R.J. Barr

Vitamin D status in postmenopausal women living at higher latitudes in the UK in relation to bone health, overweight, sunlight exposure and dietary vitamin D

For 5 months a year the UK has insufficient sunlight for cutaneous synthesis of vitamin D and winter requirements are met from stores made the previous summer. Although there are few natural dietary sources, dietary intake may help maintain vitamin D status. We investigated the relationship between 25-hydroxyvitamin D (25(OH)D), bone health, overweight, sunlight exposure and dietary vitamin D in 3113 women (age 54.8 [SD 2.3] years) living at latitude 57 degrees N between 1998-2000. Serum 25(OH)D was measured by high performance liquid chromatography (HPLC), dietary intakes (food frequency questionnaire, n=2598), sunlight exposure (questionnaire, n=2402) and bone markers were assessed. Bone mineral density (BMD) was measured by dual x-ray absorptiometry in all women at the sampling visit and 6 years before. Seasonal variation in 25(OH)D was not substantial with a peak in the autumn (23.7 [9.9] ng/ml) and a nadir in spring (19.7 [7.6] ng/ml). Daily intake of vitamin D was 4.2 [2.5] mug from food only and 5.8 [4.0] mug including vitamin D from cod liver oil and multivitamins. The latter was associated with 25(OH)D at each season whereas vitamin D simply from food was associated with 25(OH)D in winter and spring only. Sunlight exposure was associated with 25(OH)D in summer and autumn. 25(OH)D was negatively associated with increased bone resorption and bone loss (P<0.05) remaining significant after adjustment for confounders (age, weight, height, menopausal status/HRT use, physical activity and socio-economic status). Using an insufficiency cut-off of <28 ng/ml 25(OH)D, showed lower concentrations of bone resorption markers in the upper category (fDPD/Cr 5.1 [1.7] nmol/mmol compared to 5.3 [2.1] nmol/mmol, P=0.03) and no difference in BMD or bone loss. 25(OH)D was lower (P<0.01) and parathyroid hormone higher (P<0.01) in the top quintile of body mass index. In conclusion, low vitamin D status is associated with greater bone turnover, bone loss and obesity. Diet appears to attenuate the seasonal variation of vitamin D status in early postmenopausal women at northerly latitude where quality of sunlight for production of vitamin D is diminished.

Association between vitamin D receptor gene polymorphisms, falls, balance and muscle power: results from two independent studies (APOSS and OPUS)

SummaryFall prevention is a key strategy for reducing osteoporotic fractures. We investigated the association between vitamin D receptor (VDR) polymorphisms and reported falls in postmenopausal women. Bsm1 polymorphisms were associated with falls, balance and muscle power measurements. These results may explain some of the excess fracture risk associated with VDR in some studies.IntroductionFall prevention is a key strategy for reducing osteoporotic fractures. It has been suggested that vitamin D supplementation may reduce the incidence of falls by reducing body sway and increasing muscle power. The vitamin D receptor gene is a well-studied candidate gene for osteoporosis. We investigated the association between VDR polymorphisms and reported falls in postmenopausal women.MethodsFalls data were collected in two separate population cohorts. Five polymorphisms of the VDR gene were analysed (Cdx-2, Fok-1, BsmI, Taq1 and Apa1) in the Aberdeen Prospective Osteoporosis Screening Study (APOSS) cohort. Results found in APOSS were then validated in an independent cohort—the Osteoporosis and Ultrasound (OPUS) study (Bsm1 and Fok1 only), where muscle power and balance were also measured.ResultsCarriers of the ‘B’ allele (Bsm1) showed an increased risk for falls. In APOSS, this was statistically significant for visit 3 multiple falls (p = 0.047) and for recurrent falls (p = 0.043). Similar results were found in OPUS for visit 1 falls (p = 0.025) and visit 1 multiple falls (p = 0.015). Bsm1 polymorphisms were also associated with balance and muscle power measurements.ConclusionsIn conclusion, these results demonstrate an association between the Bsm1 polymorphism and risk of falling that may explain some of the excess fracture risk associated with VDR in some studies.

Predicting OA progression to total hip replacement: can we do better than risk factors alone using active shape modelling as an imaging biomarker?

OBJECTIVE Previously, active shape modelling (ASM) of the proximal femur was shown to identify those individuals at highest risk of developing radiographic OA. Here we determine whether ASM predicts the need for total hip replacement (THR) independent of Kellgren-Lawrence grade (KLG) and other known risk factors. METHODS A retrospective cohort study of 141 subjects consulting primary care with new hip pain was conducted. Pelvic radiographs taken on recruitment were assessed for KLG, centre-edge angle, acetabular depth and femoral head migration. Clinical factors (duration of pain, use of a stick and physical function) were collected by self-completed questionnaires. ASM differences between shape mode scores at baseline for individuals who underwent THR during the 5-year follow-up (n = 27) and those whose OA did not progress radiographically (n = 75) were compared. RESULTS A 1 s.d. reduction in baseline ASM mode 2 score was associated with an 81% reduction in odds of THR (OR = 0.19, 95% CI 0.52, 0.70) after adjustment for KLG, radiographic and clinical factors. A similar reduction in odds of THR was associated with a 1 s.d. reduction in mode 3 (OR = 0.45, 95% CI 0.28, 0.71) and a 1 s.d. increase in mode 4 score (OR = 2.8, 95% CI 1.7, 4.7), although these associations were no longer significant after adjustment for KLG and clinical factors. CONCLUSION ASM of the hip joint is a reliable early biomarker of radiographic OA severity, which can improve the ability to identify patients at higher risk of rapid progression and poor outcome even when KLG and clinical risk factors are taken into account.

The Functional ACTN3 577X Variant Increases the Risk of Falling in Older Females: Results From Two Large Independent Cohort Studies

BACKGROUND Falls among elderly people is a major issue in public health, causing debilitating outcomes including fracture. The identification of genetic risk factors for falling may provide a strategy for effectively targeting falls prevention programs. We investigated whether a common functional variant of skeletal muscle α-actinin-3 (ACTN3 p. R577X) previously associated with impairments in muscle strength, power, and physical functioning represents a risk factor for falls. METHODS Case-control analysis was conducted using two large cohorts of Caucasian postmenopausal women--the North of Scotland Osteoporosis Study (n = 1,245) and the Aberdeen Prospective Osteoporosis Screening Study (n = 2,918)--for whom self-reported falls status and DNA samples were available. Cross-sectional analysis of fallers versus nonfallers at baseline and follow-up was performed. In addition, individuals who reported having fallen at more than one timepoint (recurrent fallers) were compared with those who reported not falling at any timepoint. RESULTS Association between R577X genotype and falls was identified and validated. Carriage of 577X (one or two copies) was significantly associated with a 33% (10%-61%) increased risk of falling, with the effect apparent at both baseline and follow-up assessments (meta-analysis p = .003 and p = .02, respectively). No significant effect on recurrent falls was observed. CONCLUSION This study reports for the first time that the functional ACTN3 R577X genotype represents a genetic risk factor for falling in older females.

Can we improve the prediction of hip fracture by assessing bone structure using shape and appearance modelling

PURPOSE There is a continuing need to improve the prediction of hip fractures to identify those at highest risk, enabling cost-effective use of preventative therapies. METHODS The aim of this work was to validate an innovative imaging biomarker for hip fracture by modelling the shape and texture of the proximal femur assessed from dual energy X-ray absorptiometry (DXA) scans. Scans used were acquired at baseline from elderly patients participating in a prospective, placebo-controlled fracture prevention study of the bisphosphonate, clodronate. 182 subjects who subsequently suffered a hip fracture were age, weight and height matched with two controls who did not suffer a fracture during a median 4-year follow-up period. Logistic regression was used to test if variables were good predictors of fracture and adjust for bone mineral density (BMD). RESULTS Shape mode 2, reflecting variability in neck-shaft angle, neck width and the size of both trochanters (0.81 (OR), 0.68-0.97 (CI), 0.024 (P)), and appearance mode 6, recording grey-level contrast (1.33, 1.11-1.59, 0.002), were significant predictors of hip fracture and remained so after adjustment for BMD (shape mode 2 (0.77, 0.64-0.93, 0.006), appearance mode 6 (1.32, 1.10-1.59, 0.003)). Receiver Operating Curve analysis showed the combination of shape mode 2, appearance mode 6 and BMD was 3% better than any single predictor. CONCLUSION Variables derived from shape and appearance models gave a prediction of fracture comparable to BMD and in combination with BMD gave an improvement in the prediction of hip fracture that could predict an additional 2000 hip fracture cases per year in the UK, potentially saving more than £20 million per year and 10,000 cases in the US.

Screening Elderly Women for Risk of Future Fractures—Participation Rates and Impact on Incidence of Falls and Fractures

We have assessed the acceptability of a method for screening for risk of future hip fracture in elderly women. After receipt of an initial response to a mailed risk-factor questionnaire sent out to 5,306 women, women were randomly assigned to active or control groups. The active group was invited to participate in a screening visit that comprised a life-style questionnaire and a quantitative ultrasound heel scan. General practitioners (GPs) of women who were found to be in the lowest quartile of broadband ultrasound attenuation and/or who had two or more risk factors for hip fracture were advised to prescribe a calcium and vitamin D supplement. A second mailed questionnaire was sent to both groups 1 to 3 years later. Compared with the control group, the active group had a 56% lower risk of fracture (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.24–0.81 adjusted age, weight, and treatment status). At follow-up, the proportion of fallers in the active group (25.3%) was lower than that in the control group (29.6%) (P = 0.064). The control group was found to have a higher rate of falls at follow-up than the active group (95% CI, 0.02–0.22); no difference was found at baseline (95% CI, −0.08 to +0.14). The screening method used was found to be acceptable to the majority of elderly women in this study. Screening the elderly in this way together with simple advice on treatment appears to reduce the age-associated increase in fall rates and the number of subsequent fractures. This form of screening may provide a cost-effective method to reduce falls and fractures in free-living elderly women. However, no such cost-effectiveness analysis has been performed to date.

Reproducibility and Diagnostic Accuracy of Kellgren-Lawrence Grading for Osteoarthritis Using Radiographs and Dual-Energy X-ray Absorptiometry Images

Advances in image quality from modern dual-energy X-ray absorptiometry (DXA) scanners now allow near radiograph-like quality images at a low radiation dose. This opens potential new applications for the use of DXA scanners to study other musculoskeletal conditions, such as osteoarthritis, which is often investigated by visual assessment of radiographs. Together, osteoporosis and osteoarthritis are the 2 most common musculoskeletal conditions, both of which primarily affect older people. The aim of this study was to determine whether Kellgren-Lawrence grading of DXA images can be used to grade hip osteoarthritis as effectively as radiographs. People who had attended for recent pelvic radiographs underwent DXA of hips (50 hips from 25 people) using a GE Healthcare iDXA scanner. Three observers assigned Kellgren-Lawrence grades to each image, and grading was repeated at least 1 week apart. Intraobserver and interobserver reliability for radiographs and DXA images were calculated using quadratic-weighted kappa (QWK). People were recalled 12 months later, and the tests were repeated with both the radiograph and DXA scans taken within 2 weeks of each other. Hip DXA intraobserver reproducibility achieved a QWK range of 0.88-0.95 and interobserver reproducibility of 0.85-0.88, similar to QWK from hip radiographs. Intraobserver reliability between subject-matched radiograph and iDXA images revealed QWK ranging between 0.80 and 0.88. Reproducibility of hip osteoarthritis grading using DXA was comparable with that of radiographs in this study and similar to repeatability scores previously published in literature. Given the lower radiation dose and the opportunity to simultaneously investigate osteoporosis, DXA presents an attractive imaging option for osteoarthritis.

Bone morphology of the femur and tibia captured by statistical shape modelling predicts rapid bone loss in acute spinal cord injury patients

After spinal cord injury (SCI), bone loss in the paralysed limbs progresses at variable rates. Decreases in bone mineral density (BMD) in the first year range from 1% (slow) to 40% (rapid). In chronic SCI, fragility fractures commonly occur around the knee, with significant associated morbidity. Osteoporosis treatments await full evaluation in SCI, but should be initiated early and targeted towards patients exhibiting rapid bone loss. The potential to predict rapid bone loss from a single bone scan within weeks of a SCI was investigated using statistical shape modelling (SSM) of bone morphology, hypothesis: baseline bone shape predicts bone loss at 12-months post-injury at fracture-prone sites. In this retrospective cohort study 25 SCI patients (median age, 33 years) were scanned at the distal femur and proximal tibia using peripheral Quantitative Computed Tomography at <5 weeks (baseline), 4, 8 and 12 months post-injury. An SSM was made for each bone. Links between the baseline shape-modes and 12-month total and trabecular BMD loss were analysed using multiple linear regression. One mode from each SSM significantly predicted bone loss (age-adjusted P<0.05 R(2)=0.37-0.61) at baseline. An elongated intercondylar femoral notch (femur mode 4, +1 SD from the mean) was associated with 8.2% additional loss of femoral trabecular BMD at 12-months. A more concave posterior tibial fossa (tibia mode 3, +1 SD) was associated with 9.4% additional 12-month tibial trabecular BMD loss. Baseline bone shape determined from a single bone scan is a valid imaging biomarker for the prediction of 12-month bone loss in SCI patients.

Statistical shape modelling of hip and lumbar spine morphology and their relationship in the MRC National Survey of Health and Development

The anatomical shape of bones and joints is important for their proper function but quantifying this, and detecting pathological variations, is difficult to do. Numerical descriptions would also enable correlations between joint shapes to be explored. Statistical shape modelling (SSM) is a method of image analysis employing pattern recognition statistics to describe and quantify such shapes from images; it uses principal components analysis to generate modes of variation describing each image in terms of a set of numerical scores after removing global size variation. We used SSM to quantify the shapes of the hip and the lumbar spine in dual‐energy x‐ray absorptiometry (DXA) images from 1511 individuals in the MRC National Survey of Health and Development at ages 60–64 years. We compared shapes of both joints in men and women and hypothesised that hip and spine shape would be strongly correlated. We also investigated associations with height, weight, body mass index (BMI) and local (hip or lumber spine) bone mineral density. In the hip, all except one of the first 10 modes differed between men and women. Men had a wider femoral neck, smaller neck‐shaft angle, increased presence of osteophytes and a loss of the femoral head/neck curvature compared with women. Women presented with a flattening of the femoral head and greater acetabular coverage of the femoral head. Greater weight was associated with a shorter, wider femoral neck and larger greater and lesser trochanters. Taller height was accompanied by a flattening of the curve between superior head and neck and a larger lesser trochanter. Four of the first eight modes describing lumbar spine shape differed between men and women. Women tended to have a more lordotic spine than men with relatively smaller but caudally increasing anterior‐posterior (a‐p) vertebral diameters. Men were more likely to have a straighter spine with larger vertebral a‐p diameters relative to vertebral height than women, increasing cranially. A weak correlation was found between body weight and a‐p vertebral diameter. No correlations were found between shape modes and height in men, whereas in women there was a weak positive correlation between height and evenness of spinal curvature. Linear relationships between hip and spine shapes were weak and inconsistent in both sexes, thereby offering little support for our hypothesis.

Investigation of the relationship between susceptibility loci for hip osteoarthritis and DXA-derived hip shape in a population based cohort of peri-menopausal women

To examine relationships between known osteoarthritis (OA) susceptibility loci and hip shape in a population‐based cohort of perimenopausal women in order to investigate whether hip shape contributes to OA development.