. METHODS Peripheral QCT (XCT 3000, Stratec) measurements were made in 53 individuals with CF and 53 controls. Bone mineral content (BMC), total volumetric BMD (vBMD) and cross sectional area (CSA) of the bone were measured at the 4% and 66% sites of the non-dominant tibia and radius. Additionally, trabecular vBMD and bone strength index (BSIc) were measured at the 4% sites, and cortical vBMD, muscle CSA (mCSA) and strength strain index (SSI) were measured at the 66% sites. RESULTS Pre-pubertal males with CF had greater trabecular vBMD (p=0.01) and total vBMD (p=0.00) at 4% tibia, and greater total vBMD (p=0.02) at 4% radius. Pre-pubertal females with CF had greater total vBMD at 66% tibia (p=0.02) and radius (p=0.04), and cortical vBMD (p=0.04) at the radius. At puberty, the CF cohort had less BMC at 4% tibia (males, p=0.02; females, p=0.01), and smaller mCSA at 66% tibia (males, p=0.02; females, p=0.01). Pubertal CF females had a smaller bone CSA (p=0.01) at 4% tibia, and lower bone strength (SSI) at the tibia (p=0.00) and radius (p=0.05) sites. CONCLUSIONS Bone strength parameters were not compromised prior to puberty in this CF cohort. At puberty, the bone phenotype changed for this CF cohort, showing several deficits compared to the controls. However, bone strength was adapting to the mechanical demands of the muscle. Altered bone parameters and their implications for lowered bone strength with increased age may be greatly influenced by: the CF cohort remaining smaller for age and/or a reduced bone strain, secondary to reduced muscle force.

ABCD: anthropometry, body composition and Crohnʼs disease

Background: Young individuals with Crohn disease (CD) are at risk of poor bone mineral density (BMD) and reduced lean tissue mass (LTM). The importance of LTM for maintaining skeletal health, in both incident and established CD, is evidenced. We used dual-energy x-ray absorptiometry assessment to identify areal BMD and LTM in individuals with CD. Methods: In 57 patients with CD (15F; 12.99–14.16 years) anthropometric, disease activity, bone age assessment, and total body dual-energy x-ray absorptiometry measurements were acquired. A 4-step algorithm was used to assess simultaneous bone and body composition data: areal BMD and height z scores, and LTM for height and bone mineral content (BMC) for LTM z scores were calculated. Low z score cut-off values were defined as ⩽1 standard deviations below the population means. Results: The CD cohort showed: low areal BMD z scores (P = 0.00); and low LTM for height (P = 0.00) according to defined cut-off values. BMC appeared to be adapting for the lower amount of LTM. Correcting for bone age eliminated the low areal BMD z scores. As expected, LTM for height and BMC for LTM z scores remained unchanged. Conclusions: We present a useful clinical algorithm to show significant LTM for height deficits, regardless of chronological or bone age, in this CD cohort. BMC seemed to adapt to the reduced LTM, indicating clinically “normal” areal BMD for age when considered for height. The ongoing deficits in LTM may, however, create chronic long-term consequences for bone health. Improving LTM should be a focus of clinical treatment in individuals with CD.

Consensus guidelines on the use of bisphosphonate therapy in children and adolescents

Bisphosphonate therapy is the mainstay of pharmacological intervention in young people with skeletal fragility. The evidence of its use in a variety of conditions remains limited despite over three decades of clinical experience. On behalf of the Australasian Paediatric Endocrine Group, this evidence‐based consensus guideline presents recommendations and discusses the graded evidence (using the GRADE system) for these recommendations. Primary bone fragility disorders such as osteogenesis imperfecta are considered separately from osteoporosis secondary to other clinical conditions (such as cerebral palsy, Duchenne muscular dystrophy). The use of bisphosphonates in non‐fragility conditions, such as fibrous dysplasia, avascular necrosis, bone cysts and hypercalcaemia, is also discussed. While these guidelines provide an evidence‐based approach where possible, further research is required in all clinical applications in order to strengthen the recommendations made.

Bone structural parameters in pre and pubertal individuals with Cystic Fibrosis

The extracellular calcium-sensing receptor (CaR) is a class C G Protein-Coupled Receptor (GPCR) with multimodal sensing properties. The CaR responds to multivalent cation agonists including Ca, Mg and Gd and is subject to allosteric modulation by L-amino acids, glutathione and its analog S-methylglutathione (SMG) that bind in the Venus Fly Trap domain as well as phenylalkylamines including NPS R-467 and Cinacalcet that bind in the heptahelical domains. The CaR couples to the heterotrimeric G-proteins Gq/11, Gi/o & G12/13 resulting in the activation of various signalling pathways leading to intracellular calcium mobilization, ERK1/2 activation and suppression of cAMP levels. In the present study, we show that CaR-mediated suppression of cAMP arises from both a reduction in synthesis by adenylyl cyclases and enhanced degradation by phosphodiesterases. Real-time measurement of changes in intracellular cAMP levels was achieved using the cAMP biosensor CFPnd-Epac1-cpVenus in a Fluorescence Resonance Energy Transfer (FRET)-based microfluorescence assay. EPac is a guanine nucleotide exchange protein directly activated by cAMP. All allosteric modulators tested including L-Phenylalanine, SMG and cinacalcet enhanced extracellular calcium Ca2þ o induced decreases in cAMP levels. Overnight treatment of cells with pertussis toxin, an inhibitor of Gi/o, abolished not only Ca 2þ o mediated cAMP inhibition but also the effects of the allosteric modulators suggesting that Gi/o activation is critical to the receptor ’s control of cAMP levels. Isobutyl Methyl Xanthine (IBMX), a phosphodiesterase (PDE) inhibitor significantly reduced the potency ofCa2þ o . The results suggest that CaR mediated reduction in cAMP is dependent on inactivation of adenylyl cyclase via Gi/o and supported by PDE activation.

Bridging the gap in the analysis of bone health in young individuals with Cystic Fibrosis.

The extracellular calcium-sensing receptor (CaR) is a class C G Protein-Coupled Receptor (GPCR) with multimodal sensing properties. The CaR responds to multivalent cation agonists including Ca, Mg and Gd and is subject to allosteric modulation by L-amino acids, glutathione and its analog S-methylglutathione (SMG) that bind in the Venus Fly Trap domain as well as phenylalkylamines including NPS R-467 and Cinacalcet that bind in the heptahelical domains. The CaR couples to the heterotrimeric G-proteins Gq/11, Gi/o & G12/13 resulting in the activation of various signalling pathways leading to intracellular calcium mobilization, ERK1/2 activation and suppression of cAMP levels. In the present study, we show that CaR-mediated suppression of cAMP arises from both a reduction in synthesis by adenylyl cyclases and enhanced degradation by phosphodiesterases. Real-time measurement of changes in intracellular cAMP levels was achieved using the cAMP biosensor CFPnd-Epac1-cpVenus in a Fluorescence Resonance Energy Transfer (FRET)-based microfluorescence assay. EPac is a guanine nucleotide exchange protein directly activated by cAMP. All allosteric modulators tested including L-Phenylalanine, SMG and cinacalcet enhanced extracellular calcium Ca2þ o induced decreases in cAMP levels. Overnight treatment of cells with pertussis toxin, an inhibitor of Gi/o, abolished not only Ca 2þ o mediated cAMP inhibition but also the effects of the allosteric modulators suggesting that Gi/o activation is critical to the receptor ’s control of cAMP levels. Isobutyl Methyl Xanthine (IBMX), a phosphodiesterase (PDE) inhibitor significantly reduced the potency ofCa2þ o . The results suggest that CaR mediated reduction in cAMP is dependent on inactivation of adenylyl cyclase via Gi/o and supported by PDE activation.