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1.  Fracture prevention in patients with cognitive impairment presenting with a hip fracture: secondary analysis of data from the HORIZON Recurrent Fracture Randomised Controlled Trial 
PURPOSE
Patients with cognitive impairment (CI) are at high risk of fracture but often denied osteoporosis therapy. We tested whether the effects of zoledronic acid (Zol) on re-fracture and mortality differed in patients presenting with a hip fracture by cognitive status.
METHODS
We used data from the HORIZON Recurrent Fracture Trial, of yearly intravenous 5mg Zol vs. placebo in patients presenting with a hip fracture. Primary outcome was new fracture and secondary outcome mortality.
Short Portable Mental Status Questionnaire (SPMSQ) with a cut-point of >2 was used to identify CI. Fine-Gray models for competing events were fitted to study the effect of Zol on re-fracture and Cox regression for death. A multiplicative term was introduced to study a potential interaction between treatment and cognitive status on outcomes.
RESULTS
1,966/2,127 (92.4%) patients had baseline SPMSQ measured. 350 (17.8%) had CI, balanced between treatment arms. In the placebo arm, there was similar fracture incidence between those with and without CI (15.4% vs. 12.3%, p=0.26). There was no significant interaction for the effect of CI on Zol and re-fracture (p=0.66)). CI was associated with higher 1-year mortality (12.6% vs. 4.3%, p<0.001) and the interaction was bordering significance (interaction p=0.066). Zol prolonged survival only in patients with normal cognitive status (HR 0.56 [95%CI 0.40-0.80]) and not in those with CI (HR 0.90 [95%CI 0.59-1.38]).
CONCLUSIONS
While these results require confirmation, the findings support the use of bisphosphonates in patients with both osteoporotic fracture and CI expected to live for more than 6 months.
doi:10.1007/s00198-013-2420-8
PMCID: PMC3867338  PMID: 23812596
Fractures, Bone; Mortality; Zoledronic Acid; Dementia; Epidemiology
2.  SMAD3 Is Associated with the Total Burden of Radiographic Osteoarthritis: The Chingford Study 
PLoS ONE  2014;9(5):e97786.
Background
A newly-described syndrome called Aneurysm-Osteoarthritis Syndrome (AOS) was recently reported. AOS presents with early onset osteoarthritis (OA) in multiple joints, together with aneurysms in major arteries, and is caused by rare mutations in SMAD3. Because of the similarity of AOS to idiopathic generalized OA (GOA), we hypothesized that SMAD3 is also associated with GOA and tested the hypothesis in a population-based cohort.
Methods
Study participants were derived from the Chingford study. Kellgren-Lawrence (KL) grades and the individual features of osteophytes and joint space narrowing (JSN) were scored from radiographs of hands, knees, hips, and lumbar spines. The total KL score, osteophyte score, and JSN score were calculated and used as indicators of the total burden of radiographic OA. Forty-one common SNPs within SMAD3 were genotyped using the Illumina HumanHap610Q array. Linear regression modelling was used to test the association between the total KL score, osteophyte score, and JSN score and each of the 41 SNPs, with adjustment for patient age and BMI. Permutation testing was used to control the false positive rate.
Results
A total of 609 individuals were included in the analysis. All were Caucasian females with a mean age of 60.9±5.8. We found that rs3825977, with a minor allele (T) frequency of 20%, in the last intron of SMAD3, was significantly associated with total KL score (β = 0.14, Ppermutation = 0.002). This association was stronger for the total JSN score (β = 0.19, Ppermutation = 0.002) than for total osteophyte score (β = 0.11, Ppermutation = 0.02). The T allele is associated with a 1.47-fold increased odds for people with 5 or more joints to be affected by radiographic OA (Ppermutation = 0.046).
Conclusion
We found that SMAD3 is significantly associated with the total burden of radiographic OA. Further studies are required to reveal the mechanism of the association.
doi:10.1371/journal.pone.0097786
PMCID: PMC4031234  PMID: 24852296
3.  A population-based survival analysis describing the association of body mass index on time to revision for total hip and knee replacements: results from the UK general practice research database 
BMJ Open  2013;3(11):e003614.
Objectives
Against a backdrop of rising levels of obesity, we describe and estimate associations of body mass index (BMI), age and gender with time to revision for participants undergoing primary total hip (THR) or knee (TKR) replacement in the UK.
Design
Population-based cohort study.
Setting
Routinely collected primary care data from a representative sample of general practices, including linked data on all secondary care events.
Participants
Population-based cohort study of 63 162 patients with THR and 54 276 with TKR in the UK General Practice Research Database between 1988 and 2011.
Primary and secondary outcomes
Risk of THR and TKR revision associated with BMI, age and gender, after adjusting for the competing risk of death.
Results
The 5-year cumulative incidence rate for THR was 2.2% for men and 1.8% for women (TKR 2.3% for men, 1.6% for women). The adjusted overall subhazard ratio (SHR) for patients with THR undergoing subsequent hip revision surgery, with a competing risk of death, were estimated at 1.020 (95% CI 1.009 to 1.032) per additional unit (kg/m2) of BMI, 1.23 (95% CI 1.10 to 1.38) for men compared with women and 0.970 (95% CI 0.967 to 0.973) per additional year of age. For patients with TKR, the equivalent estimates were 1.015 (95% CI 1.002 to 1.028) for BMI; 1.51 (95% CI 1.32 to 1.73) for gender and 0.957 (95% CI 0.951 to 0.962) for age. Morbidly obese patients with THR had a 65.5% increase (95% CI 15.4% to 137.3%, p=0.006) in the subhazard of revision versus the normal BMI group (18.5–25). The effect for TKR was smaller (a 43.9% increase) and weaker (95% CI 2.6% to 103.9%, p=0.040).
Conclusions
BMI is estimated to have a small but statistically significant association with the risk of hip and knee revision, but absolute numbers are small. Further studies are needed in order to distinguish between effects for specific revision surgery indications.
doi:10.1136/bmjopen-2013-003614
PMCID: PMC3845068  PMID: 24285628
4.  Different Indices of Fetal Growth Predict Bone Size and Volumetric Density at 4 Years of Age 
We have demonstrated previously that higher birth weight is associated with greater peak and later-life bone mineral content and that maternal body build, diet, and lifestyle influence prenatal bone mineral accrual. To examine prenatal influences on bone health further, we related ultrasound measures of fetal growth to childhood bone size and density. We derived Z-scores for fetal femur length and abdominal circumference and conditional growth velocity from 19 to 34 weeks’ gestation from ultrasound measurements in participants in the Southampton Women’s Survey. A total of 380 of the offspring underwent dual-energy X-ray absorptiometry (DXA) at age 4 years [whole body minus head bone area (BA), bone mineral content (BMC), areal bone mineral density (aBMD), and estimated volumetric BMD (vBMD)]. Volumetric bone mineral density was estimated using BMC adjusted for BA, height, and weight. A higher velocity of 19- to 34-week fetal femur growth was strongly associated with greater childhood skeletal size (BA: r = 0.30, p < .0001) but not with volumetric density (vBMD: r = 0.03, p = .51). Conversely, a higher velocity of 19- to 34-week fetal abdominal growth was associated with greater childhood volumetric density (vBMD: r = 0.15, p = .004) but not with skeletal size (BA: r = 0.06, p = .21). Both fetal measurements were positively associated with BMC and aBMD, indices influenced by both size and density. The velocity of fetal femur length growth from 19 to 34 weeks’ gestation predicted childhood skeletal size at age 4 years, whereas the velocity of abdominal growth (a measure of liver volume and adiposity) predicted volumetric density. These results suggest a discordance between influences on skeletal size and volumetric density.
doi:10.1359/jbmr.091022
PMCID: PMC3793299  PMID: 20437610
EPIDEMIOLOGY; OSTEOPOROSIS; PROGRAMMING; DEVELOPMENTAL ORIGINS
5.  Defining Incident Radiographic Hip Osteoarthritis for Epidemiologic Studies in Women 
Arthritis and rheumatism  2009;60(4):1052-1059.
Objectives
To evaluate definitions of radiographic hip osteoarthritis (RHOA) for use in longitudinal epidemiologic studies of disease incidence in women.
Methods
We studied 5,839 women from the Study of Osteoporotic Fractures who had had serial pelvic radiographs obtained (mean of 8.3 years apart) and who were followed up (mean followup 7.1 years from the time of the second radiograph) for evaluation of clinical outcomes. Definitions of RHOA were assessed for construct validity (association with symptoms and signs at the time of the second radiograph) and predictive validity (association with total hip replacement [THR] and signs and symptoms a mean of 7.1 years later). Odds ratios (ORs) and 95% confidence intervals were calculated to assess the strength of association using logistic regression.
Results
The cumulative incidence of RHOA ranged from 2.2% to 11.7%. All definitions displayed significant construct validity; the most consistent was found for composite definitions that required the concurrent presence of 2 or more individual radiographic features and definitions based on stringent criteria for joint space narrowing. All definitions except minimum joint space ≤2.5 mm displayed consistent predictive validity. Composite definitions had the strongest associations with THR (OR 10.5–18.5) and hip pain (OR 2.6–2.9). The hips identified as having OA by each definition varied, with especially small overlap between findings using definitions based on osteophytes and those using definitions based on joint space narrowing alone.
Conclusions
Most definitions of incident RHOA display good construct and predictive validity. Composite definitions have the best overall performance, and definitions requiring the presence of both osteophytes (in particular, femoral osteophytes) and joint space narrowing would be recommended for most epidemiologic and genetic studies.
doi:10.1002/art.24382
PMCID: PMC3777428  PMID: 19333950
6.  Total or Partial Knee Arthroplasty Trial - TOPKAT: study protocol for a randomised controlled trial 
Trials  2013;14:292.
Background
In the majority of patients with osteoarthritis of the knee the disease originates in the medial compartment. There are two fundamentally different approaches to knee replacement for patients with unicompartmental disease: some surgeons feel that it is always best to replace both the knee compartments with a total knee replacement (TKR); whereas others feel it is best to replace just the damaged component of the knee using a partial or unicompartment replacement (UKR). Both interventions are established and well-documented procedures. Little evidence exists to prove the clinical and cost-effectiveness of either management option. This provides an explanation for the high variation in treatment of choice by individual surgeons for the same knee pathology.
The aim of the TOPKAT study will be to assess the clinical and cost effectiveness of TKRs compared to UKRs in patients with medial compartment osteoarthritis.
Methods/Design
The design of the study is a single layer multicentre superiority type randomised controlled trial of unilateral knee replacement patients. Blinding will not be possible as the surgical scars for each procedure differ.
We aim to recruit 500 patients from approximately 28 secondary care orthopaedic units from across the UK including district general and teaching hospitals. Participants will be randomised to either UKR or TKR. Randomisation will occur using a web-based randomisation system. The study is pragmatic in terms of implant selection for the knee replacement operation. Participants will be followed up for 5 years. The primary outcome is the Oxford Knee Score, which will be collected via questionnaires at 2 months, 1 year and then annually to 5 years. Secondary outcomes will include cost-effectiveness, patient satisfaction and complications data.
Trial registration
Current Controlled Trials ISRCTN03013488; ClinicalTrials.gov Identifier: NCT01352247
doi:10.1186/1745-6215-14-292
PMCID: PMC3848560  PMID: 24028414
Medial compartment osteoarthritis; Total knee replacement; Unicompartmental knee replacement; Equipoise; Expertise
7.  A Role for PACE4 in Osteoarthritis Pain: Evidence from Human Genetic Association and Null Mutant Phenotype 
Annals of the rheumatic diseases  2012;71(6):1042-1048.
Objectives
To assess if genetic variation in the PACE4 gene, PCSK6, influences the risk for symptomatic knee OA.
Methods
Ten PCSK6 single nucleotide polymorphisms (SNP) were tested for association in a discovery cohort of radiographic knee OA (n= 156 asymptomatic and 600 symptomatic cases). Meta-analysis of the minor allele at rs900414 was performed in three additional independent cohorts (total n=674 asymptomatic and 2068 symptomatic). Pcsk6 knockout (KO) mice and wildtype C57BL/6 mice were compared in a battery of algesiometric assays, including hypersensitivity in response to intraplantar substance P; pain behaviours in response to intrathecal substance P; and pain behaviour in the abdominal constriction test.
Results
In the discovery cohort of radiographic knee OA, an intronic SNP at rs900414 was significantly associated with symptomatic OA. Replication in three additional cohorts confirmed that the minor allele at rs900414 was consistently increased among asymptomatic compared to symptomatic radiographic knee OA cases in all four cohorts. A fixed-effects meta-analysis yielded an odds ratio =1.35 (95% CI 1.17, 1.56; p-value 4.3×10−5 and no significant between-study heterogeneity). Studies in mice revealed that Pcsk6 knockout (KO) mice were significantly protected against pain in a battery of algesiometric assays.
Conclusions
These results suggest that a variant in PCSK6 is strongly associated with protection against pain in knee OA, offering some insight as to why in the presence of the same structural damage, some individuals develop chronic pain and others are protected. Studies in Pcsk6 null mutant mice further implicate PACE4 in pain.
doi:10.1136/annrheumdis-2011-200300
PMCID: PMC3603144  PMID: 22440827
Knee osteoarthritis; pain; PACE4; genetic association; SNP
8.  Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22 
Evangelou, Evangelos | Valdes, Ana M. | Kerkhof, Hanneke J.M | Styrkarsdottir, Unnur | Zhu, YanYan | Meulenbelt, Ingrid | Lories, Rik J. | Karassa, Fotini B. | Tylzanowski, Przemko | Bos, Steffan D. | Akune, Toru | Arden, Nigel K. | Carr, Andrew | Chapman, Kay | Cupples, L. Adrienne | Dai, Jin | Deloukas, Panos | Doherty, Michael | Doherty, Sally | Engstrom, Gunnar | Gonzalez, Antonio | Halldorsson, Bjarni V. | Hammond, Christina L. | Hart, Deborah J. | Helgadottir, Hafdis | Hofman, Albert | Ikegawa, Shiro | Ingvarsson, Thorvaldur | Jiang, Qing | Jonsson, Helgi | Kaprio, Jaakko | Kawaguchi, Hiroshi | Kisand, Kalle | Kloppenburg, Margreet | Kujala, Urho M. | Lohmander, L. Stefan | Loughlin, John | Luyten, Frank P. | Mabuchi, Akihiko | McCaskie, Andrew | Nakajima, Masahiro | Nilsson, Peter M. | Nishida, Nao | Ollier, William E.R. | Panoutsopoulou, Kalliope | van de Putte, Tom | Ralston, Stuart H. | Rivadeneira, Fernado | Saarela, Janna | Schulte-Merker, Stefan | Slagboom, P. Eline | Sudo, Akihiro | Tamm, Agu | Tamm, Ann | Thorleifsson, Gudmar | Thorsteinsdottir, Unnur | Tsezou, Aspasia | Wallis, Gillian A. | Wilkinson, J. Mark | Yoshimura, Noriko | Zeggini, Eleftheria | Zhai, Guangju | Zhang, Feng | Jonsdottir, Ingileif | Uitterlinden, Andre G. | Felson, David T | van Meurs, Joyce B. | Stefansson, Kari | Ioannidis, John P.A. | Spector, Timothy D.
Annals of the rheumatic diseases  2010;70(2):349-355.
Osteoarthritis (OA) is the most prevalent form of arthritis and accounts for substantial morbidity and disability, particularly in the elderly. It is characterized by changes in joint structure including degeneration of the articular cartilage and its etiology is multifactorial with a strong postulated genetic component. We performed a meta-analysis of four genome-wide association (GWA) studies of 2,371 knee OA cases and 35,909 controls in Caucasian populations. Replication of the top hits was attempted with data from additional ten replication datasets. With a cumulative sample size of 6,709 cases and 44,439 controls, we identified one genome-wide significant locus on chromosome 7q22 for knee OA (rs4730250, p-value=9.2×10−9), thereby confirming its role as a susceptibility locus for OA. The associated signal is located within a large (500kb) linkage disequilibrium (LD) block that contains six genes; PRKAR2B (protein kinase, cAMP-dependent, regulatory, type II, beta), HPB1 (HMG-box transcription factor 1), COG5 (component of oligomeric golgi complex 5), GPR22 (G protein-coupled receptor 22), DUS4L (dihydrouridine synthase 4-like), and BCAP29 (the B-cell receptor-associated protein 29). Gene expression analyses of the (six) genes in primary cells derived from different joint tissues confirmed expression of all the genes in the joint environment.
doi:10.1136/ard.2010.132787
PMCID: PMC3615180  PMID: 21068099
9.  Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis (HERO): study protocol for a randomized controlled trial 
Trials  2013;14:64.
Background
Osteoarthritis (OA) is the most common type of arthritis, causing significant joint pain and disability. It is already a major cause of healthcare expenditure and its incidence will further increase with the ageing population. Current treatments for OA have major limitations and new analgesic treatments are needed. Synovitis is prevalent in OA and is associated with pain. Hydroxychloroquine is used in routine practice for treating synovitis in inflammatory arthritides, such as rheumatoid arthritis. We propose that treating patients with symptomatic hand OA with hydroxychloroquine will be a practical and safe treatment to reduce synovitis and pain.
Methods/design
HERO is an investigator-initiated, multicentre, randomized, double-blind, placebo-controlled trial. A total of 252 subjects with symptomatic hand OA will be recruited across primary and secondary care sites in the UK and randomized on a 1:1 basis to active treatment or placebo for 12 months. Daily medication dose will range from 200 to 400 mg according to ideal body weight. The primary endpoint is change in average hand pain during the previous two weeks (measured on a numerical rating scale (NRS)) between baseline and six months. Secondary endpoints include other self-reported pain, function and quality-of-life measures and radiographic structural change at 12 months. A health economics analysis will also be performed. An ultrasound substudy will be conducted to examine baseline levels of synovitis. Linear and logistic regression will be used to compare changes between groups using univariable and multivariable modelling analyses. All analyses will be conducted on an intention-to-treat basis.
Discussion
The HERO trial is designed to examine whether hydroxychloroquine is an effective analgesic treatment for OA and whether it provides any long-term structural benefit. The ultrasound substudy will address whether baseline synovitis is a predictor of therapeutic response. This will potentially provide a new treatment for OA, which could be of particular use in the primary care setting.
Trial registration
ISRCTN91859104.
doi:10.1186/1745-6215-14-64
PMCID: PMC3716636  PMID: 23452375
Double-blind; Hand osteoarthritis; Hydroxychloroquine; Placebo-controlled; Randomized
10.  The association of patient characteristics and surgical variables on symptoms of pain and function over 5 years following primary hip-replacement surgery: a prospective cohort study 
BMJ Open  2013;3(3):e002453.
Objectives
To identify patient characteristics and surgical factors associated with patient-reported outcomes over 5 years following primary total hip replacement (THR).
Design
Prospective cohort study.
Setting
Seven hospitals across England and Scotland.
Participants
1431 primary hip replacements for osteoarthritis.
Main outcome measures
The Oxford Hip Score (OHS) was collected preoperatively and each year up to 5 years postoperatively. Repeated measures such as linear regression modelling are used to identify patient and surgical predictors of outcome and describe trends over time.
Results
The majority of patients demonstrated substantial improvement in pain/function in the first year after surgery—between 1 and 5 years follow-up, there was neither further improvement nor decline. The strongest determinant of attained postoperative OHS was the preoperative OHS—those with worse preoperative pain/function had worse postoperative pain/function. Other predictors with small but significant effects included: femoral component offset—women with an offset of 44 or more had better outcomes; age—compared to those aged 50–60, younger (age <50) and older patients (age >60) had worse outcome, increasing body mass index (BMI), more coexisting diseases and worse Short Form 36 mental health (MH) was related to worse postoperative pain/function. Assessment of change in OHS between preoperative  and postoperative assessments revealed that patients achieved substantial and clinically relevant symptomatic improvement (change), regardless of variation in these patient and surgical factors.
Conclusions
Patients received substantial benefit from surgery, regardless of their preoperative assessments and surgical characteristics (baseline pain/function, age, BMI, comorbidities, MH and femoral component offset). Further research is needed to identify other factors that can improve our ability to identify patients at risk of poor outcomes from THR surgery.
doi:10.1136/bmjopen-2012-002453
PMCID: PMC3612787  PMID: 23457332
Epidemiology
11.  Causal Relationship between Obesity and Vitamin D Status: Bi-Directional Mendelian Randomization Analysis of Multiple Cohorts 
PLoS Medicine  2013;10(2):e1001383.
A mendelian randomization study based on data from multiple cohorts conducted by Karani Santhanakrishnan Vimaleswaran and colleagues re-examines the causal nature of the relationship between vitamin D levels and obesity.
Background
Obesity is associated with vitamin D deficiency, and both are areas of active public health concern. We explored the causality and direction of the relationship between body mass index (BMI) and 25-hydroxyvitamin D [25(OH)D] using genetic markers as instrumental variables (IVs) in bi-directional Mendelian randomization (MR) analysis.
Methods and Findings
We used information from 21 adult cohorts (up to 42,024 participants) with 12 BMI-related SNPs (combined in an allelic score) to produce an instrument for BMI and four SNPs associated with 25(OH)D (combined in two allelic scores, separately for genes encoding its synthesis or metabolism) as an instrument for vitamin D. Regression estimates for the IVs (allele scores) were generated within-study and pooled by meta-analysis to generate summary effects.
Associations between vitamin D scores and BMI were confirmed in the Genetic Investigation of Anthropometric Traits (GIANT) consortium (n = 123,864). Each 1 kg/m2 higher BMI was associated with 1.15% lower 25(OH)D (p = 6.52×10−27). The BMI allele score was associated both with BMI (p = 6.30×10−62) and 25(OH)D (−0.06% [95% CI −0.10 to −0.02], p = 0.004) in the cohorts that underwent meta-analysis. The two vitamin D allele scores were strongly associated with 25(OH)D (p≤8.07×10−57 for both scores) but not with BMI (synthesis score, p = 0.88; metabolism score, p = 0.08) in the meta-analysis. A 10% higher genetically instrumented BMI was associated with 4.2% lower 25(OH)D concentrations (IV ratio: −4.2 [95% CI −7.1 to −1.3], p = 0.005). No association was seen for genetically instrumented 25(OH)D with BMI, a finding that was confirmed using data from the GIANT consortium (p≥0.57 for both vitamin D scores).
Conclusions
On the basis of a bi-directional genetic approach that limits confounding, our study suggests that a higher BMI leads to lower 25(OH)D, while any effects of lower 25(OH)D increasing BMI are likely to be small. Population level interventions to reduce BMI are expected to decrease the prevalence of vitamin D deficiency.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Obesity—having an unhealthy amount of body fat—is increasing worldwide. In the US, for example, a third of the adult population is now obese. Obesity is defined as having a body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) of more than 30.0 kg/m2. Although there is a genetic contribution to obesity, people generally become obese by consuming food and drink that contains more energy than they need for their daily activities. Thus, obesity can be prevented by having a healthy diet and exercising regularly. Compared to people with a healthy weight, obese individuals have an increased risk of developing diabetes, heart disease and stroke, and tend to die younger. They also have a higher risk of vitamin D deficiency, another increasingly common public health concern. Vitamin D, which is essential for healthy bones as well as other functions, is made in the skin after exposure to sunlight but can also be obtained through the diet and through supplements.
Why Was This Study Done?
Observational studies cannot prove that obesity causes vitamin D deficiency because obese individuals may share other characteristics that reduce their circulating 25-hydroxy vitamin D [25(OH)D] levels (referred to as confounding). Moreover, observational studies cannot indicate whether the larger vitamin D storage capacity of obese individuals (vitamin D is stored in fatty tissues) lowers their 25(OH)D levels or whether 25(OH)D levels influence fat accumulation (reverse causation). If obesity causes vitamin D deficiency, monitoring and treating vitamin D deficiency might alleviate some of the adverse health effects of obesity. Conversely, if low vitamin D levels cause obesity, encouraging people to take vitamin D supplements might help to control the obesity epidemic. Here, the researchers use bi-directional “Mendelian randomization” to examine the direction and causality of the relationship between BMI and 25(OH)D. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the influence of a modifiable environmental exposure and the outcome of interest. Because gene variants do not change over time and are inherited randomly, they are not prone to confounding and are free from reverse causation. Thus, if a lower vitamin D status leads to obesity, genetic variants associated with lower 25(OH)D concentrations should be associated with higher BMI, and if obesity leads to a lower vitamin D status, then genetic variants associated with higher BMI should be associated with lower 25(OH)D concentrations.
What Did the Researchers Do and Find?
The researchers created a “BMI allele score” based on 12 BMI-related gene variants and two “25(OH)D allele scores,” which are based on gene variants that affect either 25(OH)D synthesis or breakdown. Using information on up to 42,024 participants from 21 studies, the researchers showed that the BMI allele score was associated with both BMI and with 25(OH)D levels among the study participants. Based on this information, they calculated that each 10% increase in BMI will lead to a 4.2% decrease in 25(OH)D concentrations. By contrast, although both 25(OH)D allele scores were strongly associated with 25(OH)D levels, neither score was associated with BMI. This lack of an association between 25(OH)D allele scores and obesity was confirmed using data from more than 100,000 individuals involved in 46 studies that has been collected by the GIANT (Genetic Investigation of Anthropometric Traits) consortium.
What Do These Findings Mean?
These findings suggest that a higher BMI leads to a lower vitamin D status whereas any effects of low vitamin D status on BMI are likely to be small. That is, these findings provide evidence for obesity as a causal factor in the development of vitamin D deficiency but not for vitamin D deficiency as a causal factor in the development of obesity. These findings suggest that population-level interventions to reduce obesity should lead to a reduction in the prevalence of vitamin D deficiency and highlight the importance of monitoring and treating vitamin D deficiency as a means of alleviating the adverse influences of obesity on health.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001383.
The US Centers for Disease Control and Prevention provides information on all aspects of overweight and obesity (in English and Spanish); a data brief provides information about the vitamin D status of the US population
The World Health Organization provides information on obesity (in several languages)
The UK National Health Service Choices website provides detailed information about obesity and a link to a personal story about losing weight; it also provides information about vitamin D
The International Obesity Taskforce provides information about the global obesity epidemic
The US Department of Agriculture's ChooseMyPlate.gov website provides a personal healthy eating plan; the Weight-control Information Network is an information service provided for the general public and health professionals by the US National Institute of Diabetes and Digestive and Kidney Diseases (in English and Spanish)
The US Office of Dietary Supplements provides information about vitamin D (in English and Spanish)
MedlinePlus has links to further information about obesity and about vitamin D (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Overview and details of the collaborative large-scale genetic association study (D-CarDia) provide information about vitamin D and the risk of cardiovascular disease, diabetes and related traits
doi:10.1371/journal.pmed.1001383
PMCID: PMC3564800  PMID: 23393431
12.  Regional and temporal variation in the treatment of rheumatoid arthritis across the UK: a descriptive register-based cohort study 
BMJ Open  2012;2(6):e001603.
Objectives
To describe current disease-modifying antirheumatic drugs (DMARDs) prescription in rheumatoid arthritis (RA) with reference to best practice and to identify temporal and regional trends in the UK.
Design
Descriptive, register-based cohort study.
Participants
Permanently registered patients aged ≥18 years with a recorded diagnosis of RA between 1 January 1995 and 31 March 2010 and matched controls. Participants with RA were identified through screening of all patients in the General Practice Research Database (GPRD) with a clinical or referral record for RA and at least 1 day of follow-up.
Setting
639 general practices in the UK supplying data to the GPRD.
Main outcome measures
Medication prescribing between 3 and 12 months of RA diagnosis by region and time period (1995–1999, 2000–2005 and 2006–April 2010).
Results
Of the 35 911 patients in the full RA cohort, 15 259 patients (42%) had incident RA. Analysis of prescribing in incident RA patients demonstrated that between 1995 (baseline) and 2010 there was a substantial increase in DMARD, and specifically methotrexate, prescribing across all regions with a less marked increase in combination DMARD prescribing. Taking 12-month prescribing as a snapshot: DMARD prescribing was 19–49% at baseline increasing to 45–74% by 2006–April 2010; methotrexate prescribing was 4–16% at baseline increasing to 32–60%; combination DMARD prescribing was 0–8% at baseline increasing to 3–17%. However, there was marked regional variation in the proportion of RA patients receiving DMARD regardless of time period.
Conclusions
There has been a substantial increase in prescribing of DMARDs for RA since 1995; however, regional variation persists across the UK with relative undertreatment, according to established best practice. Improved implementation of evidence-based best clinical practice to facilitate removal of treatment variation is warranted. This may occur as a result of the implementation of published national guidance.
doi:10.1136/bmjopen-2012-001603
PMCID: PMC3533005  PMID: 23144258
Primary Care; Rheumatology
13.  Knee Arthroplasty and Risk of Hip Fracture: A Population-Based, Case–Control Study 
Calcified Tissue International  2011;90(2):144-150.
The majority of knee arthroplasties (KAs) are performed in patients with osteoarthritis (OA). Although bone mass may be increased in these patients, subjects with knee OA may have an increased risk of hip fracture, possibly due to an increased severity of falls. However, in patients with KAs, risk of hip fracture has not been studied extensively. We evaluated the association between KAs and hip fracture risk in a population-based case–control study using the Dutch PHARMO Record Linkage System (1991–2002, n = 33,104). Cases were patients with a first admission for hip fracture; controls were matched by age, gender, and geographic location. Neither group had a previous history of fracture. Time since first KA was calculated. Analyses were adjusted for disease and drug history. A 54% increased hip fracture risk was found in patients who underwent KA (adjusted [adj.] OR = 1.54, 95% CI 1.19–2.00). We found a strong effect modification by age in these patients: the youngest patients (aged 18–70 years) were at more increased risk for hip fracture (adj. OR = 2.76, 95% CI 1.16–6.59), while we could not detect a statistical increase in patients aged >80 years. Furthermore, the association tended to be greater during the first few years after surgery, although it did not reach statistical significance. We found that KAs are associated with a 54% increased risk of hip fracture, in particular among adult patients aged <71 years old. Fracture risk assessment could be considered in patients who are about to undergo a KA.
doi:10.1007/s00223-011-9558-1
PMCID: PMC3271227  PMID: 22179584
Knee arthroplasty; Fracture; Osteoarthritis; Bone density
14.  Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium 
Objective
To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes.
Methods
Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. To investigate whether different OA definitions result in different association results, we created hip OA definitions used within the consortium in the Rotterdam Study-I and tested the association of hip OA with gender, age and BMI using one-way ANOVA. For radiographic OA, we standardized the hip, knee and hand ROA definitions and calculated prevalence's of ROA before and after standardization in 9 cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment.
Results
In this consortium, all studies with symptomatic OA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee, hip and hand radiographic OA 5, 4 and 7 different definitions were used, respectively. Different hip OA definitions do lead to different association results. For example, we showed in the Rotterdam Study-I that hip OA defined as “at least definite JSN and one definite osteophyte” was not associated with gender (p=0.22), but defined as “at least one definite osteophyte” was significantly associated with gender (p=3×10−9). Therefore, a standardization process was undertaken for radiographic OA definitions. Before standardization a wide range of ROA prevalence's was observed in the 9 cohorts studied. After standardization the range in prevalence of knee and hip ROA was small. Standardization of SOA phenotypes was not possible due to the case-control design of the studies.
Conclusion
Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies.
doi:10.1016/j.joca.2010.10.027
PMCID: PMC3236091  PMID: 21059398
15.  Forefoot pathology in rheumatoid arthritis identified with ultrasound may not localise to areas of highest pressure: cohort observations at baseline and twelve months 
Background
Plantar pressures are commonly used as clinical measures, especially to determine optimum foot orthotic design. In rheumatoid arthritis (RA) high plantar foot pressures have been linked to metatarsophalangeal (MTP) joint radiological erosion scores. However, the sensitivity of foot pressure measurement to soft tissue pathology within the foot is unknown. The aim of this study was to observe plantar foot pressures and forefoot soft tissue pathology in patients who have RA.
Methods
A total of 114 patients with established RA (1987 ACR criteria) and 50 healthy volunteers were assessed at baseline. All RA participants returned for reassessment at twelve months. Interface foot-shoe plantar pressures were recorded using an F-Scan® system. The presence of forefoot soft tissue pathology was assessed using a DIASUS musculoskeletal ultrasound (US) system. Chi-square analyses and independent t-tests were used to determine statistical differences between baseline and twelve months. Pearson's correlation coefficient was used to determine interrelationships between soft tissue pathology and foot pressures.
Results
At baseline, RA patients had a significantly higher peak foot pressures compared to healthy participants and peak pressures were located in the medial aspect of the forefoot in both groups. In contrast, RA participants had US detectable soft tissue pathology in the lateral aspect of the forefoot. Analysis of person specific data suggests that there are considerable variations over time with more than half the RA cohort having unstable presence of US detectable forefoot soft tissue pathology. Findings also indicated that, over time, changes in US detectable soft tissue pathology are out of phase with changes in foot-shoe interface pressures both temporally and spatially.
Conclusions
We found that US detectable forefoot soft tissue pathology may be unrelated to peak forefoot pressures and suggest that patients with RA may biomechanically adapt to soft tissue forefoot pathology. In addition, we have observed that, in patients with RA, interface foot-shoe pressures and the presence of US detectable forefoot pathology may vary substantially over time. This has implications for clinical strategies that aim to offload peak plantar pressures.
doi:10.1186/1757-1146-4-25
PMCID: PMC3254591  PMID: 22112624
16.  Large Scale Replication Study of the Association between HLA Class II/BTNL2 Variants and Osteoarthritis of the Knee in European-Descent Populations 
PLoS ONE  2011;6(8):e23371.
Osteoarthritis (OA) is the most common form of arthritis and a major cause of disability. This study evaluates the association in Caucasian populations of two single nucleotide polymorphisms (SNPs) mapping to the Human Leukocyte Antigen (HLA) region and deriving from a genome wide association scan (GWAS) of knee OA in Japanese populations. The frequencies for rs10947262 were compared in 36,408 controls and 5,749 knee OA cases from European-descent populations. rs7775228 was tested in 32,823 controls and 1,837 knee OA cases of European descent. The risk (major) allele at rs10947262 in Caucasian samples was not significantly associated with an odds ratio (OR)  = 1.07 (95%CI 0.94 -1.21; p = 0.28). For rs7775228 the meta-analysis resulted in OR = 0.94 (95%CI 0.81-1.09; p = 0.42) for the allele associated with risk in the Japanese GWAS. In Japanese individuals these two SNPs are in strong linkage disequilibrium (LD) (r2 = 0.86) with the HLA class II haplotype DRB1*1502 DQA1*0103 DQB1*0601 (frequency 8%). In Caucasian and Chinese samples, using imputed data, these SNPs appear not to be in LD with that haplotype (r2<0.07). The rs10947262 and rs7775228 variants are not associated with risk of knee OA in European descent populations and they do not appear tag the same HLA class II haplotype as they do in Japanese individuals.
doi:10.1371/journal.pone.0023371
PMCID: PMC3154440  PMID: 21853121
17.  Association between DHEAS and Bone Loss in Postmenopausal Women: A 15-Year Longitudinal Population-Based Study 
Calcified Tissue International  2011;89(4):295-302.
Our aim was to examine the association between serum dehydroepiandrosterone sulfate (DHEAS) at baseline and BMD change at the femoral neck (FN) and lumbar spine (LS) in postmenopausal women during a 15-year follow-up. All participants were from the Chingford Study. BMD at the FN and LS were measured eight times during the 15-year follow-up by dual-energy X-ray absorptiometry. DHEAS at baseline was measured using radioimmunoassay. Data on height, weight, and hormone-replacement therapy (HRT) status were obtained at each visit. Multilevel linear regression modeling was used to examine the association between longitudinal BMD change at the FN and LS and DHEAS at baseline. Postmenopausal women (n = 1,003) aged 45–68 years (mean 54.7) at baseline were included in the study. After adjustment for baseline age, estradiol, HRT, and BMI, BMD at the FN decreased on average 0.49% (95% CI 0.31–0.71%) per year; and the decline was slowed down by 0.028% per squared year. Increase of DHEAS (each micromole per liter) was associated with 0.49% less bone loss at the FN (95% CI 0.21–0.71%, P = 0.001). However, this strong association became slightly weaker over time. Similar but weaker results were obtained for LS BMD. Our data suggest that high serum DHEAS at baseline is associated with less bone loss at both FN and LS and this association diminishes over time. The nature of the association is unclear, but such an association implies that, in managing BMD loss, women might benefit from maintaining a high level of DHEAS.
doi:10.1007/s00223-011-9518-9
PMCID: PMC3175043  PMID: 21789637
BMD; DHEAS; Osteoporosis; Longitudinal study; Postmenopausal
18.  The effect of genome-wide association scan quality control on imputation outcome for common variants 
Imputation is an extremely valuable tool in conducting and synthesising genome-wide association studies (GWASs). Directly typed SNP quality control (QC) is thought to affect imputation quality. It is, therefore, common practise to use quality-controlled (QCed) data as an input for imputing genotypes. This study aims to determine the effect of commonly applied QC steps on imputation outcomes. We performed several iterations of imputing SNPs across chromosome 22 in a dataset consisting of 3177 samples with Illumina 610k (Illumina, San Diego, CA, USA) GWAS data, applying different QC steps each time. The imputed genotypes were compared with the directly typed genotypes. In addition, we investigated the correlation between alternatively QCed data. We also applied a series of post-imputation QC steps balancing elimination of poorly imputed SNPs and information loss. We found that the difference between the unQCed data and the fully QCed data on imputation outcome was minimal. Our study shows that imputation of common variants is generally very accurate and robust to GWAS QC, which is not a major factor affecting imputation outcome. A minority of common-frequency SNPs with particular properties cannot be accurately imputed regardless of QC stringency. These findings may not generalise to the imputation of low frequency and rare variants.
doi:10.1038/ejhg.2010.242
PMCID: PMC3083623  PMID: 21267008
genome-wide association study; imputation; quality control; single nucleotide polymorphism
20.  A case of leg pain and weakness in a man with diabetes 
Journal of Clinical Pathology  2007;60(8):938-939.
doi:10.1136/jcp.2005.032458
PMCID: PMC1994504  PMID: 17660337
motor neurone disease; creatine kinase; diabetes
21.  Improvement in symptoms and signs in the forefoot of patients with rheumatoid arthritis treated with anti-TNF therapy 
Background
Inhibition of tumour necrosis factor (TNF) is an effective way of reducing synovitis and preventing joint damage in rheumatoid arthritis (RA), yet very little is known about its specific effect on foot pain and disability. The aim of this study was to evaluate whether anti-TNF therapy alters the presence of forefoot pathology and/or reduces foot pain and disability.
Methods
Consecutive RA patients starting anti-TNF therapy (infliximab, etanercept, adalimumab) were assessed for presence of synovial hypertrophy and synovitis in the 2nd and 5th metatarso-phalangeal (MTP) joints and plantar forefoot bursal hypertrophy before and 12 weeks after therapy. Tender MTP joints and swollen bursae were established clinically by an experienced podiatrist and ultrasound (US) images were acquired and interpreted by a radiologist. Assessment of patient reported disease impact on the foot was performed using the Manchester Foot Pain and Disability Index (MFPDI).
Results
31 patients (24 female, 7 male) with RA (12 seronegative, 19 seropositive) completed the study: mean age 59.6 (SD 10.1) years, disease duration 11.1 (SD 10.5) years, and previous number of Disease Modifying Anti Rheumatic Drugs 3.0 (1.6). Significant differences after therapy were found for Erythrocyte Sedimentation Rate (t = 4.014, p < 0.001), C-reactive protein (t = 3.889, p = 0.001), 28 joint Disease Activity Score (t = 3.712, p = 0.0001), Visual Analog Scale (t = 2.735, p = 0.011) and Manchester Foot Pain and Disability Index (t = 3.712, p = 0.001).
Presence of MTP joint synovial hypertrophy on US was noted in 67.5% of joints at baseline and 54.8% of joints at twelve weeks. Presence of plantar forefoot bursal hypertrophy on US was noted in 83.3% of feet at baseline and 75% at twelve weeks. Although there was a trend for reduction in observed presence of person specific forefoot pathology, when the frequencies were analysed (McNemar) this was not significant.
Conclusions
Significant improvements were seen in patient reported foot pain and disability 12 weeks after commencing TNF inhibition in RA, but this may not be enough time to detect changes in forefoot pathology.
doi:10.1186/1757-1146-3-10
PMCID: PMC2901324  PMID: 20565792
22.  Musculoskeletal ultrasound imaging of the plantar forefoot in patients with rheumatoid arthritis: inter-observer agreement between a podiatrist and a radiologist 
Background
The use of musculoskeletal ultrasound (MSUS) in the diagnosis and management of foot and ankle musculoskeletal pathology is increasing. Due to the wide use of MSUS and the depth and breadth of training required new proposals advocate tailored learning of the technique to discrete fields of practice. The aims of the study were to evaluate the inter-observer agreement between a MSUS radiologist and a podiatrist, who had completed basic skills training in MSUS, in the MSUS assessment of the forefoot of patients with Rheumatoid Arthritis.
Methods
A consecutive sample of thirty-two patients with rheumatoid arthritis was assessed for presence of synovitis, erosions and bursitis within the forefoot using MSUS. All MSUS assessments were performed independently on the same day by a podiatrist and one of two Consultant Radiologists experienced in MSUS.
Results
Moderate agreement on image acquisition and interpretation was achieved for bursitis (kappa 0.522; p < 0.01) and erosions (kappa 0.636; p < 0.01) and fair agreement for synovitis (kappa 0.216; p < 0.05) during the primary assessments. Following a further training session, substantial agreement (kappa 0.702) between the two investigators was recorded. The sensitivity of the podiatrist using MSUS was 82.4% for detection of bursitis, 83.0% for detection of erosion and 84.0% for detection of synovitis. Specificity of the podiatrist using MSUS was 88.9% for detection of bursitis, 80.7% for detection of erosion and 35.9% for detection of synovitis.
Conclusion
This study demonstrated good inter-observer agreement between a podiatrist and radiologist on MSUS assessment of the forefoot, particularly for bursitis and erosions, in patients with rheumatoid arthritis. There is scope to further evaluate and consider the role of podiatrists in the MSUS imaging of the foot following appropriate training and also in the development of reliable protocols for MSUS assessment of the foot.
doi:10.1186/1757-1146-1-5
PMCID: PMC2553775  PMID: 18822149
25.  The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis 
Annals of the Rheumatic Diseases  2011;70(9):1556-1561.
Objective
To assess if a coding variant in the gene encoding transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is associated with genetic risk of painful knee osteoarthritis (OA).
Methods
The Ile585Val TRPV1 variant encoded by rs8065080 was genotyped in 3270 cases of symptomatic knee OA, 1098 cases of asymptomatic knee OA and 3852 controls from seven cohorts from the UK, the USA and Australia. The genetic association between the low-pain genotype Ile–Ile and risk of symptomatic and asymptomatic knee OA was assessed.
Results
The TRPV1 585 Ile–Ile genotype, reported to be associated with lower thermal pain sensitivity, was associated with a lower risk of symptomatic knee OA in a comparison of symptomatic cases with healthy controls, with an odds ratio (OR) of 0.75 (95% CI 0.64 to 0.88; p=0.00039 by meta-analysis) after adjustment for age, sex and body mass index. No difference was seen between asymptomatic OA cases and controls (OR=1.02, 95% CI 0.82 to 1.27 p=0.86) but the Ile–Ile genotype was associated with lower risk of symptomatic versus asymptomatic knee OA adjusting for covariates and radiographic severity (OR=0.73, 95% CI 0.57 to 0.94 p=0.0136). TRPV1 expression in articular cartilage was increased by inflammatory cytokines (tumour necrosis factor α and interleukin 1). However, there were no differences in TRPV1 expression in healthy and arthritic synovial tissue.
Conclusions
A genotype involved in lower peripheral pain sensitivity is significantly associated with a decreased risk of painful knee OA. This indicates a role for the pro-nociceptive gene TRPV1 in genetic susceptibility to symptomatic knee OA, which may also be influenced by a role for this molecule in cartilage function.
doi:10.1136/ard.2010.148122
PMCID: PMC3147243  PMID: 21616913

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