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Back pain lifetime incidence is 60%-70%, while 12%-20% of older women have vertebral fractures (VFs), often with back pain. We aimed to provide objective evidence, currently lacking, regarding whether back pain and VFs affect physical activity (PA). We recruited 69 women with recent back pain (age 74.5 ± 5.4 years). Low- (0.5 < g < 1.0), medium- (1.0 ≤ g < 1.5), and high-impact (g ≥ 1.5) PA and walking time were measured (100 Hz for 7 days, hip-worn accelerometer). Linear mixed-effects models assessed associations between self-reported pain and PA, and group differences (VFs from spine radiographs/no-VF) in PA. Higher daily pain was associated with reduced low (ß = -0.12, 95% confidence interval, [-0.22, -0.03], p = .013) and medium-impact PA (ß = -0.11, 95% confidence interval, [-0.21, -0.01], p = .041), but not high-impact PA or walking time (p > .11). VFs were not associated with PA (all p > .2). Higher daily pain levels but not VFs were associated with reduced low- and medium-impact PA, which could increase sarcopenia and falls risk in older women with back pain.
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Dolor de Espalda , Ejercicio Físico , Posmenopausia , Fracturas de la Columna Vertebral , Humanos , Femenino , Anciano , Fracturas de la Columna Vertebral/fisiopatología , Dolor de Espalda/fisiopatología , Dolor de Espalda/etiología , Ejercicio Físico/fisiología , Posmenopausia/fisiología , Acelerometría , Dimensión del Dolor , Caminata/fisiología , Anciano de 80 o más AñosRESUMEN
Musculoskeletal research should synergistically investigate bone and muscle to inform approaches for maintaining mobility and to avoid bone fractures. The relationship between sarcopenia and osteoporosis, integrated in the term 'osteosarcopenia', is underscored by the close association shown between these two conditions in many studies, whereby one entity emerges as a predictor of the other. In a recent workshop of Working Group (WG) 2 of the EU Cooperation in Science and Technology (COST) Action 'Genomics of MusculoSkeletal traits Translational Network' (GEMSTONE) consortium (CA18139), muscle characterization was highlighted as being important, but currently under-recognized in the musculoskeletal field. Here, we summarize the opinions of the Consortium and research questions around translational and clinical musculoskeletal research, discussing muscle phenotyping in human experimental research and in two animal models: zebrafish and mouse.
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Fenotipo , Animales , Humanos , Músculo Esquelético/metabolismo , Pez Cebra , Ratones , Sarcopenia/metabolismo , Sarcopenia/fisiopatología , Enfermedades Musculoesqueléticas/fisiopatología , Enfermedades Musculoesqueléticas/genética , Osteoporosis/metabolismo , Osteoporosis/patologíaRESUMEN
INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment. METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB. RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups. CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB. TRIAL REGISTRATION NUMBER: ISRCTN11616770.
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Difosfonatos , Osteítis Deformante , Humanos , Difosfonatos/efectos adversos , Osteítis Deformante/complicaciones , Osteítis Deformante/tratamiento farmacológico , Osteítis Deformante/genética , Proteína Sequestosoma-1/genética , Ácido Zoledrónico/uso terapéutico , Pruebas Genéticas , BiomarcadoresRESUMEN
BACKGROUND: Global sclerostin inhibition reduces fracture risk efficiently but has been associated with cardiovascular side effects. The strongest genetic signal for circulating sclerostin is in the B4GALNT3 gene region, but the causal gene is unknown. B4GALNT3 expresses the enzyme beta-1,4-N-acetylgalactosaminyltransferase 3 that transfers N-acetylgalactosamine onto N-acetylglucosaminebeta-benzyl on protein epitopes (LDN-glycosylation). METHODS: To determine if B4GALNT3 is the causal gene, B4galnt3-/- mice were developed and serum levels of total sclerostin and LDN-glycosylated sclerostin were analysed and mechanistic studies were performed in osteoblast-like cells. Mendelian randomization was used to determine causal associations. FINDINGS: B4galnt3-/- mice had higher circulating sclerostin levels, establishing B4GALNT3 as a causal gene for circulating sclerostin levels, and lower bone mass. However, serum levels of LDN-glycosylated sclerostin were lower in B4galnt3-/- mice. B4galnt3 and Sost were co-expressed in osteoblast-lineage cells. Overexpression of B4GALNT3 increased while silencing of B4GALNT3 decreased the levels of LDN-glycosylated sclerostin in osteoblast-like cells. Mendelian randomization demonstrated that higher circulating sclerostin levels, genetically predicted by variants in the B4GALNT3 gene, were causally associated with lower BMD and higher risk of fractures but not with higher risk of myocardial infarction or stroke. Glucocorticoid treatment reduced B4galnt3 expression in bone and increased circulating sclerostin levels and this may contribute to the observed glucocorticoid-induced bone loss. INTERPRETATION: B4GALNT3 is a key factor for bone physiology via regulation of LDN-glycosylation of sclerostin. We propose that B4GALNT3-mediated LDN-glycosylation of sclerostin may be a bone-specific osteoporosis target, separating the anti-fracture effect of global sclerostin inhibition, from indicated cardiovascular side effects. FUNDING: Found in acknowledgements.
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Proteínas Adaptadoras Transductoras de Señales , Densidad Ósea , N-Acetilgalactosaminiltransferasas , Animales , Ratones , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Huesos , Densidad Ósea/genética , Glucocorticoides/farmacología , Glicosilación , HumanosRESUMEN
The contribution of shape changes to hip osteoarthritis (HOA) remains unclear, as is the extent to which these vary according to HOA severity. In the present study, we used statistical shape modeling (SSM) to evaluate relationships between hip shape and HOA of different severities using UK Biobank DXA images. We performed a cross-sectional study in individuals with left hip dual-energy X-ray absorptiometry (DXA) scans. Statistical shape modeling (SSM) was used to quantify hip shape. Radiographic HOA (rHOA) was classified using osteophyte size and number and joint space narrowing. HOA outcomes ranged in severity from moderate (grade 2) to severe (grade ≥3) rHOA, hospital-diagnosed HOA, and subsequent total hip replacement (THR). Confounder-adjusted logistic regression between the top 10 hip shape modes (HSMs) and OA outcomes was performed. Further models adjusted for alpha angle (AA) and lateral center-edge angle (LCEA), reflecting acetabular dysplasia and cam morphology, respectively. Composite HSM figures were produced combining HSMs associated with separate OA outcomes. A total of 40,311 individuals were included (mean 63.7 years, 47.8% male), of whom 5.7% had grade 2 rHOA, 1.7% grade ≥3 rHOA, 1.3% hospital-diagnosed HOA, and 0.6% underwent THR. Composite HSM figures for grade 2 rHOA revealed femoral neck widening, increased acetabular coverage, and enlarged lesser and greater trochanters. In contrast, grade ≥3 rHOA, hospital-diagnosed HOA, and THR were suggestive of cam morphology and reduced acetabular coverage. Associations between HSMs depicting cam morphology and reduced acetabular coverage and more severe HOA were attenuated by AA and LCEA adjustment, respectively. Relationships between hip shape and HOA differed according to severity. Notably, cam morphology and acetabular dysplasia were features of severe HOA, but unrelated to moderate disease, suggesting possible prognostic utility. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Osteoartritis de la Cadera , Femenino , Humanos , Masculino , Bancos de Muestras Biológicas , Estudios Transversales , Articulación de la Cadera , Aprendizaje Automático , Osteoartritis de la Cadera/diagnóstico por imagen , Reino UnidoRESUMEN
BACKGROUND: osteoporotic vertebral fractures (OVFs) identify people at high risk of future fractures, but despite this, less than a third come to clinical attention. The objective of this study was to develop a clinical tool to aid health care professionals decide which older women with back pain should have a spinal radiograph. METHODS: a population-based cohort of 1,635 women aged 65+ years with self-reported back pain in the previous 4 months were recruited from primary care. Exposure data were collected through self-completion questionnaires and physical examination, including descriptions of back pain and traditional risk factors for osteoporosis. Outcome was the presence/absence of OVFs on spinal radiographs. Logistic regression models identified independent predictors of OVFs, with the area under the (receiver operating) curve calculated for the final model, and a cut-point was identified. RESULTS: mean age was 73.9 years and 209 (12.8%) had OVFs. The final Vfrac model comprised 15 predictors of OVF, with an AUC of 0.802 (95% CI: 0.764-0.840). Sensitivity was 72.4% and specificity was 72.9%. Vfrac identified 93% of those with more than one OVF and two-thirds of those with one OVF. Performance was enhanced by inclusion of self-reported back pain descriptors, removal of which reduced AUC to 0.742 (95% CI: 0.696-0.788) and sensitivity to 66.5%. Health economic modelling to support a future trial was favourable. CONCLUSIONS: the Vfrac clinical tool appears to be valid and is improved by the addition of self-reported back pain symptoms. The tool now requires testing to establish real-world clinical and cost-effectiveness.
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Fracturas Osteoporóticas , Fracturas de la Columna Vertebral , Anciano , Dolor de Espalda/diagnóstico , Dolor de Espalda/epidemiología , Dolor de Espalda/etiología , Estudios de Cohortes , Análisis Costo-Beneficio , Femenino , Humanos , Fracturas Osteoporóticas/diagnóstico por imagen , Fracturas Osteoporóticas/epidemiología , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/epidemiologíaRESUMEN
The human microbiota functions at the interface between diet, medication-use, lifestyle, host immune development and health. It is therefore closely aligned with many of the recognised modifiable factors that influence bone mass accrual in the young, and bone maintenance and skeletal decline in older populations. While understanding of the relationship between micro-organisms and bone health is still in its infancy, two decades of broader microbiome research and discovery supports a role of the human gut microbiome in the regulation of bone metabolism and pathogenesis of osteoporosis as well as its prevention and treatment. Pre-clinical research has demonstrated biological interactions between the microbiome and bone metabolism. Furthermore, observational studies and randomized clinical trials have indicated that therapeutic manipulation of the microbiota by oral administration of probiotics may influence bone turnover and prevent bone loss in humans. In this paper, we summarize the content, discussion and conclusions of a workshop held by the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society in October, 2020. We provide a detailed review of the literature examining the relationship between the microbiota and bone health in animal models and in humans, as well as formulating the agenda for key research priorities required to advance this field. We also underscore the potential pitfalls in this research field that should be avoided and provide methodological recommendations to facilitate bridging the gap from promising concept to a potential cause and intervention target for osteoporosis.
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Microbioma Gastrointestinal , Microbiota , Osteoporosis , Probióticos , Animales , Huesos/metabolismo , Microbioma Gastrointestinal/fisiología , Osteoporosis/metabolismo , Osteoporosis/prevención & control , Probióticos/uso terapéuticoRESUMEN
OBJECTIVES: Observational analyses suggest that high bone mineral density (BMD) is a risk factor for osteoarthritis (OA); it is unclear whether this represents a causal effect or shared aetiology and whether these relationships are body mass index (BMI)-independent. We performed bidirectional Mendelian randomization (MR) to uncover the causal pathways between BMD, BMI and OA. METHODS: One-sample (1S)MR estimates were generated by two-stage least-squares regression. Unweighted allele scores instrumented each exposure. Two-sample (2S)MR estimates were generated using inverse-variance weighted random-effects meta-analysis. Multivariable MR (MVMR), including BMD and BMI instruments in the same model, determined the BMI-independent causal pathway from BMD to OA. Latent causal variable (LCV) analysis, using weight-adjusted femoral neck (FN)-BMD and hip/knee OA summary statistics, determined whether genetic correlation explained the causal effect of BMD on OA. RESULTS: 1SMR provided strong evidence for a causal effect of BMD estimated from heel ultrasound (eBMD) on hip and knee OA {odds ratio [OR]hip = 1.28 [95% confidence interval (CI) = 1.05, 1.57], p = 0.02, ORknee = 1.40 [95% CI = 1.20, 1.63], p = 3 × 10-5, OR per standard deviation [SD] increase}. 2SMR effect sizes were consistent in direction. Results suggested that the causal pathways between eBMD and OA were bidirectional (ßhip = 1.10 [95% CI = 0.36, 1.84], p = 0.003, ßknee = 4.16 [95% CI = 2.74, 5.57], p = 8 × 10-9, ß = SD increase per doubling in risk). MVMR identified a BMI-independent causal pathway between eBMD and hip/knee OA. LCV suggested that genetic correlation (i.e. shared genetic aetiology) did not fully explain the causal effects of BMD on hip/knee OA. CONCLUSIONS: These results provide evidence for a BMI-independent causal effect of eBMD on OA. Despite evidence of bidirectional effects, the effect of BMD on OA did not appear to be fully explained by shared genetic aetiology, suggesting a direct action of bone on joint deterioration.
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Densidad Ósea , Osteoartritis de la Rodilla , Índice de Masa Corporal , Densidad Ósea/genética , Causalidad , Estudio de Asociación del Genoma Completo , Humanos , Análisis de la Aleatorización Mendeliana , Osteoartritis de la Rodilla/epidemiología , Osteoartritis de la Rodilla/genética , Polimorfismo de Nucleótido SimpleRESUMEN
Romosozumab is a newly available treatment for osteoporosis acting by sclerostin inhibition. Its cardiovascular safety has been questioned after finding excess cardiovascular disease (CVD)-related events in a pivotal phase 3 trial. Previous studies of relationships between circulating sclerostin levels and CVD and associated risk factors have yielded conflicting findings, likely reflecting small numbers and selected patient groups. We aimed to characterize relationships between sclerostin and CVD and related risk factors in more detail by examining these in two large cohorts, Ludwigshafen Risk and Cardiovascular Health study (LURIC; 34% female, mean age 63.0 years) and Avon Longitudinal Study of Parents and Children study (ALSPAC) mothers (mean age 48.1 years). Together these provided 5069 participants with complete data. Relationships between sclerostin and CVD risk factors were meta-analyzed, adjusted for age, sex (LURIC), body mass index, smoking, social deprivation, and ethnicity (ALSPAC). Higher sclerostin levels were associated with higher risk of diabetes mellitus (DM) (odds ratio [OR] = 1.25; 95% confidence interval [CI] 1.12, 1.37), risk of elevated fasting glucose (OR 1.15; CI 1.04, 1.26), and triglyceride levels (ß 0.03; CI 0.00, 0.06). Conversely, higher sclerostin was associated with lower estimated glomerular filtration rate (eGFR) (ß -0.20; CI -0.38, -0.02), HDL cholesterol (ß -0.05; CI -0.10, -0.01), and apolipoprotein A-I (ß -0.05; CI -0.08, -0.02) (difference in mean SD per SD increase in sclerostin, with 95% CI). In LURIC, higher sclerostin was associated with an increased risk of death from cardiac disease during follow-up (hazard ratio [HR] = 1.13; 1.03, 1.23) and with severity of coronary artery disease on angiogram as reflected by Friesinger score (0.05; 0.01, 0.09). Associations with cardiac mortality and coronary artery severity were partially attenuated after adjustment for risk factors potentially related to sclerostin, namely LDL and HDL cholesterol, log triglycerides, DM, hypertension, eGFR, and apolipoprotein A-I. Contrary to trial evidence suggesting sclerostin inhibition leads to an increased risk of CVD, sclerostin levels appear to be positively associated with coronary artery disease severity and mortality, partly explained by a relationship between higher sclerostin levels and major CVD risk factors. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Enfermedades Cardiovasculares , Enfermedad de la Arteria Coronaria , HDL-Colesterol , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
With increasing age of the population, countries across the globe are facing a substantial increase in osteoporotic fractures. Genetic association signals for fractures have been reported at the RSPO3 locus, but the causal gene and the underlying mechanism are unknown. Here we show that the fracture reducing allele at the RSPO3 locus associate with increased RSPO3 expression both at the mRNA and protein levels, increased trabecular bone mineral density and reduced risk mainly of distal forearm fractures in humans. We also demonstrate that RSPO3 is expressed in osteoprogenitor cells and osteoblasts and that osteoblast-derived RSPO3 is the principal source of RSPO3 in bone and an important regulator of vertebral trabecular bone mass and bone strength in adult mice. Mechanistic studies revealed that RSPO3 in a cell-autonomous manner increases osteoblast proliferation and differentiation. In conclusion, RSPO3 regulates vertebral trabecular bone mass and bone strength in mice and fracture risk in humans.
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Hueso Esponjoso/metabolismo , Fracturas Óseas/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple , Trombospondinas/genética , Animales , Densidad Ósea , Hueso Esponjoso/lesiones , Diferenciación Celular/genética , Proliferación Celular/genética , Células Cultivadas , Humanos , Análisis de la Aleatorización Mendeliana/métodos , Ratones Noqueados , Ratones Transgénicos , Osteoblastos/citología , Osteoblastos/metabolismo , Factores de Riesgo , Trombospondinas/deficienciaRESUMEN
Antiresorptive agents are generally recommended as first-line treatment for osteoporosis in postmenopausal women. These drugs suppress bone resorption but do not rebuild bone, limiting their efficacy. Antiresorptive use is further hampered by concerns over rare side effects, including atypical femoral fractures and osteonecrosis of the jaw. Anabolic treatments overcome limitations of antiresorptive treatment by stimulating new bone formation, reducing the risk of fracture with greater efficacy. This review summarises the latest trial data for the three anabolic agents currently available for the treatment of osteoporosis in postmenopausal women: teriparatide, abaloparatide, and romosozumab. Data from head-to-head studies comparing anabolic and antiresorptive treatments are reviewed. At present, anabolic treatments are generally reserved for use in patients with severe osteoporosis at very high fracture risk; the factors limiting their more widespread use are discussed together with how this may change in the future.
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BACKGROUND: Individuals with high bone mass (HBM) have a greater odds of prevalent radiographic hip osteoarthritis (OA), reflecting an association with bone-forming OA sub-phenotypes (e.g. osteophytosis, subchondral sclerosis). As the role of bone mineral density (BMD) in hip OA progression is unclear, we aimed to determine if individuals with HBM have increased incidence and/or progression of bone-forming OA sub-phenotypes. METHODS: We analysed an adult cohort with and without HBM (L1 and/or total hip BMD Z-score > + 3.2) with pelvic radiographs collected at baseline and 8-year follow-up. Sub-phenotypes were graded using the OARSI atlas. Superior/inferior acetabular/femoral osteophyte and medial/superior joint space narrowing (JSN) grades were summed and Δosteophyte and ΔJSN derived. Pain and functional limitations were quantified using the WOMAC questionnaire. Associations between HBM status and change in OA sub-phenotypes were determined using multivariable linear/logistic regression, adjusting for age, sex, height, total body fat mass, follow-up time and baseline sub-phenotype grade. Generalised estimating equations accounted for individual-level clustering. RESULTS: Of 136 individuals, 62% had HBM at baseline, 72% were female and mean (SD) age was 59 (10) years. HBM was positively associated with both Δosteophytes and ΔJSN (adjusted mean grade differences between individuals with and without HBM ßosteophyte = 0.30 [0.01, 0.58], p = 0.019 and ßJSN = 0.10 [0.01, 0.18], p = 0.019). Incident subchondral sclerosis was rare. HBM individuals had higher WOMAC hip functional limitation scores (ß = 8.3 [0.7, 15.98], p = 0.032). CONCLUSIONS: HBM is associated with the worsening of hip osteophytes and JSN over an average of 8 years, as well as increased hip pain and functional limitation.
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Osteoartritis de la Cadera , Osteoartritis de la Rodilla , Osteofito , Densidad Ósea , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis de la Cadera/diagnóstico por imagen , Osteofito/diagnóstico por imagen , Estudios ProspectivosRESUMEN
How exercise intensity targets, calibrated according to oxygen consumption, relate to vertical impacts during weight-bearing exercise is currently unknown. The authors investigated the relationship between vertical peaks (VPs) and metabolic equivalents (METs) of oxygen consumption in 82 women during walking and running. The magnitude of VPs, measured using a hip-worn triaxial accelerometer, was derived from recommended aerobic exercise intensity targets. VPs were 0.63 ± 0.18g at the lower recommended absolute exercise intensity target (3 METs) but >1.5g at the upper end of moderate-intensity activities (1.90 ± 1.13g at 6 METs). Multilevel linear regression analyses identified speed and type of locomotion as the strongest independent predictors of VPs, explaining 54% and 11% of variance, respectively. The authors conclude that, in contrast to lower intensities, exercising close to or above the 6-MET threshold generates VPs of osteogenic potential, suggesting this could provide simultaneous benefits to decrease all-cause mortality and osteoporosis risk.
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Aceleración , Ejercicio Físico , Posmenopausia , Carrera , Caminata , Acelerometría , Anciano , Femenino , Humanos , Persona de Mediana Edad , Consumo de OxígenoRESUMEN
OBJECTIVES: How insulin-like growth factor-1 (IGF-1) is related to OA is not well understood. We determined relationships between IGF-1 and hospital-diagnosed hand, hip and knee OA in UK Biobank, using Mendelian randomization (MR) to determine causality. METHODS: Serum IGF-1 was assessed by chemiluminescent immunoassay. OA was determined using Hospital Episode Statistics. One-sample MR (1SMR) was performed using two-stage least-squares regression, with an unweighted IGF-1 genetic risk score as an instrument. Multivariable MR included BMI as an additional exposure (instrumented by BMI genetic risk score). MR analyses were adjusted for sex, genotyping chip and principal components. We then performed two-sample MR (2SMR) using summary statistics from Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) (IGF-1, N = 30 884) and the recent genome-wide association study meta-analysis (N = 455 221) of UK Biobank and Arthritis Research UK OA Genetics (arcOGEN). RESULTS: A total of 332 092 adults in UK Biobank had complete data. Their mean (s.d.) age was 56.5 (8.0) years and 54% were female. IGF-1 was observationally related to a reduced odds of hand OA [odds ratio per doubling = 0.87 (95% CI 0.82, 0.93)], and an increased odds of hip OA [1.04 (1.01, 1.07)], but was unrelated to knee OA [0.99 (0.96, 1.01)]. Using 1SMR, we found strong evidence for an increased risk of hip [odds ratio per s.d. increase = 1.57 (1.21, 2.01)] and knee [1.30 (1.07, 1.58)] OA with increasing IGF-1 concentration. By contrast, we found no evidence for a causal effect of IGF-1 concentration on hand OA [0.98 (0.57, 1.70)]. Results were consistent when estimated using 2SMR and in multivariable MR analyses accounting for BMI. CONCLUSION: We have found evidence that increased serum IGF-1 is causally related to higher risk of hip and knee OA.
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Factor I del Crecimiento Similar a la Insulina/análisis , Osteoartritis de la Cadera/epidemiología , Osteoartritis de la Rodilla/epidemiología , Biomarcadores/sangre , Femenino , Humanos , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Medición de Riesgo , Reino Unido/epidemiologíaRESUMEN
OBJECTIVES: Hip development is influenced by mechanical loading, but associations between prenatal loading and hip shape in later life remain unexplored. METHODS: We examined associations between prenatal loading indicators (gestation length, oligohydramnios (OH) and breech) obtained from obstetric records and hip shape modes (HSMs) generated using dual-energy X-ray absorptiometry images taken at age 14- and 18-years in participants from the UK Avon Longitudinal Study of Parents and Children (ALSPAC). These associations were examined in 2453 (30 OH, 105 breech) and 2330 (27 OH, 95 breech) participants with complete data at age 14- and 18-years respectively using confounder-adjusted models. RESULTS: At 14 years HSM2 was 0.59SD lower in OH males, and HSM5 (-0.31SD) and HSM9 (-0.32SD) were lower in OH in both sexes. At 18 years HSM1 (-0.44SD) and HSM2 (-0.71SD) were lower and HSM6 (0.61SD) and HSM8 (1.06SD) were higher in OH males, whilst HSM5 was lower in OH in both sexes. OH appeared to be associated with a wider femoral neck and head, and larger lesser/greater trochanters. Only weak associations were observed between gestation length/breech and HSMs. CONCLUSIONS: These results suggest that prenatal skeletal loading, in particular oligohydramnios, may influence adolescent joint shape with associations generally stronger in males.
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Fenómenos Biomecánicos/fisiología , Fémur/crecimiento & desarrollo , Complicaciones del Embarazo , Adolescente , Femenino , Feto , Humanos , Estudios Longitudinales , Masculino , EmbarazoRESUMEN
Importance: Peak bone strength, which occurs in early adulthood, is an important marker of the future risk of osteoporosis. It is therefore important to identify modifiable early life factors that are associated with the attainment of peak hip strength. Objective: To investigate the association of time spent in moderate to vigorous-intensity and light-intensity physical activity throughout adolescence with peak hip strength in adulthood. Design, Setting, and Participants: The Avon Longitudinal Study of Parents and Children is a prospective birth cohort study that initially recruited all pregnant women residing within the catchment area of 3 health authorities in southwest England who had an expected delivery date between April 1, 1991, and December 31, 1992. In total, 15 454 eligible pregnant women were enrolled, and 15 589 infants were delivered. Of those, 14 901 infants were alive at age 1 year. The present analysis examined 2569 healthy offspring who had valid physical activity measurements obtained during a clinical assessment for at least 1 age (12, 14, 16, and/or 25 years), with up to 4 repeated accelerometer assessments performed (1 per age-associated clinical visit). Data were analyzed from June 2019 to June 2020. Exposures: Trajectories of accelerometer-assessed time spent in moderate to vigorous-intensity and light-intensity physical activity at ages 12, 14, 16, and 25 years (measured in minutes per day) were identified using latent trajectory modeling. Moderate to vigorous-intensity and light-intensity physical activity were determined using established thresholds of acceleration counts per minute. Main Outcomes and Measures: Femur neck bone mineral density (BMD; measured in g/cm2) at age 25 years assessed by dual-energy radiography absorptiometry scans of the hip. Results: A total of 2569 participants (1588 female participants [62%]) were included in the analysis. Male participants spent more time in moderate to vigorous-intensity activity at each age and had greater adult femur neck BMD than female participants. For each sex, 3 moderate to vigorous-intensity trajectory subgroups and 3 light-intensity trajectory subgroups were identified. With regard to the moderate to vigorous-intensity trajectories, most male participants (85%) were in the low adolescent subgroup, with only 6% and 9% in the high early-adolescent and high mid-adolescent subgroups, respectively. Moderate to vigorous-intensity trajectories in female participants were divided into low adolescent-low adult (73%), low adolescent-high adult (8%), and high adolescent (19%) subgroups. Light-intensity physical activity trajectories were classified into low nonlinear, moderate decreasing, and high decreasing subgroups for both sexes. Femur neck BMD in male participants was greater in the high early-adolescent subgroup (0.38 g/cm2; 95% CI, 0.11-0.66 g/cm2) and the high mid-adolescent subgroup (0.33 g/cm2; 95% CI, 0.07-0.60 g/cm2) compared with the low adolescent (reference) subgroup. Femur neck BMD in female participants was greater in the high adolescent subgroup (0.28 g/cm2; 95% CI, 0.15-0.41 g/cm2) but not in the low adolescent-high adult subgroup (-0.12 g/cm2; 95% CI, -0.44 to 0.20 g/cm2) compared with the low adolescent-low adult (reference) subgroup. A sensitivity analysis using a negative-outcome control variable to explore unmeasured confounding supported these findings. The light-intensity trajectories were not associated with femur neck BMD; for example, differences in femur neck BMD between the high decreasing and low nonlinear subgroups were 0.16 g/cm2 (95% CI, -0.08 to 0.40 g/cm2) in male participants and 0.20 g/cm2 (95% CI, -0.05 to 0.44 g/cm2) in female participants. Conclusions and Relevance: Supporting high-intensity physical activity throughout early life may help to maximize peak hip strength and prevent osteoporosis in later life. Replication of our findings in independent studies will be important.
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Densidad Ósea/fisiología , Ejercicio Físico/fisiología , Cuello Femoral/fisiología , Articulación de la Cadera/fisiología , Adolescente , Adulto , Niño , Femenino , Articulación de la Cadera/crecimiento & desarrollo , Humanos , Estudios Longitudinales , Masculino , Modelos Estadísticos , Fenómenos Fisiológicos Musculoesqueléticos , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: It is unclear if puberty timing influences future physical activity (PA). AIM: To investigate the association of puberty timing with PA across adolescence and adulthood. SUBJECTS AND METHODS: Data were from two British cohorts. Participants from an adolescent birth cohort (females = 2349, males = 1720) prospectively reported age at menarche and voice break and had PA recorded by Actigraph accelerometers at ages 14 years and 16 years. A cohort of middle-aged and older adults (40-70 years; females = 48,282; males = 36,112) recalled their age at puberty and had PA (mean acceleration; mg) measured by AxivityAX3 accelerometers. RESULTS: After adjustment for age, education, smoking and BMI, per 1-year older age at menarche was associated with higher mean counts/minute at age 14 years (0.07 SD counts/minute; 95% CI = 0.04-0.11) with associations attenuated at age 16 years (0.02; -0.03-0.07). Differences in mean acceleration per older year at menarche were close to the null in women aged 40-49 years (0.02 mg; 0.01-0.03), 50-59 years (0.01; 0.00-0.02) and 60-70 years (0.01; 0.00-0.01). Age at voice break and PA associations were close to the null in both cohorts. CONCLUSION: We found a positive association between puberty timing and PA in females which weakened at older ages and limited evidence of an association at any age in males.
Asunto(s)
Acelerometría , Ejercicio Físico , Pubertad , Adolescente , Factores de Edad , Estudios de Cohortes , Femenino , Humanos , Masculino , Menarquia , Reino UnidoRESUMEN
Several epidemiological studies have reported a relationship between statin treatment and increased bone mineral density (BMD) and reduced fracture risk, but the mechanism underlying the purported relationship is unclear. We used Mendelian randomization (MR) to assess whether this relationship is explained by a specific effect in response to statin use or by a general effect of lipid lowering. We utilized 400 single-nucleotide polymorphisms (SNPs) robustly associated with plasma lipid levels as exposure. The outcome results were obtained from a heel estimated BMD (eBMD) genomewide association study (GWAS) from the UK Biobank and dual-energy X-ray absorptiometry (DXA) BMD at four body sites and fracture GWAS from the GEFOS consortium. We performed univariate and multivariable MR analyses of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride levels on BMD and fracture. Univariate MR analyses suggested a causal effect of LDL-C on eBMD (ß = -0.06; standard deviation change in eBMD per standard deviation change in LDL-C, 95% confidence interval [CI] = -0.08 to -0.04; p = 4 × 10-6 ), total body BMD (ß = -0.05, 95% CI = -0.08 to -0.01, p = 6 × 10-3 ) and potentially on lumbar spine BMD. Multivariable MR suggested that the effects of LDL-C on eBMD and total body BMD were independent of HDL-C and triglycerides. Sensitivity MR analyses suggested that the LDL-C results were robust to pleiotropy. MR analyses of LDL-C restricted to SNPs in the HMGCR region showed similar effects on eBMD (ß = -0.083; -0.132 to -0.034; p = .001) to those excluding these SNPs (ß = -0.063; -0.090 to -0.036; p = 8 × 10-6 ). Bidirectional MR analyses provided some evidence for a causal effect of eBMD on plasma LDL-C levels. Our results suggest that effects of statins on eBMD and total body BMD are at least partly due to their LDL-C lowering effect. Further studies are required to examine the potential role of modifying plasma lipid levels in treating osteoporosis. © 2020 American Society for Bone and Mineral Research.
Asunto(s)
Densidad Ósea , Lípidos , Análisis de la Aleatorización Mendeliana , Densidad Ósea/genética , Estudio de Asociación del Genoma Completo , Humanos , Lípidos/sangre , PlasmaRESUMEN
Mutations in SQSTM1 are strongly associated with Paget's disease of bone (PDB), but little is known about the clinical characteristics of those with early disease. Radionuclide bone scans, biochemical markers of bone turnover, and clinical characteristics were analyzed in SQSTM1 mutation carriers who took part in the Zoledronic acid in the Prevention of Paget's disease (ZiPP) study. We studied 222 individuals, of whom 54.9% were female, with mean ± SE age of 50.1 ± 0.6 years. Twelve SQSTM1 mutations were observed, including p.Pro392Leu, which was present in 141 of 222 (63.5%) subjects. Bone scan examination revealed evidence of PDB in 20 subjects (9.0%), ten of whom (50%) had a single affected site. Participants with lesions were older than those without lesions but the difference was not significant (53.6 ± 9.1 versus 49.8 ± 8.9; p = .07). The mean age of participants with lesions was not significantly different from the age at which their parents were diagnosed with PDB (55 years versus 59 years, p = .17). All individuals with lesions were asymptomatic. Serum concentrations of total alkaline phosphatase (ALP) normalized to the upper limit of normal in each center were higher in those with lesions (0.75 ± 0.69 versus 0.42 ± 0.29 arbitary units; p < .0001). Similar findings were observed for other biochemical markers of bone turnover, but the sensitivity of ALP and other markers in detecting lesions was poor. Asymptomatic PDB is present in about 9% of SQSTM1 mutation carriers by the fifth decade. Further follow-up of this cohort will provide important information on the natural history of early PDB and its response to treatment. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.