Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone.

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.

Daily Pain Severity but Not Vertebral Fractures Is Associated With Lower Physical Activity in Postmenopausal Women With Back Pain.

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.

Role of the Microbiome in Regulating Bone Metabolism and Susceptibility to Osteoporosis.

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.

A clinical tool to identify older women with back pain at high risk of osteoporotic vertebral fractures (Vfrac): a population-based cohort study with exploratory economic evaluation.

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.

Mendelian randomization provides evidence for a causal effect of higher serum IGF-1 concentration on risk of hip and knee osteoarthritis.

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.

Investigation of the Relationship Between Peak Vertical Accelerations and Aerobic Exercise Intensity During Graded Walking and Running in Postmenopausal Women.

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.

Unpicking observational relationships between hip shape and osteoarthritis: hype or hope?

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

Metabolomics analysis in adults with high bone mass identifies a relationship between bone resorption and circulating citrate which replicates in the general population.

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

Associations between prenatal indicators of mechanical loading and proximal femur shape: findings from a population-based study in ALSPAC offspring.

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.

Age at puberty and accelerometer-measured physical activity: Findings from two independent UK cohorts.

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.

Correlates of high-impact physical activity measured objectively in older British adults.

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

Do subjective memory complaints predict falls, fractures and healthcare utilization? A two-year prospective study based on a cohort of older women recruited from primary care.

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

Postural Stability During Standing Balance and Sit-to-Stand in Master Athlete Runners Compared With Nonathletic Old and Young Adults.

The aim of this study was to compare postural sway during a series of static balancing tasks and during five chair rises between healthy young (mean [SEM], age 26 [1] years), healthy old (age 67 [1] years) and master athlete runners (age 67 [1] years; competing and training for the previous 51 [5] years) using the Microsoft Kinect One. The healthy old had more sway than the healthy young in all balance tasks. The master athletes had similar sway to young athletes during two-leg balancing and one-leg standing with eyes open. When balancing on one leg with eyes closed, both the healthy old and the master athletes had around 17-fold more sway than the young athletes. The healthy old and master athletes also had less anterio-posterior movement during chair rising compared with young athletes. These results suggest that masters runners are not spared from the age-associated decline in postural stability and may benefit from specific balance training.

Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure.

Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n = 5,878) followed by replication (n = 1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p = 3.6×10⁻¹4; LOC285735, rs271170, p = 2.7×10⁻¹²; OPG, rs7839059, p = 1.2×10⁻¹°; and ESR1/C6orf97, rs6909279, p = 1.1×10⁻9). The trabecular vBMD GWA meta-analysis (n = 2,500) followed by replication (n = 1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p = 1.9×10⁻9). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n = 729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60-0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.

Anxiety at 13 and its effect on pain, pain-related anxiety, and pain-related disability at 17: An ALSPAC cohort longitudinal analysis.

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

Characterization of Vertical Accelerations Experienced by Older People Attending an Aerobics Class Designed to Produce High Impacts.

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 performance battery, and an aerobics class with seven different components, performed at low and high intensity. Maximum g and jerk values were identified for each activity. Forty-one participants (mean 69 years) were included. Mean maximal values approached or exceeded the 4g threshold for four of the seven exercises. In multivariate analyses, age (-0.53; -0.77, -0.28) (standardized beta coefficient; 95% CI) and 4-m walk time (-0.39; -0.63, -0.16) were inversely related to maximum g. Aerobics classes can be used to produce relatively high vertical accelerations in older individuals, although the outcome is strongly dependent on age and physical function.

Quantifying Habitual Levels of Physical Activity According to Impact in Older People: Accelerometry Protocol for the VIBE Study.

Physical activity (PA) may need to produce high impacts to be osteogenic. The aim of this study was 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. Recordings were obtained from 19 Master Athlete Cohort (MAC; mean 67.6 years) and 15 Hertfordshire Cohort Study (HCS; mean 77.7 years) participants. Data cleaning protocols were developed to exclude artifacts. Accelerations expressed in g units were categorized into three bands selected from the distribution of positive Y-axis peak accelerations. Data were available for 6.6 and 4.4 days from MAC and HCS participants respectively, with approximately 14 hr recording daily. Three-fold more 0.5-1.0g impacts were observed in MAC versus HCS, 20-fold more 1.0-1.5g impacts, and 140-fold more impacts ≥ 1.5g. Our analysis protocol successfully distinguishes PA levels in active and sedentary older individuals.

Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances.

Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption, we performed a population-based genome-wide association study of 'age at first tooth' and 'number of teeth' using 5998 and 6609 individuals, respectively, from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2 446 724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of 15 independent loci, with 10 loci reaching genome-wide significance (P < 5 × 10(-8)) for 'age at first tooth' and 11 loci for 'number of teeth'. Together, these associations explain 6.06% of the variation in 'age of first tooth' and 4.76% of the variation in 'number of teeth'. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including an SNP in the protein-coding region of BMP4 (rs17563, P = 9.080 × 10(-17)). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.

45-day mortality after 467,779 knee replacements for osteoarthritis from the National Joint Registry for England and Wales: an observational study.

BACKGROUND: Understanding the risk factors for early death after knee replacement could help to reduce the risk of mortality after this procedure. We assessed secular trends in death within 45 days of knee replacement for osteoarthritis in England and Wales, with the aim of investigating whether any change that we recorded could be explained by alterations in modifiable perioperative factors. METHODS: We took data for knee replacements done for osteoarthritis in England and Wales between April 1, 2003, and Dec 31, 2011, from the National Joint Registry for England and Wales. Patient identifiers were used to link these data to the national mortality database and the Hospital Episode Statistics database to obtain details of death, sociodemographics, and comorbidity. We assessed mortality within 45 days by Kaplan-Meier analysis and assessed the role of patient and treatment factors by Cox proportional hazards models. FINDINGS: 467,779 primary knee replacements were done to treat osteoarthritis during 9 years. 1183 patients died within 45 days of surgery, with a substantial secular decrease in mortality from 0·37% in 2003 to 0·20% in 2011, even after adjustment for age, sex, and comorbidity. The use of unicompartmental knee replacement was associated with substantially lower mortality than was total knee replacement (hazard ratio [HR] 0·32, 95% CI 0·19­0·54, p<0·0005). Several comorbidities were associated with increased mortality: myocardial infarction (HR 3·46, 95% CI 2·81­4·14, p<0·0005), cerebrovascular disease (3·35, 2·7­4·14, p<0·0005), moderate/severe liver disease (7·2, 3·93­13·21, p<0·0005), and renal disease (2·18, 1·76­2·69, p<0·0005). Modifiable perioperative risk factors, including surgical approach and thromboprophylaxis were not associated with mortality. INTERPRETATION: Postoperative mortality after knee replacement has fallen substantially between 2003 and 2011. Efforts to further reduce mortality should concentrate more on older patients, those who are male and those with specific comorbidities, such as myocardial infarction, cerebrovascular disease, liver disease, and renal disease. FUNDING: National Joint Registry for England and Wales.