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2.
J Bone Miner Res ; 35(1): 92-105, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31525280

RESUMO

Novel anabolic drug targets are needed to treat osteoporosis. Having established a large national cohort with unexplained high bone mass (HBM), we aimed to identify a novel monogenic cause of HBM and provide insight into a regulatory pathway potentially amenable to therapeutic intervention. We investigated a pedigree with unexplained HBM in whom previous sequencing had excluded known causes of monogenic HBM. Whole exome sequencing identified a rare (minor allele frequency 0.0023), highly evolutionarily conserved missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in this autosomal dominant family. The same mutation was identified in another two unrelated individuals both with HBM. In silico protein modeling predicts the mutation severely disrupts the MH1 DNA-binding domain of SMAD9. Affected individuals have bone mineral density (BMD) Z-scores +3 to +5, mandible enlargement, a broad frame, torus palatinus/mandibularis, pes planus, increased shoe size, and a tendency to sink when swimming. Peripheral quantitative computed tomography (pQCT) measurement demonstrates increased trabecular volumetric BMD and increased cortical thickness conferring greater predicted bone strength; bone turnover markers are low/normal. Notably, fractures and nerve compression are not found. Both genome-wide and gene-based association testing involving estimated BMD measured at the heel in 362,924 white British subjects from the UK Biobank Study showed strong associations with SMAD9 (PGWAS = 6 × 10-16 ; PGENE = 8 × 10-17 ). Furthermore, we found Smad9 to be highly expressed in both murine cortical bone-derived osteocytes and skeletal elements of zebrafish larvae. Our findings support SMAD9 as a novel HBM gene and a potential novel osteoanabolic target for osteoporosis therapeutics. SMAD9 is thought to inhibit bone morphogenetic protein (BMP)-dependent target gene transcription to reduce osteoblast activity. Thus, we hypothesize SMAD9 c.65T>C is a loss-of-function mutation reducing BMP inhibition. Lowering SMAD9 as a potential novel anabolic mechanism for osteoporosis therapeutics warrants further investigation. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

3.
Clin Endocrinol (Oxf) ; 92(1): 29-37, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31667854

RESUMO

OBJECTIVE: Bone turnover, which regulates bone mass, may exert metabolic consequences, particularly on markers of glucose metabolism and adiposity. To better understand these relationships, we examined cross-sectional associations between bone turnover markers (BTMs) and metabolic traits in a population with high bone mass (HBM, BMD Z-score ≥+3.2). DESIGN: ß-C-terminal telopeptide of type-I collagen (ß-CTX), procollagen type-1 amino-terminal propeptide (P1NP) and osteocalcin were assessed by electrochemiluminescence immunoassays. Metabolic traits, including lipids and glycolysis-related metabolites, were measured using nuclear magnetic resonance spectroscopy. Associations of BTMs with metabolic traits were assessed using generalized estimating equation linear regression, accounting for within-family correlation, adjusting for potential confounders (age, sex, height, weight, menopause, bisphosphonate and oral glucocorticoid use). RESULTS: A total of 198 adults with HBM had complete data, mean [SD] age 61.6 [13.7] years; 77% were female. Of 23 summary metabolic traits, citrate was positively related to all BTMs: adjusted ßß-CTX  = 0.050 (95% CI 0.024, 0.076), P = 1.71 × 10-4 , ßosteocalcin  = 6.54 × 10-4 (1.87 × 10-4 , 0.001), P = .006 and ßP1NP  = 2.40 × 10-4 (6.49 × 10-5 , 4.14 × 10-4 ), P = .007 (ß = increase in citrate (mmol/L) per 1 µg/L BTM increase). Inverse relationships of ß-CTX (ß = -0.276 [-0.434, -0.118], P = 6.03 × 10-4 ) and osteocalcin (-0.004 [-0.007, -0.001], P = .020) with triglycerides were also identified. We explored the generalizability of these associations in 3664 perimenopausal women (age 47.9 [4.4] years) from a UK family cohort. We confirmed a positive, albeit lower magnitude, association between ß-CTX and citrate (adjusted ßwomen  = 0.020 [0.013, 0.026], P = 1.95 × 10-9 ) and an inverse association of similar magnitude between ß-CTX and triglycerides (ß = -0.354 [-0.471, -0.237], P = 3.03 × 10-9 ). CONCLUSIONS: Bone resorption is positively related to circulating citrate and inversely related to triglycerides. Further studies are justified to determine whether plasma citrate or triglyceride concentrations are altered by factors known to modulate bone resorption, such as bisphosphonates.

4.
Curr Opin Rheumatol ; 32(1): 110-118, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31644466

RESUMO

PURPOSE OF REVIEW: To review recent findings concerning the observational relationship between hip shape and hip osteoarthritis (HOA) and their shared genetic influences, and the potential for clinical application. RECENT FINDINGS: Recent observational studies have strengthened the evidence that specific shape deformities, such as cam and acetabular dysplasia, are related to HOA. Statistical shape modelling has emerged as a method to measure hip shape holistically, with the added advantage that this can be applied to dual X-ray absorptiometry scan images. This has led to several additional aspects of hip shape variation being identified, such as a wider femoral neck and larger lesser trochanter, in association with HOA. Furthermore, this method has formed the basis of genetic studies identifying novel genetic influences on hip shape, several of which are shared with known genetic risk factors for HOA. SUMMARY: Shared genetic influences of hip shape and HOA raise the possibility that hip shape plays a casual role in the development of HOA, justifying preventive approaches aiming to combat these adverse consequences.

5.
BMJ Open ; 9(9): e030689, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31488492

RESUMO

INTRODUCTION: Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget's disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carry SQSTM1 mutations. METHODS AND ANALYSIS: People with a family history of PDB aged >30 years who test positive for SQSTM1 mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events. ETHICS AND DISSEMINATION: The study was approved by the Fife and Forth Valley Research Ethics Committee on 22 December 2008 (08/S0501/84). Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results of this trial will inform clinical practice by determining if early intervention with ZA in presymptomatic individuals with SQSTM1 mutations can prevent or slow the development of bone lesions with an adverse event profile that is acceptable. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

6.
JAMA Netw Open ; 2(8): e198918, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31397863

RESUMO

Importance: Bone health in early life is thought to influence the risk of osteoporosis in later life. Objective: To examine whether puberty timing is associated with bone mineral density accrual up to adulthood. Design, Setting, and Participants: This cohort study used data from the Avon Longitudinal Study of Parents and Children, a prospective population-based birth cohort initiated in 1991 to 1992 in southwest England. The participants were 6389 healthy British people who underwent regular follow-up, including up to 6 repeated bone density scans from ages 10 to 25 years. Data analysis was performed from June 2018 to June 2019. Exposures: Age at puberty from estimated age at peak height velocity (years). Main Outcomes and Measures: Gains per year in whole-body bone mineral density (grams per square centimeter), assessed by dual-energy x-ray absorptiometry at ages 10, 12, 14, 16, 18, and 25 years and modeled using linear splines. Results: A total of 6389 participants (3196 [50.0%] female) were included. The mean (SD) age at peak height velocity was 13.5 (0.9) years for male participants and 11.6 (0.8) years for female participants. Male participants gained bone mineral density at faster rates than did female participants, with the greatest gains in both male participants (0.139 g/cm2/y; 95% CI, 0.127-0.151 g/cm2/y) and female participants (0.106 g/cm2/y; 95% CI, 0.098-0.114 g/cm2/y) observed between the year before and 2 years after peak height velocity. When aligned by chronological age, per 1-year older age at puberty was associated with faster subsequent gains in bone mineral density; the magnitudes of faster gains were greatest between ages 14 and 16 years in both male participants (0.013 g/cm2/y; 95% CI, 0.011-0.015 g/cm2/y) and female participants (0.014 g/cm2/y; 95% CI, 0.014-0.015 g/cm2/y), were greater in male participants (0.011 g/cm2/y; 95% CI, 0.010-0.013 g/cm2/y) than in female participants (0.003 g/cm2/y; 95% CI, 0.003-0.004 g/cm2/y) between ages 16 and 18 years, and were least in both male participants (0.002 g/cm2/y; 95% CI, 0.001-0.003 g/cm2/y) and female participants (0.000 g/cm2/y; 95% CI, -0.001 to 0.000 g/cm2/y) between ages 18 and 25 years. Despite faster gains, older age at puberty was associated with persistently lower bone mineral density, changing from 0.050 g/cm2 (95% CI, -0.056 to -0.045 g/cm2) lower at age 14 years to 0.047 g/cm2 (95% CI, -0.051 to -0.043 g/cm2) lower at age 25 years in male participants and from 0.044 g/cm2 (95% CI, -0.046 to -0.041 g/cm2) to 0.034 g/cm2 (95% CI, -0.036 to -0.032 g/cm2) lower at the same ages in female participants. Conclusions and Relevance: People with older pubertal age should be advised on how to maximize bone mineral density and minimize its decrease in later life to help prevent fracture and osteoporosis.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31293695

RESUMO

Background: Little is known about how different physical activity (PA) parameters relate to cognitive function in older adults. Using accelerometers calibrated to detect vertical impacts from ground reaction forces we examined the associations of low, medium and higher impact PA with processing speed, verbal memory and cognitive state in older adults. Methods: Participants were 69-year old British men and women from the Medical Research Council National Survey of Health and Development included in a vertical impacts and bone sub-study (n = 558; 48.2% female). Counts of low (0.5 < g < 1.0 g), medium (1 < g < 1.5 g), or higher (≥1.5 g) magnitude impacts were derived from vertical acceleration peaks recorded over 7 days by hip-worn accelerometers. Processing speed was assessed by a timed visual letter search task, verbal memory by a 15-word list learning test and cognitive state by the Addenbrooke's Cognitive Examination (ACE-III). Potential confounders were childhood cognitive ability, adult socioeconomic position, body mass index and depression. Results: In initial sex-adjusted models, low magnitude impacts were associated with better performance in all three cognitive function tests; standard deviation differences in test scores per doubling in number of low impacts: letter search speed = 0.10 (95% confidence intervals (CI): 0.03 to 0.16), word learning test = 0.05 (95% CI: 0.00 to 0.11), ACE-III scale = 0.09 (95% CI: 0.03 to 0.14). After adjustment for confounders, differences persisted for letter search speed (0.09; 95% CI: 0.02 to 0.16) but were closer to the null for the word learning test (0.02; 95% CI: - 0.04 to 0.07) and ACE-III scores (0.04; 95% CI: - 0.01 to 0.09). Low impacts remained associated with letter search speed after sensitivity analyses excluding those with functional and musculoskeletal problems, and after adjustment for impacts in higher bands. Modest positive associations between higher magnitude impacts and cognitive test scores were most likely due to chance. Conclusion: Accelerometer-derived low impact physical activity was associated with better visual processing speed in 69-year old men and women independently of childhood cognitive ability and other measured confounders. Day-to-day low impact physical activity may therefore have the potential to benefit cognitive health in older adults.

8.
Int J Epidemiol ; 48(4): 1152-1160, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535285

RESUMO

BACKGROUND: Little is understood about the causes of adolescent onset idiopathic scoliosis (AIS). No prospective studies assessing the association between physical activity and idiopathic adolescent scoliosis have been carried out. We aimed to carry out the first prospective population-based study of this association. METHODS: The Avon Longitudinal Study of Parents and Children (ALSPAC) collected self-reported measures of physical ability/activity at ages 18 months and 10 years. Objective measures of physical activity were collected by accelerometry at age 11 years. scoliosis was identified using the dxa scoliosis Method at age 15 years. Participants with scoliosis at age 10 years were excluded. RESULTS: Of 4640 participants at age 15 years who had DXA scans, 267 (5.8%) had scoliosis. At age 18 months, those infants who were able to stand up without being supported were 66% less likely to have developed scoliosis by age 15 (P = 0.030) compared with infants who could not. Those children whose mothers reported they did most vigorous physical activity at age 10 years were 53% less likely to develop scoliosis (P = 0.027). Those children who did more objectively measured moderate/vigorous physical activity at age 11 were 30% less likely to have developed scoliosis (P < 0.001). Results were not affected by adjustment for age, gender, lean mass, fat mass or back pain. CONCLUSIONS: We report reduced physical ability and activity as early as age 18 months in those who go on to develop scoliosis by age 15 years. Further research is justified to examine the mechanisms underlying this association.

9.
Bone ; 114: 62-71, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29883787

RESUMO

BACKGROUND: Generalised high bone mass (HBM), associated with features of a mild skeletal dysplasia, has a prevalence of 0.18% in a UK DXA-scanned adult population. We hypothesized that the genetic component of extreme HBM includes contributions from common variants of small effect and rarer variants of large effect, both enriched in an extreme phenotype cohort. METHODS: We performed a genome-wide association study (GWAS) of adults with either extreme high or low BMD. Adults included individuals with unexplained extreme HBM (n = 240) from the UK with BMD Z-scores ≥+3.2, high BMD females from the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) (n = 1055) with Z-scores +1.5 to +4.0 and low BMD females also part of AOGC (n = 900), with Z-scores -1.5 to -4.0. Following imputation, we tested association between 6,379,332 SNPs and total hip and lumbar spine BMD Z-scores. For potential target genes, we assessed expression in human osteoblasts and murine osteocytes. RESULTS: We observed significant enrichment for associations with established BMD-associated loci, particularly those known to regulate endochondral ossification and Wnt signalling, suggesting that part of the genetic contribution to unexplained HBM is polygenic. Further, we identified associations exceeding genome-wide significance between BMD and four loci: two established BMD-associated loci (5q14.3 containing MEF2C and 1p36.12 containing WNT4) and two novel loci: 5p13.3 containing NPR3 (rs9292469; minor allele frequency [MAF] = 0.33%) associated with lumbar spine BMD and 11p15.2 containing SPON1 (rs2697825; MAF = 0.17%) associated with total hip BMD. Mouse models with mutations in either Npr3 or Spon1 have been reported, both have altered skeletal phenotypes, providing in vivo validation that these genes are physiologically important in bone. NRP3 regulates endochondral ossification and skeletal growth, whilst SPON1 modulates TGF-ß regulated BMP-driven osteoblast differentiation. Rs9292469 (downstream of NPR3) also showed some evidence for association with forearm BMD in the independent GEFOS sample (n = 32,965). We found Spon1 was highly expressed in murine osteocytes from the tibiae, femora, humeri and calvaria, whereas Npr3 expression was more variable. CONCLUSION: We report the most extreme-truncate GWAS of BMD performed to date. Our findings, suggest potentially new anabolic bone regulatory pathways that warrant further study.


Assuntos
Densidade Óssea/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla/métodos , Vértebras Lombares/diagnóstico por imagem , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Proteínas da Matriz Extracelular/genética , Feminino , Humanos , Vértebras Lombares/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade
10.
J Gerontol A Biol Sci Med Sci ; 73(5): 643-651, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29028919

RESUMO

Background: High impact physical activity (PA) is thought to improve skeletal health, but its relation to other health outcomes are unclear. We investigated associations between PA impact magnitude and body mass index (BMI) in older adults. Methods: Data were taken from the Cohort for Skeletal Health in Bristol and Avon (COSHIBA), Hertfordshire Cohort Study, and MRC National Survey of Health and Development. Vertical acceleration peaks from 7-day hip-worn accelerometer recordings were used to classify PA as low (0.5 < g < 1.0g), medium (1 < g < 1.5g), or higher (≥1.5g) impact. Cohort-specific associations of low, medium, and higher impact PA with BMI were examined using linear regressions and estimates combined using random-effects meta-analysis. Results: A total of 1182 participants (mean age = 72.7 years, 68% female) were included. Low, medium, and higher impact PA were inversely related to BMI in initial models. After adjustment for confounders and other impacts, low, but not medium or higher, impacts were inversely related to BMI (-0.31, p < .001: overall combined standard deviation change in BMI per doubling in the number of low impacts). In adjusted analyses of body composition measured by dual-energy X-ray absorptiometry in COSHIBA, low, but not medium or higher, impacts were inversely related to total body fat mass (-0.19, p < .001) and android:gynoid fat mass ratio (-0.16, p = .01), whereas high impact PA was weakly and positively associated with lean mass (0.05, p = .06). Conclusions: Greater exposure to PA producing low magnitude vertical impacts was associated with lower BMI and fat mass at older age. Low impact PA may help reduce obesity risk in older adults.


Assuntos
Índice de Massa Corporal , Atividade Motora/fisiologia , Absorciometria de Fóton , Acelerometria , Idoso , Composição Corporal , Estudos de Coortes , Feminino , Humanos , Pós-Menopausa , Inquéritos e Questionários
11.
J Gerontol A Biol Sci Med Sci ; 73(5): 652-659, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29182712

RESUMO

Background: Sarcopenia has been associated with reduced physical activity (PA). We aimed to determine if sarcopenia, and specific components of muscle size, function, and physical performance, are associated with high impacts achieved during habitual PA, as these are related to bone strength in community-dwelling older women. Methods: Participants were older women from the Cohort of Skeletal Health in Bristol and Avon. We defined sarcopenia using the EWGSOP criteria. Lower limb peak muscle power and force were assessed using Jumping Mechanography (JM). High vertical impacts were assessed by tri-axial accelerometry (at least 1.5g above gravity). Cross-sectional associations were analyzed by linear regression, adjusting for age, height and weight (or fat mass for models including appendicular lean mass index), comorbidities, smoking, alcohol, and Index of Multiple Deprivation. Results: Our analyses included 380 participants, with mean age 76.7 (SD 3.0) years; 242 (64%) also completed JM. In age-adjusted analysis, a negative relationship was observed between severity of sarcopenia and high, but not medium or low, impacts (p = .03 for trend). Regarding components of sarcopenia underlying this relationship, multivariable analyses revealed that gait speed (ß 1.47 [95% CI 1.14, 1.89], [ß-1] reflects the proportionate increase in high impacts per SD increase in exposure) and peak force (1.40 [1.07, 1.84]) were independently associated with high impacts. Conclusions: Older women with sarcopenia experienced fewer bone-strengthening high impacts than those with presarcopenia or without sarcopenia. To increase bone strengthening activity in older women, interventions need to improve both lower limb muscle force and walking speed.


Assuntos
Densidade Óssea/fisiologia , Atividade Motora/fisiologia , Força Muscular/fisiologia , Sarcopenia/fisiopatologia , Absorciometria de Fóton , Acelerometria , Idoso , Antropometria , Inglaterra , Feminino , Avaliação Geriátrica , Gravitação , Força da Mão/fisiologia , Humanos , Tomografia Computadorizada por Raios X/métodos , Velocidade de Caminhada/fisiologia
12.
J Public Health (Oxf) ; 40(4): 727-737, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29237047

RESUMO

Background: Exposure to higher magnitude vertical impacts is thought to benefit bone health. The correlates of this high-impact physical activity (PA) in later life are unknown. Methods: Participants were from the Cohort for Skeletal Health in Bristol and Avon, Hertfordshire Cohort Study and MRC National Survey of Health and Development. Associations of demographic, behavioural, physiological and psychological factors with vertical acceleration peaks ≥1.5 g (i.e. high-impact PA) from 7-day hip-worn accelerometer recordings were examined using linear regression. Results: A total of 1187 participants (mean age = 72.7 years, 66.6% females) were included. Age, sex, education, active transport, self-reported higher impact PA, walking speed and self-rated health were independently associated with high-impact PA whereas BMI and sleep quality showed borderline independent associations. For example, differences in log-high-impact counts were 0.50 (P < 0.001) for men versus women and -0.56 (P < 0.001) for worst versus best self-rated health. Our final model explained 23% of between-participant variance in high impacts. Other correlates were not associated with high-impact activity after adjustment. Conclusions: Besides age and sex, several factors were associated with higher impact PA in later life. Our findings help identify characteristics of older people that might benefit from interventions designed to promote osteogenic PA.


Assuntos
Exercício , Aptidão Física , Acelerometria , Idoso , Idoso de 80 Anos ou mais , Feminino , Nível de Saúde , Humanos , Masculino , Reino Unido/epidemiologia
13.
Prev Med Rep ; 8: 183-189, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29134173

RESUMO

High impact physical activity (PA) is thought to benefit bone. We examined associations of lifetime walking and weight bearing exercise with accelerometer-measured high impact and overall PA in later life. Data were from 848 participants (66.2% female, mean age = 72.4 years) from the Cohort for Skeletal Health in Bristol and Avon, Hertfordshire Cohort Study and MRC National Survey of Health and Development. Acceleration peaks from seven-day hip-worn accelerometer recordings were used to derive counts of high impact and overall PA. Walking and weight bearing exercise up to age 18, between 18-29, 30-49 and since age 50 were recalled using questionnaires. Responses in each age category were dichotomised and cumulative scores derived. Linear regression was used for analysis. Greater lifetime walking was related to higher overall, but not high impact PA, whereas greater lifetime weight bearing exercise was related to higher overall and high impact PA. For example, fully-adjusted differences in log-overall and log-high impact PA respectively for highest versus lowest lifetime scores were: walking [0.224 (0.087, 0.362) and 0.239 (- 0.058, 0.536)], and weight bearing exercise [0.754 (0.432, 1.076) and 0.587 (0.270, 0.904)]. For both walking and weight bearing exercise, associations were strongest in the 'since age 50' category. Those reporting the most walking and weight bearing exercise since age 50 had highest overall and high impact PA, e.g. fully-adjusted difference in log-high impact PA versus least walking and weight bearing exercise = 0.588 (0.226, 0.951). Promoting walking and weight bearing exercise from midlife may help increase potentially osteogenic PA levels in later life.

14.
Int J Geriatr Psychiatry ; 32(9): 968-976, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-27428711

RESUMO

OBJECTIVE: A proportion of older individuals report subjective memory complaints (SMCs), which can predict the development of cognitive impairment and dementia. Previous studies based on secondary care suggest that SMC is also associated with other adverse health consequences, including falls, fractures and increased healthcare utilization. In this study, we aimed to establish whether similar findings are observed in the wider population. METHODS: Prospective analysis of the Cohort for Skeletal Health in Bristol and Avon, a population-based cohort recruited from primary care, was carried out. Data were collected by self-completion questionnaire at baseline and 2 years. SMC was assessed at baseline. Fractures, measures of falls, mobility and healthcare utilization were assessed 2 years later. A random 5% subsample of data was validated against electronic general practitioner records. Logistic regression was used to identify independent associations, following adjustment for a range of confounders assessed at baseline. RESULTS: Data were available on 3184 women. Three hundred and fifty participants (11.0%) reported SMC. They were older (73.3 ± 4.5 vs 72.0 ± 4.2 years) and less mobile compared with those not reporting SMC. SMCs at baseline were associated with an increased risk of upper limb fractures over the following 2 years (OR 1.72, 95% CI 1.02-2.90). SMCs were also associated with an increased risk of falls (OR 1.83, 95% CI 1.41-2.38) and increased healthcare utilization (OR for hospital appointments 2.20, 95% CI 1.26-3.86). No association was observed with bone mineral density at any site. CONCLUSIONS: Subjective memory complaints are important markers of adverse health outcomes and should prompt interventions to reduce fractures such as physiotherapy-led fall reduction programmes. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Acidentes por Quedas/estatística & dados numéricos , Fraturas Ósseas/epidemiologia , Transtornos da Memória/complicações , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/complicações , Inglaterra/epidemiologia , Feminino , Humanos , Modelos Logísticos , Prevalência , Atenção Primária à Saúde/estatística & dados numéricos , Estudos Prospectivos , Risco , Inquéritos e Questionários
15.
J Pain ; 18(3): 285-294, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27845196

RESUMO

Although many studies have investigated the overlap between pain phenotypes and chronic fatigue syndrome (CFS) in adults, little is known about the relationship between these conditions in adolescents. The study's aim was therefore to identify whether a relationship exists between chronic widespread pain (CWP) and CFS in adolescents and investigate whether the two share common associations with a set of covariates. A questionnaire was administered to offspring of the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 17, asking about site, duration, and pain intensity, from which participants with CWP were identified. At the same research clinic, a computer-based Revised Clinical Interview Schedule was filled out, from which a classification of CFS was obtained. The relationship between selected covariates and CFS and CWP was investigated using a variety of logistic, ordinal logistic, and multinomial regressions. We identified 3,214 adolescents with complete data for all outcomes and covariates. There were 82 (2.6%) individuals classified as CFS and 145 (4.5%) as CWP. A classification of CFS resulted in an increased likelihood of having CWP (odds ratio = 3.87; 95% confidence interval, 2.05-7.31). Female adolescents were approximately twice as likely to have CFS or CWP, with multinomial regression revealing a greater sex effect for CWP compared with CFS. Those with exclusive CFS were more likely to report higher levels of pain and greater effect of pain compared with those without CFS, although associations attenuated to the null after adjustment for covariates, which did not occur in those with exclusive CWP. Multinomial regression revealed that relative to having neither CFS nor CWP, a 1-unit increase in the depression and anxiety scales increased the risk of having exclusive CFS and, to a greater extent, the risk of having comorbid CFS and CWP, but not exclusive CWP, which was only related to anxiety. PERSPECTIVE: In this cohort, 14.6% of adolescents with CFS have comorbid CWP. The likely greater proportion of more mild cases observed in this epidemiological study means that prevalence of overlap may be underestimated compared with those attending specialist services. Clinicians should be aware of the overlap between the 2 conditions and carefully consider treatment options offered.


Assuntos
Dor Crônica/epidemiologia , Síndrome de Fadiga Crônica/epidemiologia , Adolescente , Ansiedade/epidemiologia , Ansiedade/etiologia , Dor Crônica/complicações , Estudos de Coortes , Comorbidade , Depressão/epidemiologia , Depressão/etiologia , Síndrome de Fadiga Crônica/complicações , Feminino , Humanos , Masculino , Medição da Dor , Fatores Sexuais , Reino Unido/epidemiologia
17.
J Bone Miner Res ; 31(12): 2139-2148, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27357175

RESUMO

Osteoporosis and cardiovascular disease (CVD) are both common causes of morbidity and mortality. Previous studies, mainly of people older than 60 years, suggest a relationship between these conditions. Our aim was to determine the association between bone characteristics and CVD markers in younger and middle-aged individuals. Women (n = 3366) and their adolescent offspring (n = 4368) from the UK population-based cohort study, Avon Longitudinal Study of Parents and Children (ALSPAC), were investigated. We measured total body (TB) and hip bone mineral density (BMD), TB bone area (BA) and bone mineral content (BMC) by dual-energy X-ray absorptiometry (DXA), and carotid intima-media thickness (cIMT) by high-resolution ultrasound. Arterial distensibility was calculated as the difference between systolic and diastolic arterial diameters. Linear regression determined associations between bone exposures and cIMT (in adolescents) and both cIMT and arterial distensibility (in women), generating partial correlation coefficients. Mean (SD) age of women was 48 (4.2) years, body mass index (BMI) was 26.2 (5.0) kg/m2 , and 71% were premenopausal. In confounder-adjusted analyses (age, height, lean mass, fat mass, menopause, smoking, estrogen replacement, calcium/vitamin D supplementation, and education) TB and hip BMD were both positively associated with cIMT (0.071 [0.030, 0.112], p = 0.001; 0.063 [0.025, 0.101], p = 0.001, respectively). Femoral neck BMD and TB BMD, BMC, and BA were positively associated with arterial distensibility. Mean (SD) age of adolescents was 17 (0.4) years, BMI was 23 (4.1) kg/m2 , and 44.5% were male. Total hip and TB measurements were positively associated with cIMT, with similar magnitudes of association to those found in their mothers. In contrast to most published findings, we identified weak positive associations between BMD and cIMT in predominantly premenopausal women and their adolescent offspring. We found greater femoral neck BMD and TB DXA measurements to be associated with reduced arterial stiffness. Rather than a relationship with preclinical atherosclerosis, in these relatively young populations, we speculate our associations between BMD, cIMT, and arterial distensibility may reflect a shared relationship between bone and vascular growth and development. © 2016 American Society for Bone and Mineral Research.


Assuntos
Densidade Óssea , Espessura Intima-Media Carotídea , Pré-Menopausa/fisiologia , Absorciometria de Fóton , Adolescente , Adulto , Artérias/fisiologia , Estudos de Coortes , Feminino , Quadril/diagnóstico por imagem , Humanos
18.
J Bone Miner Res ; 31(10): 1855-1864, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-26999363

RESUMO

We investigated relationships between placental size and offspring adolescent bone indices using a population-based, mother-offspring cohort. The Avon Longitudinal Study of Parents and Children (ALSPAC) recruited pregnant women from the southwest of England between 1991 and 1993. There were 12,942 singleton babies born at term who survived at least the first 12 months. From these, 8933 placentas were preserved in formaldehyde, with maternal permission for their use in research studies. At the approximate age of 15.5 years, the children underwent a dual-energy X-ray absorptiometry (DXA) scan (measurements taken of the whole body minus head bone area [BA], bone mineral content [BMC], and areal bone mineral density [aBMD]). A peripheral quantitative computed tomography (pQCT) scan (Stratec XCT2000L; Stratec, Pforzheim, Germany) at the 50% tibial site was performed at this visit and at approximately age 17.7 years. In 2010 a sample of 1680 placentas were measured and photographed. To enable comparison of effect size across different variables, predictor and outcome variables were standardized to Z-scores and therefore results may be interpreted as partial correlation coefficients. Complete placental, DXA, and pQCT data were available for 518 children at age 15.5 years. After adjustment for gender, gestational age at birth, and age at time of pQCT, the placental area was positively associated with endosteal circumference (ß [95% CI]: 0.21 [0.13, 0.30], p < 0.001), periosteal circumference (ß [95% CI]: 0.19 [0.10, 0.27], p < 0.001), and cortical area (ß [95% CI]: 0.10 [0.01, 0.18], p = 0.03), and was negatively associated with cortical density (ß [95% CI]: -0.11 [-0.20, -0.03], p = 0.01) at age 15.5 years. Similar relationships were observed for placental volume, and after adjustment for additional maternal and offspring covariates. These results suggest that previously observed associations between placental size and offspring bone development persist into older childhood, even during puberty, and that placental size is differentially related to bone size and volumetric density. © 2016 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Absorciometria de Fóton , Densidade Óssea , Placenta/anatomia & histologia , Tíbia , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Tamanho do Órgão , Gravidez , Estudos Prospectivos , Tíbia/diagnóstico por imagem , Tíbia/metabolismo
19.
J Bone Miner Res ; 31(3): 640-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26348019

RESUMO

High bone mass (HBM) can be an incidental clinical finding; however, monogenic HBM disorders (eg, LRP5 or SOST mutations) are rare. We aimed to determine to what extent HBM is explained by mutations in known HBM genes. A total of 258 unrelated HBM cases were identified from a review of 335,115 DXA scans from 13 UK centers. Cases were assessed clinically and underwent sequencing of known anabolic HBM loci: LRP5 (exons 2, 3, 4), LRP4 (exons 25, 26), SOST (exons 1, 2, and the van Buchem's disease [VBD] 52-kb intronic deletion 3'). Family members were assessed for HBM segregation with identified variants. Three-dimensional protein models were constructed for identified variants. Two novel missense LRP5 HBM mutations ([c.518C>T; p.Thr173Met], [c.796C>T; p.Arg266Cys]) were identified, plus three previously reported missense LRP5 mutations ([c.593A>G; p.Asn198Ser], [c.724G>A; p.Ala242Thr], [c.266A>G; p.Gln89Arg]), associated with HBM in 11 adults from seven families. Individuals with LRP5 HBM (∼prevalence 5/100,000) displayed a variable phenotype of skeletal dysplasia with increased trabecular BMD and cortical thickness on HRpQCT, and gynoid fat mass accumulation on DXA, compared with both non-LRP5 HBM and controls. One mostly asymptomatic woman carried a novel heterozygous nonsense SOST mutation (c.530C>A; p.Ser177X) predicted to prematurely truncate sclerostin. Protein modeling suggests the severity of the LRP5-HBM phenotype corresponds to the degree of protein disruption and the consequent effect on SOST-LRP5 binding. We predict p.Asn198Ser and p.Ala242Thr directly disrupt SOST binding; both correspond to severe HBM phenotypes (BMD Z-scores +3.1 to +12.2, inability to float). Less disruptive structural alterations predicted from p.Arg266Cys, p.Thr173Met, and p.Gln89Arg were associated with less severe phenotypes (Z-scores +2.4 to +6.2, ability to float). In conclusion, although mutations in known HBM loci may be asymptomatic, they only account for a very small proportion (∼3%) of HBM individuals, suggesting the great majority are explained by either unknown monogenic causes or polygenic inheritance.


Assuntos
Osso e Ossos/patologia , Loci Gênicos , Mutação/genética , Adulto , Idoso , Estudos de Casos e Controles , Terapia de Reposição de Estrogênios , Éxons/genética , Feminino , Humanos , Masculino , Menopausa , Pessoa de Meia-Idade , Modelos Moleculares , Tamanho do Órgão , Fenótipo , Adulto Jovem
20.
Psychol Health Med ; 21(1): 1-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26042587

RESUMO

The aim of the present study was to investigate the influence of anxiety at 13 years of age on the presence of chronic pain, pain-related anxiety, and pain-related disability at 17 years of age in a large longitudinal cohort. We hypothesized that mother-reported anxiety at 13 would be associated with the presence of chronic pain at 17 and an increase in pain-related anxiety using all available data from the longitudinal cohort. Further, we hypothesized that anxiety at 13 would predict pain-related disability in adolescents who reported chronic pain at 17 years of age. Participants were recruited from the Avon Longitudinal Study of Parents and Children based in the UK who attended a university research clinic at 17. Child anxiety (reported by the mother) was extracted at child age 13, and self-report of the presence of chronic pain, pain-related anxiety, and pain-related disability at 17. Analyses revealed that child anxiety at 13 was not significantly associated with the presence of chronic pain at 17 (n = 842). However, anxiety at 13 was significantly associated with pain-related anxiety at 17 (n = 1831). For the subsample of adolescents who reported chronic pain, anxiety at 13 was associated with pain-related disability at 17 (n = 393). Further analyses revealed that pain-related anxiety at 17 mediated the association between anxiety at 13 and pain-related disability at 17, suggesting that pain-related anxiety should be a target for treatment in adolescents with chronic pain, to reduce the impact of pain in later adolescence. General anxiety at 13 was unrelated to the presence of chronic pain at 17, but should be considered a risk factor for later pain-related anxiety and disability in a subset of adolescents who develop chronic pain.


Assuntos
Ansiedade/complicações , Dor Crônica/etiologia , Dor Crônica/psicologia , Pessoas com Deficiência/psicologia , Adolescente , Pessoas com Deficiência/estatística & dados numéricos , Feminino , Humanos , Estudos Longitudinais , Masculino , Autorrelato
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