The nervous system and chronic kidney disease in children This paper provides a review of the literature on the nervous system involvement incurred by children and adolescents with chronic kidney disease -LRB- CKD -RRB- , with a particular focus on neuropsychological functioning . In addition to an historical overview of earlier literature , published studies from the past 14 years that address both central and peripheral nervous system function in children with CKD are reviewed -LRB- 1990 -- 2003 -RRB- . These studies span work in neuroimaging , electrophysiology , and neuropsychology . A key focus for this review is on variables that might affect neurodevelopmental status in these children . The paper concludes with suggestions for achieving progress in the understanding of this complication of kidney disease in children . Introduction Associations between end-stage renal disease -LRB- ESRD -RRB- and neurocognitive dysfunction have been reported for over 25 years . Between 1977 and 1986 , approximately 15 publications described dialysis in infants . In these early studies , approximately 65 % of infants were reported to have developmental delay and 49 % encephalopathy -LSB- 1 -RSB- . Between 1976 and 1984 , the neurocognitive effects of aluminum-induced neurotoxicity secondary to then current treatments for chronic kidney disease -LRB- CKD -RRB- were reported -LSB- 2 , 3 , 4 -RSB- . These neurocognitive effects included seizures , speech disorders , dementia , and a slow electroencephalogram -LRB- EEG -RRB- pattern -LSB- 2 , 3 -RSB- . These findings were important for the field in that they encouraged modifications to the treatment regimen for dialysis patients and highlighted a confounding factor in the relationship between CKD and neurocognitive integrity . By 1990 the use of aluminum was generally eliminated with improved dialysis water purification techniques and avoidance of aluminum-containing medications . In the early 1990s , erythropoietin was introduced into standard practice , resulting in improved anemia management for children and adults with ESRD and a diminution of anemia-related EEG and cognitive deficits reported in the adult ESRD population -LSB- 5 , 6 , 7 -RSB- . The purpose of this paper is to review the contemporary published literature that focuses on the neurological impact of CKD in children . Papers selected for this review have been published from 1990 to the present , and were selected to coincide with the improvements in treatment , including the diminution of aluminum exposure and availability of erythropoietin that occurred circa 1990 . These studies span work in neuroimaging , electrophysiology , and neuropsychology to address central nervous system -LRB- CNS -RRB- function . We also present available studies addressing the integrity of the peripheral nervous system . Central nervous system studies Neuroimaging Imaging of the brain with computed tomography and magnetic resonance imaging -LRB- MRI -RRB- has been used to document the structural impact of ESRD in children . Contemporary estimates of the prevalence of cerebral atrophy are obtained from a report of 13 children with chronic renal failure from infancy . Brain atrophy was reported in 3 -LRB- 23 % -RRB- of these patients -LSB- 8 -RSB- . Publications with a focus on certain disease groups with a high risk for CNS disease , such as cystinosis , Lowe syndrome , and congenital nephrotic syndrome , estimate the prevalence of cerebral atrophy to range between 15 % and 100 % -LSB- 9 , 10 , 11 -RSB- . A recent study by Qvist et al. -LSB- 11 -RSB- described a cohort of 33 children , largely composed of children with ESRD from congenital nephrotic syndrome , tested an average of 6 years after renal transplant . MRI documented CNS infarcts or ischemic changes from both silent and clinically significant cerebrovascular events in 19 -LRB- 58 % -RRB- . Although relevant for children with CKD , the frequency of brain structure abnormalities in these specific disorders may be greater than in a general pediatric CKD population with a variety of renal diseases . Electrophysiology findings Three reports of EEG findings in a cohort of children with CKD have been published since 1990 . In one study focal and paroxysmal EEG abnormalities were observed in 12 -LRB- 36 % -RRB- of 33 children after renal transplant , with 5 -LRB- 15 % -RRB- receiving anticonvulsant therapy -LSB- 11 -RSB- . The second report of 14 patients documented unspecified EEG abnormalities in 6 -LRB- 42 % -RRB- -LSB- 8 -RSB- . This study also documented a normal auditory brain stem evoked response in 12 of 12 children tested -LSB- 8 -RSB- . Hurkx et al. -LSB- 12 -RSB- evaluated 22 children with chronic renal insufficiency -LRB- CRI -RRB- and dialysis dependence using somatosensory evoked potential of the right median nerve . They reported an increased interpeak latency -LRB- N13 -- N20 -RRB- suggesting a delayed thalamocortical conduction . No differences in CRI versus dialysis subgroups were found . Investigations of adults with ESRD demonstrate that these tools are sensitive to kidney disease-related effects and may prove useful in future pediatric studies -LSB- 5 , 6 , 13 -RSB- . Neuropsychology findings Table 1 provides a brief description of 11 published studies that have been conducted over the past 15 years , with follow-up discussion on each of the studies within the broad domains of cognition listed below . These studies have employed samples ranging from 9 to 62 infants , children , and adolescents with CKD . The subjects experienced different types of treatment for their CKD -LRB- e.g. , hemodialysis , peritoneal dialysis , kidney transplant , conservative -RRB- . The research design varied -LRB- e.g. , longitudinal , pre-post transplant , control groups -RRB- and different kinds of assessment methodology were used -LRB- e.g. , infant development batteries , IQ batteries , specific measures of cognition , experimental tasks -RRB- . In this regard , drawing specific conclusions for neuropsychological findings will be tentative , at best , but should provide guidance to clinicians and researchers as to how the field should move forward within this assessment domain.Table 1 Cognitive functioning in children and adolescents with end-stage renal disease -LRB- ESRD -RRB- , 1990 -- 2003 -LRB- CKD chronic kidney disease , SD standard deviation , CAPD continuous ambulatory peritoneal dialysis -RRB- Author/dateSample featuresComparison groupFindingsDavis et al. 1990 -LSB- 28 -RSB- n = 37Pre-post transplant designMental development20 Dialysis at pre-transplant evaluation Improved from pre - -LRB- mean = 77.0 , range 50 -- 116 -RRB- to post-transplant -LRB- mean = 91.4 , range 50 -- 117 -RRB- 17 Conservative at pre-transplant evaluationMean age at transplant = 17.6 monthsMotor development Improved from pre - -LRB- mean = 68.7 , range 50 -- 86 -RRB- to post-transplant -LRB- mean = 85.6 , range 65 -- 109 -RRB- Cognition No change from pre - -LRB- mean = 92.0 -RRB- to post-transplant -LRB- mean = 90.4 -RRB- Overall development worse with early onset of ESRDFennell et al. 1990 -LSB- 22 -RSB- n = 56n = 56 healthy childrenCognitionMean age = 13.6 yearsTesting at 6-month intervals Decreased verbal ability in CKDMean age of CKD onset = 6.05 yearsVisual motor skills Decreased in CKDModality : Memory and learning Hemodialysis -LRB- 7 -RRB- Decreased in CKD and loss of function over time Peritoneal dialysis -LRB- 12 -RRB- Attention Kidney transplant -LRB- 10 -RRB- No differences between CKD and controls Conservative -LRB- 27 -RRB- Lawry et al. 1994 -LSB- 18 -RSB- n = 24Transplant compared with dialysis plus conservativeCognitionModality : IQ : no differences between dialysis plus conservative -LRB- mean = 92.91 , SD = 16.86 -RRB- vs. transplant -LRB- mean = 103.00 , SD = 11.97 -RRB- Dialysis -LRB- 9 -RRB- Conservative -LRB- 2 -RRB- Kidney transplant -LRB- 13 -RRB- Correlation between age at onset of illness and IQ -LRB- r = 0.49 -RRB- Achievement Dialysis plus conservative less than transplant in maths -LRB- P = 0.020 -RRB- , reading -LRB- P = 0.028 -RRB- , and written language -LRB- P = 0.028 -RRB- Elzouki et al. 1994 -LSB- 8 -RSB- N = 15NoneDevelopmental screeningModality : 3 of 15 with developmental delay Dialysis -LRB- 6 -RRB- Transplant -LRB- 3 -RRB- Conservative -LRB- 6 -RRB- Hulstijn-Dirkmaat et al. 1995 -LSB- 14 -RSB- n = 31NoneDevelopmental indexMean age = 2.5 yearsTesting every 6 months Conservative -LRB- mean = 90.3 , SD = 14.3 -RRB- greater than ESRD -LRB- mean = 67.6 , SD = 17.3 -RRB- Modality : Dialysis -LRB- 16 -RRB- Conservative -LRB- 15 -RRB- Verbal , perceptual performance , and quantitative scales No change over timeMendley and Zelko 1999 -LSB- 19 -RSB- n = 9Pre-post transplant designCognition -LRB- baseline only -RRB- Full-scale IQ mean = 91.6 Mean age at pre-transplant testing = 14.2 years Verbal IQ mean = 91.4 Performance IQ mean = 95.1 Mean age at post-transplant testing = 15.8 yearsAttention Improvement in sustained attention 1-year post-transplant -LRB- P = 0.039 -RRB- Pre-transplant modality : Executive functioning Peritoneal dialysis -LRB- 5 -RRB- Improvement in mental processing speed 1 year post transplant -LRB- P = 0.008 -RRB- Hemodialysis -LRB- 3 -RRB- Conservative -LRB- 1 -RRB- Mean age of onset of ESRD = 11.9 yearsMemoryMean duration of ESRD prior to transplant = 2.5 years Improvement in working memory 1 year post transplant -LRB- P = 0.016 -RRB- Warady et al. 1999 -LSB- 16 -RSB- n = 28 infantsLongitudinal designDevelopment , generalModality : 6 of 28 children below the average range at 1 year of age CAPD at ≤ 3 months of ageCognitionTransplant at mean age = 2.1 ± 0.8 years Verbal IQ : 5 of 18 children below the average range at ≥ 4 years of ageMean age at follow-up = 7.8 ± 2.8 years -LRB- range 2.5 -- 12.0 years -RRB- Non-verbal IQ : 8 of 18 children below the average range at ≥ 4 years of age 1 child within impaired range on both verbal and non-verbal IQLedermann et al. 2000 -LSB- 15 -RSB- , Madden et al. 2003 -LSB- 17 -RSB- n = 16 infants with ESRDLongitudinal designDevelopment , generalMean age at start of dialysis = 0.38 years -LRB- range 0.02 -- 1 year -RRB- 2 of 8 school-aged children had general delaysDuration of dialysis = 17.3 months -LRB- range = 1 -- 59 months -RRB- 2 of 8 children < 5 years of age had general delaysMean age at assessment = 5.84 -LRB- range 1.58 -- 12.00 years -RRB- Cognition IQ : 67 % in average range , and 20 % in low-average range -LRB- mean = 86.5 , range 50 -- 102 -RRB- Lower IQ scores for children with co-morbid diagnoses -LRB- mean = 67.0 -RRB- than for those with ESRD alone -LRB- mean = 94.2 -RRB- Attention 7 of 14 children with hyperactivity problemsSocial-behavioral 6 of 14 children displaying conduct problemsBrouhard et al. 2000 -LSB- 21 -RSB- n = 62n = 62 siblingsCognitionMean age : 13.8 ± 0.4 years IQ : ESRD less than siblingsModality : 26 dialysis , 36 transplant No difference in dialysis vs. transplantAcademic achievement ESRD less than controls for all measures of spelling , reading , and mathematics No difference dialysis vs. transplantCorrelation between age of diagnosis and academic achievementCorrelation between parental education and academic achievementQvist et al. 2002 -LSB- 11 -RSB- n = 33 transplant recipientsNoneCognitionMean age at assessment = 8 years -LRB- range = 7 -- 12 years -RRB- Verbal IQ : mean = 87.5 Non-verbal IQ : mean = 87.5 IQ range Low : 3/33 Low-average : 14/33 Average : 14/33 Above average : 2/33Neuropsychological battery No overall group deficits with attention , language , memory , or visuospatial abilities when compared with normative populationNeuropsychological deficits Attention : 8 of 33 children Language : 2 of 33 children Memory : 6 of 33 children Visuospatial : 8 of 33 childrenMotor function Hemiplegia : 3 of 33 children Bilateral infarction : 1 of 33 Cerebral palsy : 1 of 33Auditory function 2 of 33 children with moderate sensorineural hearing loss General neurocognitive function In infants and toddlers neurodevelopmental testing is conducted and analyzed in broad categories of overall development , mental development , and motor development . Hulstijn-Dirkmaat et al. -LSB- 14 -RSB- compared the general development in 15 toddlers receiving conservative therapy -LRB- CRI -RRB- with 16 dialysis-dependent children . The children with CRI had a better developmental index compared with the dialysis-dependent children -LRB- mean ± standard deviation 90.3 ± 14.3 vs. 67.6 ± 17.3 -RRB- -LSB- 14 -RSB- . Ledermann et al. -LSB- 15 -RSB- evaluated the long-term outcome of infants requiring peritoneal dialysis . In this study , 2 of 8 -LRB- 25 % -RRB- young children demonstrated developmental delay . Warady et al. -LSB- 16 -RSB- evaluated 28 infants at 1 year of age , all of whom were dialysis dependent . Of these 28 infants , 6 -LRB- 21 % -RRB- scored in the low-average or impaired range of general development . Based on these studies , approximately 20 % -- 25 % of children less than 5 years of age with CKD might be expected to show general developmental delays -LSB- 8 , 15 , 16 -RSB- . For older children , IQ is the typical measure of general cognitive function . In the sample of children studied with CKD , the distribution of IQ scores is shifted downward compared with the normal population , with low-average -LRB- IQ 80 -- 89 -RRB- and average -LRB- IQ 90 -- 109 -RRB- range scores predominating -LSB- 11 , 14 , 15 , 16 , 17 , 18 , 19 , 20 -RSB- . In a study of 62 children with ESRD , dialysis and transplant combined , Brouhard et al. -LSB- 21 -RSB- described a significantly lower IQ in the children with kidney disease compared with their sibling controls . In 19 children with a mean age of 6.6 ± 1.3 years who had ESRD from infancy , Warady et al. -LSB- 16 -RSB- reported a relatively intact IQ , with 15 of 19 -LRB- 79 % -RRB- in the average range . In this group , 13 of 18 -LRB- 72 % -RRB- achieved average verbal IQ scores , while only 10 -LRB- 56 % -RRB- scored in the average range in the nonverbal subtest -LSB- 16 -RSB- . When comparing transplanted patients with dialysis-dependent patients , variable results have been reported . Lawry et al. -LSB- 18 -RSB- compared 13 transplanted children with 11 dialysis-dependent children in a cross-sectional study and found a higher mean IQ in the transplant group -LRB- 103.0 ± 11.97 vs. 92.9 ± 16.86 -RRB- . Conversely , Brouhard et al. -LSB- 21 -RSB- compared 36 transplant and 26 dialysis-dependent children in their cross-sectional study and found no significant difference between these patient groups . In aggregate it appears that general cognitive function is impaired in children with CKD , but the published literature is inadequate to fully characterize this effect with respect to CKD modality and differences between verbal and non-verbal IQ -LSB- 11 , 16 , 19 , 22 -RSB- . Attention and executive function The findings in the pediatric CKD literature are mixed with respect to attention and executive function -LSB- 11 , 19 , 22 -RSB- . Fennell et al. -LSB- 22 -RSB- reported no differences in measures of sustained attention between children with all treatment modalities of CKD combined and matched controls . Conversely , Mendley and Zelko -LSB- 19 -RSB- documented longitudinal improvements in sustained attention -LRB- pre-transplant 2.19 ± 1.29 vs. post-transplant 2.95 ± 1.33 , P = 0.04 -RRB- and mental processing speed -LRB- pre-transplant 2.28 ± 0.72 vs. post-transplant 1.64 ± 0.31 s , P = 0.008 -RRB- 1 year after transplant in 9 children . After renal transplant , Qvist et al. -LSB- 11 -RSB- reported no overall group deficits of attention in 33 children compared with the normative population -LSB- standard deviation score -LRB- SDS -RRB- = − 0.2 ± 0.4 -RSB- , although 24 % of the sample showed generalized attention deficits . Language The prevalence of hearing loss among children with CKD is approximately 18 % , and unrecognized or delayed diagnosis of hearing impairment may impede language development -LSB- 11 , 23 -RSB- . Children with known hearing loss tend to be excluded from studies of cognitive function , and so their challenges are not likely to be fully reflected in the published literature -LSB- 17 -RSB- . Fennell et al. -LSB- 22 -RSB- documented deficits with verbal abstracting abilities in their matched control design for children with CKD . Qvist et al. -LSB- 11 -RSB- documented no overall group deficits of language compared with the normative population -LRB- SDS = − 0.2 ± 0.4 -RRB- , with only 6 % of children showing evidence of generalized language deficits . More research needs to be conducted before determining whether language abilities will prove to be an area of concern for children with CKD , particularly with respect to potential delays secondary to hearing impairment . Visuospatial abilities Compared with a matched control population , early studies by Fennell et al. -LSB- 22 -RSB- documented deficits in visual-motor abilities in a cohort of 56 children with CKD . Qvist et al. -LSB- 11 -RSB- documented no overall group deficits with visuospatial abilities in 33 transplant recipients when compared with the normative population -LRB- SDS = − 0.5 ± 0.5 -RRB- ; however , 24 % of the cases did show generalized visuospatial deficits . Memory In a heterogeneous sample of children with CKD , Fennell et al. -LSB- 22 -RSB- reported lower memory scores for children with CKD compared with controls . In addition , a general loss of memory function over time was observed in 26 children with all treatment modalities of CKD over a 12-month testing period -LSB- 24 -RSB- . After kidney transplantation , Qvist et al. -LSB- 11 -RSB- reported no overall group deficits with memory compared with the normative population -LRB- SDS = − 0.4 ± 0.5 -RRB- , although 20 % of the cases displayed generalized memory deficits . Conversely , Mendley and Zelko -LSB- 19 -RSB- documented longitudinal improvements in working memory in 9 children 1 year after transplant compared with the pre-transplant evaluation . Academic achievement Academic achievement in children with CKD is vulnerable to deficits in each cognitive domain noted above as well as an increased frequency of school absences . In a study by Lawry et al. -LSB- 18 -RSB- , the combined dialysis and CRI group -LRB- n = 11 -RRB- with a mean chronological age of 14.9 ± 3.3 years achieved at an age equivalent of 13.8 ± 5.8 in mathematics , 15.6 ± 7.7 in reading , and 11.2 ± 7.2 in language . In comparison , the transplant group -LRB- n = 13 -RRB- with a mean chronological age of 13.8 ± 3.2 years , achieved at an age equivalent of 16.2 ± 7.8 in mathematics , 16.4 ± 7.7 in reading , and 16.2 ± 9.1 in language . This paper suggested that transplant recipients may have superior academic achievement compared with dialysis-dependent children -LSB- 18 -RSB- . Conversely , Brouhard et al. -LSB- 21 -RSB- compared the academic achievement of dialysis and transplant patients and normal sibling controls . They reported no difference in academic achievement between dialysis and transplant groups . However , the combined ESRD group of dialysis and transplant achieved below their sibling controls in spelling , arithmetic , and reading -LSB- 21 -RSB- . Observational studies of academic placement further indicate that regular education -LRB- with or without remedial tutoring -RRB- is used for 79 % -- 94 % of children with CKD , while 13 % -- 15 % receive special education services not related to hearing or visual impairments -LSB- 11 , 16 -RSB- . This compares with national data in which approximately 10 % -- 15 % of students receive special education services -LSB- 25 -RSB- . Given the observed frequency of abnormalities across multiple areas of cognitive function , the frequency of special education services used by children with CKD appears low . Peripheral nervous system Peripheral neuropathy including diabetic neuropathy and dialysis-related amyloidosis has been reported in adults with ESRD -LSB- 26 , 27 -RSB- . The frequency of peripheral neuropathy in children with CKD can only be grossly estimated based on the following study . Elzouki et al. -LSB- 8 -RSB- assessed nerve conduction velocity in 11 children with CKD and found 1 -LRB- 9 % -RRB- had diminished motor nerve conduction . Electromyograms performed in 9 of these patients revealed increased polyphagia of motor unit potentials in 4 -LRB- 44 % -RRB- -LSB- 8 -RSB- . At present , we are unable to find additional published studies examining peripheral neuropathies in children with CKD . Key variables affecting neurodevelopmental outcomes CKD is a complex disorder and , similar to other pediatric disorders , there are undoubtedly a variety of variables that contribute to the neurodevelopmental status of this population . Key variables presented here are postulates for the most part as the studies conducted since 1990 have not been adequately powered to assess multiple influential factors . The duration of CKD and the age at onset of CKD may affect cognition . Two separate studies have reported a poorer developmental prognosis for children with earlier-onset ESRD -LSB- 18 , 28 -RSB- . It has been postulated that this may be the result of insults to the CNS at particularly vulnerable periods in development or the result of continuous insults over the majority of postnatal life among some children with long-standing kidney disease . The congenital disorders presenting with kidney disease early in life may influence the perceived relationship between duration of CKD and cognition , as these disorders may have other associated CNS abnormalities , such as pulmonary hypoplasia and hypoxia associated with obstructive uropathies , or structural anomalies with Joubert syndrome and Smith-Lemli-Opitz syndrome -LSB- 29 -RSB- . Hulstijn-Dirkmaat et al. -LSB- 14 -RSB- identified the presence of co-morbid conditions as a risk factor for cognitive impairment based on mean IQ scored -LRB- CKD alone 86.7 vs. CKD with co-morbidity 61.4 , P = 0.001 -RRB- . Conversely , Fennell et al. -LSB- 24 -RSB- found no correlation between age at onset of ESRD and cognition . The available data suggest that the duration of CKD and the age at onset of CKD negatively impact on cognitive functioning , but it remains unclear how these variables contribute to the type and severity of cognitive dysfunction . Having reached ESRD , the modality of renal replacement therapy may have an impact on neurodevelopment . Several studies have examined small groups of children either before and after renal transplant or as a cross-sectional study comparing renal replacement therapy modality groups -LSB- 30 , 31 -RSB- . Fennell et al. -LSB- 24 -RSB- compared 10 transplant , 7 hemodialysis , and 12 peritoneal dialysis patients . Patients in both the transplant and peritoneal dialysis groups tended to have better attention and memory skills when compared with the performance of hemodialysis patients . Additional investigation is warranted to determine the differential effect of hemodialysis and peritoneal dialysis among children with ESRD with current dialysis adequacy standards -LSB- 32 , 33 , 34 -RSB- . From previous studies , a hypothesis can be formulated that motor skills , memory , attention , and mental processing may improve after renal transplantation -LSB- 11 , 16 , 21 -RSB- . Although existing literature suggests that a successful renal transplant may diminish the adverse developmental effects of ESRD , these same studies document the type and frequency of residual deficits in pediatric renal transplant recipients to be greater than in the normative American population -LSB- 11 , 16 , 21 -RSB- . Complications of CKD such as anemia , hypertension , and malnutrition likely affect neurodevelopment . Anemia has been shown to slow the cognitive event related potential in adults with CKD -LRB- mean hematocrit = 23.7 % -RRB- and impair cognitive function among otherwise healthy children aged 6 -- 11 years with hemoglobin levels less than 11.8 g/dl -LSB- 6 , 35 -RSB- . The optimal hemoglobin for cognitive function in children with CKD remains to be determined . The effects of hypertension on cognition may be related to the degree of blood pressure elevation , brain injury consequent to hypertensive or hypotensive episodes , and side effects of antihypertensive therapy . A recent study by Lande et al. -LSB- 36 -RSB- analyzed National Health and Nutrition Examination Survey III -LRB- NHANES III -RRB- data comparing 217 children with systolic blood pressure greater than or equal to the 90th percentile for age and gender with 4,860 normotensive children . The NHANES III study used subtests of the Wechsler Intelligence Scale for Children and reading and arithmetic subtests of a standardized academic achievement test . In this study , results suggested that hypertension was associated with lower scores in subtests representing memory , attention , and arithmetic . Furthermore , malnutrition in young infants without kidney or other chronic disease has been linked to impaired brain growth and developmental delay -LSB- 37 , 38 , 39 -RSB- . Significant effort has been applied to the nutritional support of children with CKD . However , in national registries of children with CKD , the mean weight z-score is 1.0 -- 1.4 standard deviations below the American age-matched mean , and mean height z-scores are approximately 1.6 standard deviations below the American age-matched mean -LSB- 40 -RSB- . Anemia , hypertension , and malnutrition are likely key factors contributing to the cognitive deficits of children with CKD . Children with CKD are at risk for additional disorders that may accompany congenital kidney disease . Prematurity occurs with a greater frequency in children with congenital kidney disease and is associated with a greater frequency of CNS injuries and later developmental deficits -LSB- 11 , 41 -RSB- . Socioeconomic status and parental education have a known impact on academic achievement among all children -LSB- 42 -RSB- . Although not unique to children with CKD , the identification of poor socioeconomic status or limited parental education may trigger additional educational evaluation and or services for children with CKD in these families . School absences are increased in children with CKD due to the need for outpatient medical visits , hospitalizations , hemodialysis , and acute illness -LSB- 20 -RSB- . Finally , the CKD population is at excess risk for sensory deficits , including congenital and acquired hearing impairment -LRB- 9 % -18 % -RRB- and visual impairment , although the latter has not been examined thoroughly -LSB- 11 , 43 -RSB- . All of these factors may contribute to the neurodevelopmental dysfunction of children with kidney disease . Conclusions Emergent findings appear to apply to three broad groups of children and adolescents : mild-to-moderate CKD , dialysis-dependent children , and transplant-dependent children . What is known about children with mild-to-moderate CKD is severely limited , with no focused studies addressing their neurodevelopmental needs . More is known about the pediatric dialysis population , with deficits in the areas of attention , language , visual-spatial abilities , and memory . However , the differentiation of problems that may relate to disease-specific variables , such as age at onset of kidney failure , anemia , and hypertension , remain relatively unknown and modestly examined at best . For the transplant-dependent group , cognitive deficits appear to persist , supporting the conclusion that the transplant does not result in complete neurocognitive `` recovery . '' The low frequency of peripheral neuropathy in children with CKD observed clinically and reported in a single study may be attributed to the low prevalence of diseases with microvascular complications such as diabetes mellitus , advanced atherosclerosis , and dialysis-related amyloidosis -LSB- 8 -RSB- . This pediatric advantage may be lost as patients survive into young adulthood . It is unlikely that purely pediatric follow-up studies will be able to characterize this potential late-term complication . Given the expected long-term patient survival of children with CKD , established guidelines for the provision of renal replacement therapy for children , and the data provided by studies among children with CKD , we believe that an organized , adequately powered approach toward the characterization of the neurodevelopmental impact of CKD is warranted -LSB- 32 , 33 , 34 , 44 -RSB- . Ideally , this study or set of studies will include measures of neuroimaging , electrophysiology , and neuropsychology . Future research in this area should characterize potential risk factors , such as age at onset of disease , anemia management , and hypertension to advance our understanding of the magnitude of cognitive dysfunction and aid the identification of modifiable mediators of CNS deficits in children with CKD .

O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

neurodevelopment
cognition
renal failure


Bone loss in elderly men : increased endosteal bone loss and stable periosteal apposition . The prospective MINOS study Introduction Longitudinal studies on the age-related bone loss in men concerns the decrease in areal bone mineral density -LRB- aBMD -RRB- , which can be qualified as `` apparent bone loss '' because it does not reflect the change in bone mineral content -LRB- BMC -RRB- . Loss of BMC can be referred to as `` net bone loss '' because it does not take into account the morphological basis of the bone loss -LRB- decreased periosteal apposition ; endosteal bone loss , i.e. bone loss on the trabecular , endocortical and intracortical surfaces -RRB- . The aim of this study was to assess age-related apparent net and endosteal bone loss as well as their morphological basis and age-related changes during a prospective follow-up in a large cohort of elderly men . Introduction Osteoporosis in elderly men is a major problem of public health . Fracture incidence increases exponentially with age , thus , total number of fragility fractures in men increases rapidly , mainly due to the increasing life expectancy -LSB- 1 -RSB- . Currently , 25 -- 30 % of fragility fractures occur in men -LSB- 1 , 2 -RSB- . Moreover , postfracture morbidity and mortality are higher in men than in women -LSB- 3 , 4 -RSB- . Bone loss is defined usually as the rate of decrease in areal bone mineral density -LRB- aBMD -RRB- measured by dual X-ray absorptiometry -LRB- DXA -RRB- -LSB- 5 -- 7 -RSB- . However , aBMD of a given region of interest -LRB- ROI -RRB- is determined by its bone mineral content -LRB- BMC -RRB- and by its projected area . For tubular bones , ROI length is kept constant , and the projected area depends on bone width . Bone width increases with ageing due to the periosteal apposition -LSB- 8 , 9 -RSB- . Thus , if the amount of bone deposited on the periosteal surface and that resorbed on the endosteal surfaces -LRB- i.e. trabecular , endocortical and intracortical -RRB- are equal , BMC remains constant , but aBMD decreases because bone width and its projected area have increased . Therefore , it is more appropriate to refer the decrease in aBMD assessed longitudinally as `` apparent bone loss '' . Changes in BMC of a given ROI are determined not only by the quantity of bone resorbed on the endosteal surfaces but also by the quantity of bone deposited on the periosteal surface . Thus , change in BMC does not reflect the quantity of bone really lost on the endosteal surfaces and , therefore , the decrease in BMC is better qualified as `` net bone loss '' . Estimation of bone gain due to periosteal apposition would allow assessment of the quantity of bone really lost on the endosteal surfaces . This quantity of bone could be referred as to `` endosteal bone loss '' . In elderly men , apparent bone loss accelerates with age -LSB- 5 -- 7 -RSB- . However , the morphological basis underlying this acceleration has not been studied , and it is unclear whether it is related to faster outward displacement of a constant amount of bone , to higher endosteal bone loss and/or to a lower periosteal apposition . Moreover , only a few studies have compared the rate of apparent bone loss at different sites of measurement in elderly men -LSB- 10 -- 12 -RSB- , although it appears that the morphological basis underlying apprent bone loss may vary according to ROI -LSB- 13 -RSB- . Therefore , the aim of this study was to assess age-related apparent net and endosteal bone loss as well as their morphological basis and the age-related changes during a long-term prospective follow-up in a large cohort of elderly men -LRB- the MINOS study -RRB- . Subjects and methods Cohort The MINOS study is a prospective study of osteoporosis and its determinants in men , which was initiated in 1995 -LSB- 14 -RSB- . It is the result of a collaboration between the National Institute of Health and Medical Research -LRB- INSERM -RRB- and Société de Secours Minière de Bourgogne -LRB- SSBM -RRB- in Montceau les Mines , a town located 130 km northwest of Lyon in the Department -LRB- District -RRB- of Saône et Loire . The town has a population of 21,000 inhabitants , including 7,150 men > 19 years if age . SSMB is one of the largest health insurance companies in this town . The study was performed in accord with the Helsinki Declaration of 1975 as revised in 1983 . The MINOS cohort consists of 1,040 men aged 19 -- 85 recruited between 1995 and 1998 . All men responded to an epidemiological questionnaire covering demographic and behavioural information as well as detailed medical history . Men aged 19 -- 50 were examined once , whereas 790 men aged 50 -- 85 were followed up prospectively for 90 months . Every 18 months , they were invited to attend the follow-up examination composed of an epidemiological questionnaire and DXA measurement . Radiograph of the spine were performed at baseline , 36 and 90 months . Measurements aBMD and BMC were measured at the lumbar spine -LRB- L2 -- L4 -RRB- , hip and whole body using pencil-beam DXA -LRB- QDR 1500 , Hologic Inc. , Waltham , MA , USA -RRB- and at the distal nondominant forearm using single energy X-ray absorptiometry -LRB- Osteometer , DTX-100 , Denmark -RRB- . The OsteoDyne Hip Positioner System -LRB- HPS -RRB- was used to minimise hip positioning error . ROI of the femoral neck was positioned perpendicularly to the axis of the femoral neck to cover its narrowest part . When necessary , the femoral neck edges were adjusted manually . The QDR 1500 device was calibrated daily using a lumbar spine phantom , yielding a CV for aBMD of 0.33 % . Twice a month , the Hologic hip phantom was measured , yielding a long-term CV of 0.94 % for femoral neck aBMD and 1.05 % for the femoral neck projected area . Also twice a month , a human lumbar spine embedded in methyl methacrylate was measured . Its long-term CV was 1.07 % for BMC of L2 -- L4 , 1.07 % for the projected area of L2 -- L4 , and 0.62 % for aBMD of L2 -- L4 . At the distal forearm , the distal site includes 20 mm of radius situated proximally to the site where the spacing between the medial edge of the radius and the lateral edge of the ulna is 8 mm . Scans with evident error of positioning were excluded . The densitometer was calibrated daily using a calibration standard for DTX 100 ; its long-term CV was 0.47 % for aBMD and 0.15 % for the projected area . Dimensions of the vertebral body of the third lumbar vertebra -LRB- L3 -RRB- were measured on the anteroposterior and lateral radiographs of the lumbar spine performed at baseline and at 90 months . The cross-sectional area of L3 was calculated based on the anteroposterior and frontal diameters measured in the narrowest site of the vertebral body . Osteoarthritis of the lumbar spine was assessed , as described previously -LSB- 14 -RSB- . The external diameter of bone was calculated as the projected area of ROI divided by its length . The rate of age-related periosteal expansion was calculated as the average annual increase in the external diameter -LRB- femoral neck , distal radius and distal ulna -RRB- , projected area -LRB- total hip -RRB- or cross-sectional area -LRB- L3 -RRB- . Age-related periosteal apposition -LRB- ΔBMCPA -RRB- was estimated as the mass of bone deposited on the outer surface of bone since the first measurement -LRB- Fig. 1 -RRB- . The volume of the ellipsoid cylinder was calculated assuming that the short axis was 0.75 of the long axis -LRB- external diameter -RRB- . Then , the mass of the deposited bone was calculated as the product of the cylinder volume and the volumetric density of bone mineral -LRB- 1.15 g/cm3 -RRB- -LSB- 15 -RSB- . We assumed that during the follow-up , BMC was determined by baseline BMC , bone mass deposited on the outer surface -LRB- ΔBMCPA -RRB- and endosteal bone loss -LRB- ΔBMCEBL -RRB- . Thus , ΔBMCEBL can be calculated using BMC at baseline and during the follow-up and the calculated value of ΔBMCPA . The concept of endosteal bone loss does not make any assumption as to its underlying morphological basis -LRB- cortical thinning , increased cortical porosity , trabecular bone loss -RRB- nor on the proportion of cortical to trabecular bone . It only reflects the loss of bone mineral `` inside '' bone , which is represented in Fig. 1 by the change of the colour from black to grey . Fig. 1Calculation of bone mass deposited by periosteal apposition -LRB- ΔBMCPA -RRB- and of endosteal bone loss -LRB- ΔBMCEBL -RRB- between baseline -LRB- t0 -RRB- and follow-up -LRB- t1 -RRB- . Long semi-axes of the ellipse at baseline -LRB- R0 -RRB- and during the followup -LRB- R1 -RRB- are equal to half the external diameter of the region of interest -LRB- ROI -RRB- . Bone mass deposited by periosteal apposition -LRB- ΔBMCPA -RRB- is the product of the ellipsoid volume and the vBMD of cortical bone -LRB- d = 1.15 g/cm3 -RRB- . Coefficient 0.75 reflects bone flattening in the anteroposterior projection in comparison with its diameter in the frontal projection . Endosteal bone loss -LRB- ΔBMCEBL -RRB- is presented graphically as the brighter colour of the entire cross-sectional area of bone -LRB- black at baseline and light grey at follow-up -RRB- in order to indicate that the `` endosteal bone loss '' makes no distinction as to the morphological basis -LRB- cortical thninning , increase in cortical porosity , trabecular bone loss -RRB- Statistical methods All calculations were performed by using SAS version 8.2 software -LRB- SAS Institute Inc. , Cary , NC , USA -RRB- . Correlation between continuous variables was assessed by Pearson 's simple correlation coefficient . Individual slopes were calculated by using simple linear regression . Comparisons of the individual slopes between age groups were performed by analysis of variance -LRB- ANOVA -RRB- and adjusted for multiple comparisons by Dunnett-Hsu test . Participants attended two to six exams ; those who had few measurements , e.g. two , had them over different periods of follow-up -LRB- 18 -- 90 months -RRB- . Individual slopes were calculated by using two to six points distributed over 18 -- 90 months , which could influence accuracy of the calculation . We adjusted for the duration of follow-up or the number of measurements to check whether duration of follow-up and number of measurements influenced the results . Each of them entered significant in the majority of models , although they influenced the results only to a limited degree . We present data adjusted for the duration of follow-up because this variable attained higher level of significance in the models and contributed more to the final model . Results Characteristics of the investigated cohort Sixty-five men who abandoned the study after the first examination were , at baseline , older and had lower physical activity but higher prevalence of diabetes mellitus , rheumatoid arthritis and parkinsonism than the 725 men who participated in the follow-up -LRB- Table 1 -RRB- . They had lower aBMD and BMC at all sites of measurement except for the lumbar spine . The difference between the groups became weaker after the adjustment for age ; however , it remained significant for certain sites . Table 1Comparison of 725 men participating in the prospective study and 65 men lost to follow-up after recruitmentParameterFollow-up -LRB- n = 725 -RRB- No follow-up -LRB- n = 65 -RRB- p value * p value ** Age -LRB- years -RRB- 65 ± 770 ± 8 < 0.0001 Body weight -LRB- kg -RRB- 80 ± 1379 ± 150.29 Body height -LRB- cm -RRB- 169 ± 6168 ± 70.21 BMI -LRB- kg/m2 -RRB- 27.98 ± 3.6427.75 ± 4.510.63 Fat mass -LRB- kg -RRB- 22.02 ± 7.4823.23 ± 9.110.28 Lean mass -LRB- kg -RRB- 54.54 ± 6.6652.16 ± 7.56 < 0.01 NSTobacco smoking -LRB- % -RRB- 11.811.60.98 Physical activity -LRB- h/week -RRB- 21.8 ± 12.717.2 ± 11.3 < 0.005 NSPrevalent fractures -LRB- % -RRB- 13.819.70.18 Diabetes -LRB- % -RRB- 6.515.7 < 0.005 Rhumatoid arthritis -LRB- % -RRB- 1.45.7 < 0.01 Parkinsonism -LRB- % -RRB- 1.55.7 < 0.02 Lumbar spine BMD -LRB- g/cm2 -RRB- 1.031 ± 0.1841.052 ± 0.2130.21 Femoral neck BMD -LRB- g/cm2 -RRB- 0.845 ± 0.1210.803 ± 0.127 < 0.01 NSFemoral neck BMC -LRB- g -RRB- 5.111 ± 0.8494.883 ± 0.934 < 0.04 NSFemoral neck width -LRB- cm -RRB- 4.082 ± 0.3164.123 ± 0.3560.31 Trochanter BMD -LRB- g/cm2 -RRB- 0.740 ± 0.1090.691 ± 0.121 < 0.001 < 0.03 Total hip BMD -LRB- g/cm2 -RRB- 0.966 ± 0.1270.910 ± 0.157 < 0.001NSWhole-body BMC -LRB- g -RRB- 2706.6 ± 410.42550.3 ± 472.7 < 0.005NSWhole-body BMD -LRB- g/cm2 -RRB- 1.210 ± 0.1081.167 ± 0.121 < 0.003 < 0.05 Distal forearm BMD0 .524 ± 0.0650.483 ± 0.070 < 0.0001 < 0.01 Ultradistal radius BMD0 .430 ± 0.0640.399 ± 0.072 < 0.001 < 0.05 Radius BMD -LRB- g/cm2 -RRB- 0.556 ± 0.0680.513 ± 0.075 < 0.0001 < 0.01 Radius BMC -LRB- g -RRB- 2.743 ± 0.4032.527 ± 0.422 < 0.0001 < 0.01 Radius width -LRB- cm -RRB- 2.471 ± 0.2072.468 ± 0.2160.94 Ulna BMD0 .476 ± 0.0660.438 ± 0.070 < 0.0001 < 0.01 Ulna BMC -LRB- g -RRB- 1.502 ± 0.2441.401 ± 0.246 < 0.0001 < 0.01 Ulna width -LRB- cm -RRB- 1.659 ± 0.1361.684 ± 0.1520.16 BMD bone mineral density , BMC bone mineral content , NS not significantp * difference between the groupsp ** age-adjusted difference between the groups Characteristics of bone loss BMC and aBMD of the lumbar spine increased significantly -LRB- Table 2 -RRB- faster in men with severe arthritis -LRB- 5.95 ± 16.15 vs 1.74 ± 10.96 mg/cm2/year ; p < 0.0001 -RRB- . At the femoral neck , aBMD decreased , whereas BMC increased . For other sites of measurement -LRB- hip , whole body , distal forearm -RRB- , both aBMD and BMC decreased . The fractional apparent and net bone loss -LRB- percentage of initial value -RRB- were fastest at the distal forearm and slowest at the whole body . All the above absolute and fractional changes in aBMD and BMC were significantly different from 0 for all ROIs . Table 2Average rate of apparent bone loss -LSB- change in areal bone mineral density -LRB- aBMD -RRB- -RSB- , net bone loss -LSB- change in bone mineral content -LRB- BMC -RRB- -RSB- and of periosteal expansion -LRB- increase in bone width or area -RRB- as well as the simple correlation coefficients of these variables with age in 725 men aged 50 -- 85 at baseline followed up prospectively for 90 months -LRB- the prospective MINOS study -RRB- Site of measurementYearly changeCorrelation with ageBone mineral density -LRB- mg/cm2/year -RRB- -LRB- % / year -RRB- rp Lumbar spine4 .205 ± 14.210.495 ± 2.910 − 0.0690.07 Femoral neck − 2.463 ± 8.305 − 0.282 ± 1.019 − 0.154 < 0.0001 Trochanter − 1.963 ± 8.031 − 0.276 ± 1.123 − 0.196 < 0.0001 Total hip − 4.714 ± 8.451 − 0.496 ± 0.930 − 0.213 < 0.0001 Whole body − 2.081 ± 8.712 − 0.177 ± 0.723 − 0.0450.22 Distal forearm − 2.937 ± 4.178 − 0.580 ± 0.870 − 0.202 < 0.0001 Distal radius − 2.986 ± 5.340 − 0.561 ± 1.041 − 0.180 < 0.0001 Distal ulna − 3.353 ± 5.131 − 0.730 ± 1.206 − 0.119 < 0.002 Ultradistal radius − 1.823 ± 5.334 − 0.426 ± 1.285 − 0.128 < 0.001 Bone mineral content -LRB- mg/year -RRB- -LRB- % / year -RRB- − 0.0410.27 L3118 .17 ± 552.900.658 ± 2.954 Femoral neck12 .67 ± 50.380.263 ± 1.010 − 0.0510.18 Total hip − 226.1 ± 0.687 − 0.504 ± 1.551 − 0.120 < 0.002 Whole body − 7565.9 ± 22500.9 − 0.294 ± 0.877 − 0.192 < 0.0001 Distal radius − 11.26 ± 25.90 − 0.426 ± 0.978 − 0.179 < 0.0001 Distal ulna − 8.64 ± 16.82 − 0.559 ± 1.164 − 0.123 < 0.001 Bone size L3 cross-section -LRB- mm2/year -RRB- 35.64 ± 225.400.167 ± 1.184 − 0.0560.10 Femoral neck -LRB- μm/year -RRB- 133.1 ± 217.20.321 ± 0.5030.0700.06 Total hip -LRB- mm2/year -RRB- 4.82 ± 42.230.112 ± 0.9150.0070.85 Distal radius -LRB- μm/year -RRB- 60.48 ± 362.660.257 ± 1.4970.0340.36 Distal ulna -LRB- μm/year -RRB- 58.27 ± 156.610.355 ± 0.9370.0130.73 External diameter of the femoral neck , distal radius and distal ulna as well as the cross-sectional area of L3 and the projected area of total hip increased significantly during the follow-up . Fractional increase in bone size varied from 0.17 % to 0.36 % per year across the sites . Characteristics of the rate of bone loss according to age at baseline At the hip and distal forearm , rate of apparent bone loss -LRB- change in aBMD -RRB- was negatively correlated with age , indicating and age-related acceleration of apparent bone loss -LRB- Table 2 -RRB- . After the age of 70 , the apparent bone loss was two -LRB- for distal forearm -RRB- to 23 -LRB- for trochanter -RRB- times faster than in men aged younger than 60 at baseline -LRB- Fig. 2 -RRB- . A similar trend was found when apparent bone loss was expressed as the percentage of the baseline value of aBMD . Fig. 2Comparison of the absolute values of apparent bone loss -LSB- change in areal bone mineral density -LRB- aBMD -RRB- -RSB- according to age group -LRB- black bars 50 -- 60 years , pointed bars 61 -- 70 years , white bars > 70 years at baseline -RRB- . The slopes are significantly different from 0 -LRB- p < 0.005 -- 0.0001 -RRB- for all regions of interest -LRB- ROIs -RRB- and for all age groups , except for the trochanter in the youngest group Net bone loss -LRB- change in BMC -RRB- also accelerated with age at the total hip , whole body and bones of distal forearm . In men aged older than 70 , net bone loss was two to four times as fast in comparison with men aged younger than 60 at baseline , both for the absolute values of net bone loss and for data expressed as percentage of baseline BMC -LRB- Fig. 3 -RRB- . Fig. 3Comparison of the absolute values of net bone loss -LSB- -LRB- change in bone mineral content -LRB- BMC -RRB- -RSB- according to age group -LRB- black bars 50 -- 60 years , pointed bars 61 -- 70 years , white bars > 70 years old -RRB- . The slopes are different from 0 -LRB- p < 0.005 -- 0.0001 -RRB- for all regions of interest -LRB- ROIs -RRB- and for all age groups In 183 men aged 50 -- 60 , rates of apparent and net bone loss were significantly different from 0 for all ROIs , except the trochanter . In 387 men aged 61 -- 70 and in 155 men aged older than 70 at baseline , rates of apparent and net bone loss were significantly different from 0 for all ROIs . The rate of periosteal expansion -LRB- expressed as the change in the projected area of bone -RRB- was significantly different from 0 for all ROIs and for all three age groups . However , it did not vary across age groups for any site of measurement . Similarly , at distal forearm bones , periosteal apposition estimated as bone mass deposited annually did not change across the age groups -LRB- Fig. 4 -RRB- . By contrast , estimated endosteal bone loss was about twice as high after the age of 70 compared with men aged younger than 60 at baseline . Fig. 4Upper panel : comparison of absolute values of annual rates of increase in external diameter at the distal radius and ulna according to age group . Lower panel : comparison of absolute values of rates of deposition of bone mass by periosteal apposition -LRB- positive hatched bars -RRB- and rate of endosteal bone loss -LRB- negative pointed bars -RRB- at the distal radius and ulna according to age group . The slopes are significantly different from 0 -LRB- < 0.005 -- 0.0001 -RRB- for periosteal apposition and for endosteal bone loss for both bones and for all age groups . Please note , in the lower panel , scales are different for radius and ulna Discussion In men , aBMD increased at the spine and decreased at the hip , distal forearm and whole body . At these sites , apparent bone loss -LRB- change in aBMD -RRB- was associated with net bone loss -LRB- change in BMC -RRB- except for the femoral neck . Apparent and net bone loss accelerated with age , whereas periosteal expansion rate remained stable . At the distal radius and ulna , endosteal bone loss accelerated with age , whereas the rate of periosteal expansion remained stable . Apparent bone loss at the hip and distal forearm was associated with a parallel net bone loss . At these ROIs , endosteal bone loss exceeded the periosteal apposition , and apparent bone loss was determined by outward displacement of lower quantity of bone mineral . Longitudinally assessed age-related apparent bone loss at the hip and distal forearm has been described in several cohorts of Caucasian men -LSB- 5 -- 7 , 10 , 16 -RSB- , but their morphological basis has not been investigated . In elderly men , apparent bone loss was associated with net bone loss at the intertrochanter ROI but with a gain in BMC at the total hip and femoral neck -LRB- narrow neck ROI -RRB- -LSB- 13 -RSB- . We found the same trend for the femoral neck but not for the total hip . This discrepancy is surprising because our cohort is younger . As the net bone loss accelerates with age , faster net bone loss -LRB- and not bone gain -RRB- could be expected in the older British cohort . We confirm longitudinal and cross-sectional data on the gain in aBMD of lumbar spine in elderly men -LSB- 7 , 12 , 14 , 16 -- 18 -RSB- . Increase in the cross-sectional area of L3 at the midheight of the vertebral body is determined mainly by the periosteal expansion . This part is less involved in arthritis . Measurements performed on the X-rays allow for exclusion of the pathological calcifications . We do not speculate on the morphological basis underlying the increase in spine aBMD . Vertebral BMC and aBMD in the posteroanterior projection are determined by changes in the vertebral body and the posterior arch . Posterior arch and its processes are built mainly of cortical bone . As their periosteal surface is relatively high , its age-related gain of BMC due to periosteal apposition may be considerable . At the vertebral body , changes in BMC are determined by loss of trabecular bone inside and by the increase in BMC due to the periosteal apposition and the aggravation of arthritis . At the hip and distal forearm , both aBMD and BMC decreased , in agreement with previous studies -LSB- 6 , 16 , 17 -RSB- . Both apparent and net bone loss accelerated with ageing ; by contrast , periosteal apposition remained constant . Thus , age-related acceleration of the apparent and net bone loss is determined by the acceleration of bone loss on endosteal surfaces . Apparent and net bone loss were significant in all age groups . In women , menopause results in the acceleration of endocortical resorption and deceleration of periosteal apposition -LSB- 19 -RSB- . Thus , after menopause , periosteal apposition continues , as reported previously by Ahlborg et al. -LSB- 20 -RSB- . However , it does not increase sufficiently to offset endocortical bone loss . On the contrary , it decreases , which may contribute to the deterioration of bone strength and increased fracture risk . We postulated that postmenopausal osteoporosis is a disease of failed adaptation of bone -LSB- 19 -RSB- . However , in men also , age-related increase in endosteal bone loss is not accompanied by an increase in periosteal apposition that would offset the possible loss of strength . Periosteal apposition does not adapt to the endosteal bone loss and remains stable . This imbalance may result in a decrease of bone strength . Thus , in men also , osteoporosis seems to be a disease of failed adaptation . Our data are consistent with the cross-sectional data obtained in elderly men by using the high-resolution peripheral quantitative computerised tomography -LRB- hr-pQCT -RRB- showing the increase in bone size at the axial and peripheral skeleton , as well as endosteal bone loss characterised by decrease in the trabecular volumetric BMD -LRB- vBMD -RRB- determined mainly by the decrease in the trabecular number , increase in total marrow area and cortical thinning , indicating endocortical resorption , and decrease in cortical vBMD -LSB- 21 , 22 -RSB- . The decrease in cortical vBMD is determined mainly by the increase in the midcortical and subendocortical porosity , whereas subperiosteal porosity and real volumetric density of the mineral of cortical bone remain relatively stable during ageing -LSB- 15 , 23 -RSB- . Our data help in understanding the difference in the age-related increase in fracture incidence . Young men have bigger bones than women , even after adjustment for age , weight and height -LSB- 24 , 25 -RSB- . Then , aBMD and BMC decrease . Age-related acceleration of apparent and net bone loss is consistent with the exponential increase in fracture incidence . However , in contrast to women , periosteal apposition rate remains stable in men and may partly offset the endosteal bone loss and associated loss of bone strength . In elderly men , bones are larger than in women -LRB- because they were larger in youth and age-related periosteal apposition was greater -RRB- , net bone loss is less -LRB- because periosteal apposition continues to deposit bone on the outer surface -RRB- and loss of bone strength starts later -LRB- because continuing periosteal expansion compensates partly for the loss of bone strength due to endosteal bone loss -RRB- . These data are consistent with epidemiological observations that in men , fracture incidence increases later and , for a given age , is lower than in women -LSB- 1 , 26 , 27 -RSB- . Our study has limitations . Montceau les Mines is a small town , and its inhabitants may not be representative of the French population . The response rate for the invitation was 23 % . Men who abandoned the study after the first examination were older and sicker , although they represent only 8 % of the initial cohort . Men who were followed up may have been healthier than the general population , especially in the oldest group . However , this difference would have underestimated the age-related bone loss and its age-related acceleration . A number of men had lower number of DXA scans because they did not attend examinations regularly or abandoned the study before the end of the follow-up . A low number of DXA values and shorter follow-up could influence the accuracy of estimation of slopes . However , adjustment for the follow-up duration or the number of scans did not influence the results . DXA presents limitations in the evaluation of bone width . In very old men , subperiosteal bone mass can be low and not recognised by the edge-detection system . This artefact can underestimate the bone width in elderly men and the age-related increase in bone width mainly in the cross-sectional studies -LRB- where the age range is large -RRB- but less so in the longitudinal study -LRB- where the follow-up period is shorter -RRB- . The projected area of femoral neck may be overestimated because of calcifications in fibrous tissue . The measured radius site is established by the device . According to the individual anatomy , this site may be more distal -LRB- larger and more trabecular -RRB- or more proximal -LRB- narrower and cortical -RRB- . Again , this artefact may introduce a bias mainly in cross-sectional studies . Calculation of endosteal bone loss is indirect and based on the assumptions such as uniform bone flattening , constant subperiosteal bone vBMD and proportional periosteal expansion in all axes . By contrast , the advantage of this concept is that we do not make any assumption on the morphological basis underlying the endosteal bone loss -LRB- cortical thinning or trabecular bone loss , proportion of cortical to trabecular bone , similar or different rates of trabecular and cortical bone loss , etc. -RRB- . Finally , our calculation of endosteal bone loss was carried out for the predominantly cortical sites and , although globally consistent with the cross-sectional data obtained by hr-pQCT , may not necessarily apply for the predominantly trabecular sites . In conclusion , in a large cohort of elderly men , age-related apparent bone loss -LRB- aBMD -RRB- at the hip , distal forearm and whole body was determined by the net bone loss -LRB- BMC -RRB- , except for the femoral neck . Apparent and net bone loss accelerated with age , whereas the periosteal expansion rate -LRB- widening of ROI -RRB- remained constant . At the distal forearm , age-related acceleration of the apparent bone loss was determined by the higher endosteal bone loss , whereas the periosteal apposition rate -LRB- estimated mass of deposited bone -RRB- remained constant .

B I O O B O O O B I O O B I O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O B I O O B I O O B I O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B O O B O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B I 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O O O O O O O O B I O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O 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O O O O O O O O O

bone loss
men
osteoporosis
periosteal apposition