Jon H. Tobias's research while affiliated with University of Bristol and other places
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Publications (123)
Background/Aims
The use of digital tools to deliver healthcare interventions has increased rapidly. Inadequate engagement and retention are two major barriers to widespread and long-term adoption of electronic patient-reported outcomes (ePROs) for monitoring in clinical practice. Whilst retention rates are high in research studies, these are often...
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...
Objectives
Hip shape is thought to be an important causal risk factor for hip osteoarthritis and fracture. We aimed to identify genetic determinants of hip shape and use these to assess causal relationships with hip osteoarthritis.
Methods
Statistical hip shape modelling was used to derive 10 hip shape modes (HSMs) from DXA images in UK Biobank and...
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 plac...
Background
Rheumatoid arthritis (RA) has a relapsing-remitting nature, making it difficult to predict when patients should be seen. Collection of patient-reported outcomes (PROs) effectively communicates patients’ disease experiences. However, certain factors could impact the utilization and persistence of PROs collection.
Objectives
To explore th...
Background/Aims
Patient-reported outcome measures (PROMs) allow effective communication of disease experiences and encourage shared decision-making for people with inflammatory arthritis (IA). This analysis examines the long-term utilization of PROMs collection in a real-world clinical environment.
Methods
Clinical practice review at North Bristol...
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-acet...
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 modelling (SSM) to evaluate relationships between hip shape and HOA of different severities using UK Biobank DXA images. We performed a cross‐sectional study i...
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 popul...
The human microbiota functions at the interface between diet, medication-use, lifestyle, host immune development and health; thus it is aligned closely 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...
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 pathwa...
Musculoskeletal conditions, including fractures, can have severe and long-lasting consequences. Higher body mass index in adulthood is widely acknowledged to be protective for most fracture sites, indicated through previous clinical and epidemiological observational research. However, the association between weight and bone health is complex and so...
Romososumab 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 III trial. Previous studies of relationships between circulating sclerostin levels and CVD and associated risk factors have yie...
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...
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. Anaboli...
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 pathw...
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 h...
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 H...
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 us...
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 lig...
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, measur...
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 mena...
Objective
High bone mass (HBM) is associated with an increased prevalence of radiographic knee OA (kOA), characterized by osteophytosis. We aimed to determine if progression of radiographic kOA, and its sub-phenotypes, is increased in HBM and whether observed changes are clinically relevant.
Design
A cohort with and without HBM (L1 and/or total hi...
Background
Patient-reported outcome measures are a cornerstone of the current early inflammatory arthritis audit and part of the best practice tariff. However, outcome data are collected infrequently meaning longitudinal changes in disease activity cannot be accurately examined. We report results of a twelve-month clinical pilot of a cloud-enabled...
Objectives:
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.
Methods:
Radionuclide bone scans, biochemical markers of bone turnover and clinical characteristics were analysed in SQSTM1 mutation carriers who took part in the Zoledroni...
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...
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 adu...
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)....
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 acetab...
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 pr...
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 impro...
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 popu...
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 Longitudi...
To identify targets for novel anabolic medicines for osteoporosis, we recruited a large cohort with unexplained high bone mass (HBM). Exome sequencing identified a rare (minor allele frequency 0.0014) missense mutation in SMAD9 (c.65T>C, p.Leu22Pro) segregating with HBM in an autosomal dominant family. The same mutation was identified in another tw...
Supplementary material (supplementary methods, supplementary tables 1 to 9, supplementary acknowledgements)
Supplementary figures 1 to 5
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 ph...
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. Associa...
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 we...
Lifetime self-reported walking and weight-bearing exercise in relation to accelerometer-measured overall and high impact physical activity (PA) in later life.
Spearman rank correlation coefficients for lifetime daily miles walked and weight bearing exercise.
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 Coh...
Prospectively reported walking and weight bearing exercise at ages 36 and 60–64 in relation to accelerometer-measured overall and high impact physical activity (PA) at age 69 in the MRC NSHD.
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 from the Cohort for Skeletal Health in Bristol and Avon (COSHIBA), Hertfordshire Cohort Stud...
Supporting Information.
Perspective:
In this cohort, 14.6% of adolescents with CFS have co-morbid CWP. The likely greater proportion of more mild cases observed in this epidemiological study means that prevalence of overlap may be underestimated compared to those attending specialist services. Clinicians should be aware of the overlap between the two conditions and caref...
In the current issue of the Journal, Yau et al report a heritability study based on computed tomography (CT) scans, intended to quantify genetic influences on thoracic spinal curvature. In the same issue, Nielson et al report a genome wide association study (GWAS) of CT-derived lumbar spine volumetric bone mineral density (vBMD), followed by a ‘loo...
Supporting Information.
Supporting Information.
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 thi...
Osteoporosis and cardiovascular disease(CVD) are both common causes of morbidity and mortality. Previous studies, mainly of people over 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 = 3,366) and their a...
Health-related quality of life in osteoporotic patients with vertebral fracture is of increasing interest, but relevant studies have yielded debatable results. This systematic review and meta-analysis of 16 observational studies demonstrate a clear association between physical health status and presence of vertebral fracture after accounting for ag...
Supporting Information.
Introduction: Bone mineral density (BMD) is a highly heritable trait used to assess skeletal health in children and risk of osteoporosis later in life. To date >60 loci associated with bone-related traits measured at different skeletal sites have been identified. We conducted a genome-wide association study (GWAS) meta-analysis of total body (TB-)B...
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 South West of England between 1991 and 1993. 12,942 singleton babies were born at term and survived at least the f...
The onset of walking in early childhood results in exposure of the lower limb to substantial forces from weight bearing activity which ultimately contribute to adult bone strength. Relationships between gross motor score (GMS), at 18 months and bone outcomes measured at age 17 years were examined in 2327 participants in the Avon Longitudinal Study...
Study design:
Prospective population-based birth cohort study OBJECTIVE:: To identify whether there is any hidden burden of disease associated with smaller spinal curves.
Summary of background data:
Adolescent idiopathic scoliosis is present in 3-5% of the general population. Large curves are associated with increased pain and reduced quality of...
Background:
Fracture risk is rising in countries undergoing rapid rural to urban migration, but whether this reflects an adverse effect of urbanization on intrinsic bone strength, as reflected by bone mineral density (BMD), is currently unknown.
Methods:
Lumbar spine (LS) and total hip (TH) BMD, and total body fat and lean mass, were obtained fr...
The purpose of this study was to establish the feasibility of using an aerobics class to produce potentially bone protective vertical impacts of >4g in older adults and to determine whether impacts can be predicted by physical function. Participants recruited from older adult exercise classes completed an SF-12 questionnaire, short physical perform...
Background:
Physical activity (PA) may need to produce high impacts to be osteogenic.
Aims:
to identify threshold(s) for defining high impact PA for future analyses in the VIBE (Vertical Impact and Bone in the Elderly) study, based on home recordings with triaxial accelerometers.
Methods:
Recordings were obtained from 19 Master Athlete Cohort...
High bone mass (HBM) can be an incidental clinical finding; however, monogenic HBM disorders (e.g. LRP5 or SOST mutations) are rare. We aimed to determine to what extent HBM is explained by mutations in known HBM genes. 258 unrelated HBM cases were identified from review of 335,115 DXA scans from 13 UK centers. Cases were assessed clinically and un...
eQTL analysis in human osteoblasts.
(PDF)
Cortical vBMD SNPs conditioned on known aBMD SNPs.
(PDF)
Characteristics of the MrOS Sweden fracture cohort.
(PDF)
Association of top cortical and trabecular vBMD signals with pQCT and HRpQCT parameters in the GOOD cohort at the five-year follow-up visit.
(PDF)
Associations between cortical and trabecular vBMD SNPs and fractures in MrOS Sweden.
(PDF)
Associations with cortical and trabecular vBMD for 64 reported genome-wide significant aBMD SNPs.
(PDF)
A: homologous recombination removing the first two coding exons of Fam3c. Sequence information (deletion, insertion site, flanking sequence) is provided on the Taconic Farms website (http://www.taconic.com/wmspage.cfm?parm1=16 catalogue number TF3787). B: confirmation by Southern hybridization analysis.
(DOCX)
SNP rs9525638 regional association plot of the discovery genome-wide meta-analysis of cortical thickness. Circles show GWA meta-analysis p-values, with different colors indicating varying linkage disequilibrium with rs9525638 (diamond).
(DOCX)
A: Retroviral insertion disrupted Fam3c gene prior to the exon encoding amino acid 19 in a protein of 227 amino acids. Sequence information (deletion, insertion site, flanking sequence) is provided on the Taconic Farms website (http://www.taconic.com/wmspage.cfm?parm1=16 catalogue number TF3786). B: RT-PCR analysis revealed that the wild-type trans...
54 genome-wide significant SNPs in 7q31 for forearm BMD GWAS meta-analysis.
(XLSX)
SNP rs2707466 associations with pQCT derived bone parameters at different ages and meta-analyses results for cortical bone thickness study.
(DOCX)
Quantile-quantile plots of the observed P values versus the expected P values for association for GWAS Meta-Analysis of cortical thickness. The scatters in black showed a clear deviation at the tail of the distribution from the null distribution (the red line).
(DOCX)
Genome-wide genotyping, imputation and genotype-phenotype analysis by study for BMD meta-analysis.
(XLSX)
Citations
... In Lancaster in the north-west of England the prevalence of PDB has fallen by an order of magnitude-from 8 to 0.8%-in 40 years [21]. In the ZiPP study of SQSTM1 mutation carriers, the rate at which PDB had developed in the placebo group by the end of the study (2021) was only one eighth that anticipated when the study was registered 13 years earlier [22]. So there is little question that the nature of Paget's disease has changed from its apparent peak in the late nineteenth and early twentieth century. ...
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... In addition to its impact on mesenchymal stem cells, research has observed that B4GALNT3, belonging to the glycosyltransferase family, can glycosylate the cyclic hardening of N-acetylglucosamine-benzyl group on protein epitopes. This alteration may change protein hardening levels, ultimately leading to the occurrence of osteoporosis [87]. Therefore, there is a hypothesis suggesting that B3GNT2 may pose a potential risk for type 2 osteoporosis. ...
... A more detailed description of the methods, including positions of the 85 points outlining the hip, is provided in our previous publication. 17 ...
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... Content was informed by guidance from NICE [46] and the National Osteoporosis Guidelines Group (NOGG) [47] to ensure it reflected best practice. Symptoms of vertebral fractures included in the infographic were based on the VFrac checklist, an evidence-based tool to identify descriptions of back pain in patients presenting with vertebral fractures [48]. To enhance readability, patient resources were reviewed and refined by patient involvement representatives. ...
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... The scientific rationale of detecting and improving the strategy of addressing the osteoporotic fractures in the general population (and in type 2 diabetic individuals in particular) comes from a major burden that may be reflected by impressive data: the mortality within the first year following a hip fracture may rise to 25% while disability and dysfunctionality might affect up to 60% of affected persons following this type of fracture; the projections of osteoporotic fractures as increasing numbers of patients involve both females and males; a call for action has been released by World Health Organization to address the issue of fragility fractures and osteoporosis detection due to the associated burden; remaining lifetime probability of suffering from a fracture is one out of three females and one out of five men aged over 50 in Europe and, respectively, one out of two and one out of four in the US; the number and costs of hospitalizations due to fractures surpasses those related to cardiovascular events; the panel of osteoporosis-associated disability represents a heterogeneous spectrum that is also reflected by the aggravation of other co-morbidities, increased costs, and an overall impaired quality of life. On the other hand, only 2 out of 10 patients with osteoporosis are recognized with this diagnosis, and only 3 out of 10 subjects with an osteoporotic fracture who should receive specific anti-osteoporotic medication are actually treated for this condition in order to reduce the increased fracture risk, while almost half of the patients that start this medication will no longer be compliant after the first year since drug initiation [20][21][22][23][24][25][26]. ...
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... However, though readily automated, these are often under-powered, and other methods may need to be considered. For example, since IVs for bone mineral density (BMD) identified by GWAS are also related to BMI, multivariable MR is required to evaluate causal effects of BMD on osteoarthritis risk independently of the effects of BMI (11). Correlated pleiotropy is a particular form of pleiotropy which arises where two traits, call X and Y, are correlated, for example as a consequence of shared underlying biology (12). ...
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... In recent years, it also has become evident that the gut microbiome may affect bone metabolism [52,53]. Although the participants reported intakes of traditional Norwegian food, it cannot be ruled out entirely that diet variations may affect gut microbiomes of bone donors, possibly impacting the outcome of the study. ...
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... This athermal supersaturation constitutes an important example of a mechanism making calcium available at neutral pH from calcium compounds of low aqueous solubility . A unique role of citrate in human bone is also indicated by the surprising correlation between the level of circulating citrate and mineral turnover important for maintenance of bone strength demonstrated recently (Hartley et al., 2020). Calcium citrate has also been found to promote regeneration of damaged bones in animals under experimental surgery despite the low solubility of calcium citrate (Wang et al., 2012). ...
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... Speci cally, the loading of bone by dynamic mechanical forces is "sensed" by mature osteocytes within the mineralized matrix. Mechanical loading results in the suppression of the SOST gene, an inhibitor of the Wnt/β-catenin pathway speci c to bone tissue, whereas bone unloading induces osteocytes to synthesize and secrete SOST, which promotes osteoclast genesis and results in reduced bone formation and bone mass loss ( (Frysz et al. 2022). In addition, several GWAS have also found an association between SOST and blood eosinophil counts (Astle et al. 2016;Chen et al. 2020; Vuckovic et al. 2020), white blood cells whose functions include modulation of in ammatory responses as well as anti-parasitic and bactericidal activity. ...
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... [4][5][6] Currently, glucocorticoid-induced osteoporosis (GIOP) is the most prevalent form of secondary osteoporosis. 7 Glucocorticoids (GCs) find applications in clinical management of numerous ailments, with systemic lupus erythematosus (SLE) being one of the most common and representative instances. 8,9 The pathogenesis of SLE involves multiple immune cells and cytokines, yielding a complex immunopathological mechanism that companined with severe osteoporosis. ...
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