Using Mendelian randomization to investigate a possible causal relationship between adiposity and increased bone mineral density at different skeletal sites in children

Lean mass is positively associated with bone mineral density (BMD). However, the relationship between adiposity and BMD is more controversial. In particular, it is unclear if the observational association between the two reflects a causal effect of fat mass on BMD. Previous Mendelian randomization (MR) studies using variants in the FTO and MC4R genes as genetic instruments for adiposity have suggested that fat mass does indeed causally influence BMD. However, it is possible that these genetic variants pleiotropically influence lean mass and affect BMD through pathways independent of adiposity, invalidating one of the core assumptions of MR and complicating interpretation of the analysis.To investigate whether adiposity causally affects BMD, we investigated the relationship between fat mass and BMD at the skull (SK), upper limbs (UL) and lower limbs (LL), spine (SP) and pelvis (PE), using 32 body mass index (BMI)-associated SNPs, including a variant near ADCY3 that was strongly associated with fat but not lean mass in our sample. Dual-energy X-ray absorptiometry (DXA) scans and genetic data were available for 5221 subjects (mean age 9.9 years) from the Avon Longitudinal Study of Parents and Children. We performed a series of MR analyses involving single BMI-associated SNPs and allelic scores of these SNPs. We used new extensions of the MR method including MR Egger regression and multivariable MR, which are more robust to possible confounding effects due to horizontal pleiotropy and, in the case of multivariable MR, specifically account for the effect of lean mass in the analysis. Bidirectional Mendelian randomization analysis was also performed to examine whether BMD causally affected BMI and adiposity.Observationally, fat mass was strongly positively related to BMD at all sites, but more weakly at the skull. Instrumental variables (IV) analyses using an allelic score of BMI SNPs suggested that fat mass was causally related to LL-BMD, UL-BMD, SP-BMD and PE-BMD but not SK-BMD. Multivariable MR, Egger regression and IV analyses involving the ADCY3 variant suggested a positive causal effect of adiposity on all sites except the skull, and that an effect was present even after taking lean mass into account. Finally, IV analyses using BMD allelic scores showed no evidence of reverse causality between BMD and fat mass.Our results suggest that adiposity is causally related to increased BMD at all sites except the skull, perhaps reflecting positive effects of loading on bone formation at weighted but not unweighted sites. In contrast, we found no evidence for BMD causally affecting BMI or measures of adiposity. Our results illustrate how MR can be used profitably to investigate clinical questions relevant to osteoporosis

High impact activity is related to lean but not fat mass:findings from a population-based study in adolescents

Background Objective measures of physical activity calibrated against energy expenditure may have limited utility in studying relationships with musculoskeletal phenotypes. We wished to assess an alternative approach using an accelerometer calibrated according to impact loading. Methods Of the 17-year olds from the Avon Longitudinal Study of Parents and Children (ALSPAC), 732 wore Newtest accelerometers while performing day-to-day activities for a mean of 5.8 days. Outputs were categorized as light, moderate, high and very high impact, based on the thresholds identified in 22 adolescents during graded activities. In subsequent regression analyses, activity data and fat mass were normalized by log transformation. Results The number of counts relating to high impact activity was ∼2% that of light impact activity, and 33% greater in boys when compared with girls. High impact activity was more strongly related to lean mass [light: 0.033 (95% CI −0.023 to 0.089), moderate: 0.035 (95% CI −0.010 to 0.080) and high: 0.044 (95% CI 0.010 to 0.078)] (β = SD change in outcome per doubling in activity, height adjusted, boys and girls combined). In contrast, lower impact activity was more strongly related to fat mass [light: −0.069 (95% CI −0.127 to −0.011), moderate: −0.060 (95% CI −0.107 to −0.014) and high: −0.033 (95% CI −0.069 to 0.003)]. In a more fully adjusted model including other activity types and fat/lean mass, lean mass was related to only high activity (boys and girls combined), whereas fat mass was related to only moderate activity (girls only). Conclusions Using an accelerometer calibrated according to impact loading revealed that high impact activity is related to lean but not fat mass

Association between surgical volume and failure of primary total hip replacement in England and Wales: findings from a prospective national joint replacement register

Objective To investigate the association of volume of total hip arthroplasty (THA) between consultants and within the same consultant in the previous year and the hazard of revision using multilevel survival models. Design Prospective cohort study using data from a national joint replacement register. Setting Elective THA across all private and public centres in England and Wales between April 2003 and February 2017. Participants Patients aged 50 years or more undergoing THA for osteoarthritis. Intervention The volume of THA conducted in the preceding 365 days to the index procedure. Main outcome and measure Revision surgery (excision, addition or replacement) of a primary THA. Results Of the 579 858 patients undergoing primary THA (mean baseline age 69.8 years (SD 10.2)), 61.1% were women. Multilevel survival found differing results for between and within-consultant effects. There was a strong volume–revision association between consultants, with a near-linear 43.3% (95% CI 29.1% to 57.4%) reduction of the risk of revision comparing consultants with volumes between 1 and 200 procedures annually. Changes in individual surgeons (within-consultant) case volume showed no evidence of an association with revision. Conclusion Separation of between-consultant and within- consultant effects of surgical volume reveals how volume contributes to the risk of revision after THA. The lack of association within-consultants suggests that individual changes to consultant volume alone will have little effect on outcomes following THA. These novel findings provide strong evidence supporting the practice of specialisation of hip arthroplasty. It does not support the practice of low-volume consultants increasing their personal volume as it is unlikely their results would improve if this is the only change. Limiting the exposure of patients to consultants with low volumes of THA and greater utilisation of centres with higher volume surgeons with better outcomes may be beneficial to patients

Motor Competence in Early Childhood Is Positively Associated with Bone Strength in Late Adolescence

The onset of walking in early childhood results in exposure of the lower limb to substantial forces from weight bearing activity that 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 of Parents and Children (ALSPAC). Higher GMS indicated greater motor competence in weight‐bearing activities. Total hip bone mineral density (BMD) and hip cross‐sectional moment of inertia (CSMI) were assessed from dual‐energy X‐ray absorptiometry (DXA). Bone measures including cortical bone mineral content (BMC), periosteal circumference (PC), cortical thickness (CT), cortical bone area (CBA), cortical BMD (BMD(C)) and cross‐sectional moment of inertia (CSMI) were assessed by peripheral quantitative computed tomography (pQCT) at 50% distal‐proximal length. Before adjustment, GMS was associated with hip BMD, CSMI, and tibia BMC, PC, CT, CBA and CSMI (all p < 0.001) but not BMD(C) (p > 0.25). Strongest associations (standardized regression coefficients with 95% CI) were between GMS and hip BMD (0.086; 95% CI, 0.067 to 0.105) and tibia BMC (0.105; 95% CI, 0.089 to 0.121). With the exception of hip BMD, larger regression coefficients were observed in males (gender interactions all p < 0.05). Adjustment for lean mass resulted in substantial attenuation of regression coefficients, suggesting associations between impaired motor competence and subsequent bone development are partly mediated by alterations in body composition. In conclusion, impaired motor competence in childhood is associated with lower adolescent bone strength, and may represent a risk factor for subsequent osteoporosis. © 2015 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR)

The association of body mass index with risk of long-term revision and 90-day mortality following primary total hip replacement:Findings from the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man

BACKGROUND: The influence of obesity on outcomes following total hip replacement is unclear. Restriction of total hip replacement on the basis of body mass index (BMI) has been suggested. The purpose of this study was to assess the influence of BMI on the risk of revision and 90-day mortality. METHODS: This was a population-based, longitudinal cohort study of the National Joint Registry (NJR) for England, Wales, Northern Ireland and the Isle of Man. Using data recorded from April 2003 to December 2015, linked to Office for National Statistics data, we ascertained revision and 90-day mortality rates following primary total hip replacement by BMI category. The probability of revision was estimated using Kaplan-Meier methods. Associations of BMI with revision and mortality were explored using adjusted Cox proportional hazards regression models. RESULTS: We investigated revision and 90-day mortality among 415,598 and 413,741 primary total hip replacements, respectively. Each data set accounts for approximately 52% of the total number of recorded operations in the NJR. Thirty-eight percent of the patients were classified as obese. At 10 years, class-III obese patients had the highest cumulative probability of revision (6.7% [95% confidence interval (CI), 5.5% to 8.2%]), twice that of the underweight group (3.3% [95% CI, 2.2% to 4.9%]). When the analysis was adjusted for age, sex, American Society of Anesthesiologists [ASA] grade, year of operation, indication, and fixation type, compared with patients with normal BMI, significantly elevated hazard ratios (HRs) for revision were observed for patients in the BMI categories of class-I obese (≥30 to <35 kg/m) (HR, 1.14 [95% CI, 1.07 to 1.22]), class-II obese (≥35 to <40 kg/m) (HR, 1.30 [95% CI, 1.19 to 1.40]), and class-III obese (≥40 to ≤60 kg/m) (HR, 1.43 [95% CI, 1.27 to 1.61]) (p < 0.0005 for all). Underweight patients had a substantially higher cumulative probability of 90-day mortality (1.17%; 95% CI, 0.86% to 1.58%) compared with patients with normal BMI (0.43%; 95% CI, 0.39% to 0.48%). The risk of 90-day mortality was significantly higher for the underweight group (HR, 2.09 [95% CI, 1.51 to 2.89]; p < 0.0005) and significantly lower for patients who were categorized as overweight (HR, 0.70; 95% CI, 0.61 to 0.81; p < 0.0005), class-I obese (HR, 0.69 [95% CI, 0.59 to 0.81]; p < 0.0005), and class-II obese (HR, 0.79 [95% CI, 0.63 to 0.98]; p = 0.049) compared with patients with normal BMI. CONCLUSIONS: Although long-term revision rates following total hip replacement were higher among obese patients, we believe that the rates remained acceptable by contemporary standards and were balanced by a lower risk of 90-day mortality. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence

Epidemiology of Generalized Joint Laxity (Hypermobility) in Fourteen-Year-Old Children From the UK: A Population-Based Evaluation

Objective Although diagnostic criteria for generalized ligamentous laxity (hypermobility) in children are widely used, their validity may be limited, due to the lack of robust descriptive epidemiologic data on this condition. The present study was undertaken to describe the point prevalence and pattern of hypermobility in 14-year-old children from a population-based cohort. Methods We performed a cross-sectional analysis using the Avon Longitudinal Study of Parents and Children, a large population-based birth cohort. Hypermobility among children in the cohort (mean age 13.8 years) was measured using the Beighton scoring system. Objective measures of physical activity were ascertained by accelerometry. Data on other variables, including puberty and socioeconomic status, were collected. Simple prevalence rates were calculated. Chi-square tests and logistic regression analyses were used to assess associations of specific variables with hypermobility. Results Among the 6,022 children evaluated, the prevalence of hypermobility (defined as a Beighton score of ≥4 [i.e., ≥4 joints affected]) in girls and boys age 13.8 years was 27.5% and 10.6%, respectively. Forty-five percent of girls and 29% of boys had hypermobile fingers. There was a suggestion of a positive association between hypermobility in girls and variables including physical activity, body mass index, and maternal education. No associations were seen in boys. Conclusion We have shown that the prevalence of hypermobility in UK children is high, possibly suggesting that the Beighton score cutoff of ≥4 is too low or that this scoring is not appropriate for use in subjects whose musculoskeletal system is still developing. These results provide a platform to evaluate the relationships between the Beighton criteria and key clinical features (including pain), thereby testing the clinical validity of this scoring system in the pediatric population. Copyright © 2011 by the American College of Rheumatology

Analysis of change in patient-reported outcome measures with floor and ceiling effects using the multilevel Tobit model:a simulation study and an example from a National Joint Register using body mass index and the Oxford Hip Score

OBJECTIVES: This study has three objectives. (1) Investigate the association between body mass index (BMI) and the efficacy of primary hip replacement using a patient-reported outcome measure (PROMs) with a measurement floor and ceiling, (2) Explore the performance of different estimation methods to estimate change in PROMs score following surgery using a simulation study and real word data where data has measurement floors and ceilings and (3) Lastly, develop guidance for practising researchers on the analysis of PROMs in the presence of floor and ceiling effects. DESIGN: Simulation study and prospective national medical device register. SETTING: National Register of Joint Replacement and Medical Devices. METHODS: Using a Monte Carlo simulation study and data from a national joint replacement register (162 513 patients with pre- and post-surgery PROMs), we investigate simple approaches for the analysis of outcomes with floor and ceiling effects that are measured at two occasions: linear and Tobit regression (baseline adjusted analysis of covariance, change-score analysis, post-score analysis) in addition to linear and multilevel Tobit models. PRIMARY OUTCOME: The primary outcome of interest is change in PROMs from pre-surgery to 6 months post-surgery. RESULTS: Analysis of data with floor and ceiling effects with models that fail to account for these features induce substantial bias. Single-level Tobit models only correct for floor or ceiling effects when the exposure of interest is not associated with the baseline score. In observational data scenarios, only multilevel Tobit models are capable of providing unbiased inferences. CONCLUSIONS: Inferences from pre- post-studies that fail to account for floor and ceiling effects may induce spurious associations with substantial risk of bias. Multilevel Tobit models indicate the efficacy of total hip replacement is independent of BMI. Restricting access to total hip replacement based on a patients BMI can not be supported by the data