Obesity, bone density relative to body weight and prevalent vertebral fracture at age 62 years: the Newcastle thousand families study.

Obesity increases the likelihood of prevalent vertebral fracture (VF) in men and women at age 62 years. The higher absolute bone mineral density (BMD) observed in obese individuals is disproportionate to body weight, and this may partly explain the greater prevalence of VF in this group. INTRODUCTION: Obesity is a global epidemic, and there remains uncertainty over the effect of obesity on skeletal health, particularly in the context of osteoporosis. The aim of this study was to investigate associations of body mass index (BMI) and obesity with BMD and prevalent VF in men and women aged 62 years. METHODS: Three hundred and forty-two men and women aged 62.5 ± 0.5 years from the Newcastle Thousand Families Study birth cohort underwent DXA evaluations of femoral neck and lumbar spine BMD and of the lateral spine for vertebral fracture assessment. RESULTS: The likelihood of prevalent VF was significantly increased in men when compared to women (OR = 2.7, p < 0.001, 95% Cl 1.7-4.4). As BMI increased in women, so did the likelihood of prevalent any-grade VF (OR = 1.09, p = 0.006, 95% CI 1.02-1.17). Compared to normal weight women, obese women were more likely to have at least one VF (OR = 2.65, p = 0.025, CI 1.13-6.20) and at least one grade 1 vertebral deformity (OR = 4.39, p = 0.005, CI 1.57-12.28). Obese men were more likely to have a grade 2 and/or grade 3 VF compared to men of normal weight (OR = 3.36, p = 0.032, CI 1.11-10.16). In men and women, BMI was negatively associated with femoral neck BMD/weight (R = - 0.65, R = - 0.66, p < 0.001) and lumbar spine BMD/weight (R = - 0.66, R - 0.60, p < 0.001). CONCLUSIONS: Obesity appears to be a risk factor for prevalent VF, and although absolute BMD is higher in obese individuals, this does not appear commensurate to their increased body weight.

No effect of monthly supplementation with 12000 IU, 24000 IU or 48000 IU vitamin D3 for one year on muscle function: The vitamin D in older people study.

Vitamin D plays a role in muscle function through genomic and non-genomic processes. The objective of this RCT was to determine the effect of monthly supplemental vitamin D3 onmuscle function in 70+ years old adults. Participants (n = 379) were randomized to receive, 12,000 IU, 24,000 IU or 48,000 IU of vitamin D3 monthly for 12 months. Standardized Hand Grip Strength (GS) and Timed-Up and Go (TUG) were measured before and after vitamin D3 supplementation. Fasting total plasma 25 hydroxyvitamin D (25OHD) and Parathyroid Hormone (PTH) concentrations were measured by Liquid Chromatography Tandem Mass Spectrometry (LC-MSMS) and immunoassay, respectively. Baseline plasma 25OHD concentrations were 41.3 (SD 19.9), 39.5 (SD 20.6), 38.9 (SD 19.7) nmol/L; GS values were 28.5 (SD 13.4), 28.8 (SD 13.0) and 28.1 (SD 12.1) kg and TUG test values were 10.8 (SD 2.5), 11.6 (SD 2.9) and 11.9 (SD 3.6) s for the 12,000 IU, 24,000 IU and 48,000 IU dose groups, respectively. Baseline plasma 25OHD concentration < 25 nmol/L was associated with lower GS (P = 0.003). Post-interventional plasma 25OHD concentrations increased to 55.9 (SD 15.6), 64.6 (SD15.3) and 79.0 (SD 15.1) nmol/L in the 12,000 IU, 24,000 IU and 48,000 IU dose groups, respectively and there was a significant dose-related response in post-interventional plasma 25OHD concentration (p<0.0001). Post-interventional GS values were 24.1 (SD 10.1), 26.2 (SD10.6) and 25.7 (SD 9.4) kg and TUG test values were 11.5 (SD 2.6), 12.0 (SD 3.7) and 11.9 (SD 3.2) s for 12,000 IU, 24,000 IU and 48,000 IU dose groups, respectively. The change (Δ) in GS and TUG from pre to post-intervention was not different between treatment groups before and after the adjustment for confounders, suggesting no effect of the intervention. Plasma 25OHD concentration was not associated with GS and TUG test after supplementation. In conclusion, plasma 25OHD concentration < 25 nmol/L was associated with lower GS at baseline. However, monthly vitamin D3 supplementation with 12,000 IU, 24,000 IU and 48,000 IU, for 12 months had no effect on muscle function in older adults aged 70+ years. Trial Registration : EudraCT 2011-004890-10 and ISRCTN35648481.

Does regional loss of bone density explain low trauma distal forearm fractures in men (the Mr F study)?

The pathogenesis of low trauma wrist fractures in men is not fully understood. This study found that these men have lower bone mineral density at the forearm itself, as well as the hip and spine, and has shown that forearm bone mineral density is the best predictor of wrist fracture. INTRODUCTION: Men with distal forearm fractures have reduced bone density at the lumbar spine and hip sites, an increased risk of osteoporosis and a higher incidence of further fractures. The aim of this case-control study was to investigate whether or not there is a regional loss of bone mineral density (BMD) at the forearm between men with and without distal forearm fractures. METHODS: Sixty-one men with low trauma distal forearm fracture and 59 age-matched bone healthy control subjects were recruited. All subjects underwent a DXA scan of forearm, hip and spine, biochemical investigations, health questionnaires, SF-36v2 and Fracture Risk Assessment Tool (FRAX). The non-fractured arm was investigated in subjects with fracture and both forearms in control subjects. RESULTS: BMD was significantly lower at the ultradistal forearm in men with fracture compared to control subjects, in both the dominant (mean (SD) 0.386 g/cm2 (0.049) versus 0.436 g/cm2 (0.054), p < 0.001) and non-dominant arm (mean (SD) 0.387 g/cm2 (0.060) versus 0.432 g/cm2 (0.061), p = 0.001). Fracture subjects also had a significantly lower BMD at hip and spine sites compared with control subjects. Logistic regression analysis showed that the best predictor of forearm fracture was ultradistal forearm BMD (OR = 0.871 (0.805-0.943), p = 0.001), with the likelihood of fracture decreasing by 12.9% for every 0.01 g/cm2 increase in ultradistal forearm BMD. CONCLUSIONS: Men with low trauma distal forearm fracture have significantly lower regional BMD at the ultradistal forearm, which contributes to an increased forearm fracture risk. They also have generalised reduction in BMD, so that low trauma forearm fractures in men should be considered as indicator fractures for osteoporosis.

pophelper: an R package and web app to analyse and visualize population structure.

The pophelper r package and web app are software tools to aid in population structure analyses. They can be used for the analyses and visualization of output generated from population assignment programs such as admixture, structure and tess. Some of the functions include parsing output run files to tabulate data, estimating K using the Evanno method, generating files for clumpp and functionality to create barplots. These functions can be streamlined into standard r analysis workflows. The latest version of the package is available on github (https://github.com/royfrancis/pophelper). An interactive web version of the pophelper package is available which covers the same functionalities as the r package version with features such as interactive plots, cluster alignment during plotting, sorting individuals and ordering of population groups. The interactive version is available at http://pophelper.com/.

Serum 25-hydroxyvitamin D concentration and its determinants in the very old: the Newcastle 85+ Study.

SUMMARY: Data on vitamin D status in very old adults are lacking. The aim of this study was to assess 25-hydroxyvitamin D [25(OH)D] concentrations and its predictors in 775 adults aged 85 years old living in North-East England. Low 25(OH)D was alarmingly high during winter/spring months, but its biological significance is unknown. INTRODUCTION: Despite recent concerns about the high prevalence of vitamin D deficiency in much of the British adult and paediatric population, there is a dearth of data on vitamin D status and its predictors in very old adults. The objective of the present study was to describe vitamin D status and its associated factors in a broadly representative sample of very old men and women aged 85 years living in the North East of England (55° N). METHODS: Serum concentrations of 25-hydroxyvitamin D [25(OH)D] were analysed in 775 participants in the baseline phase of the Newcastle 85+ cohort study. Season of blood sampling, dietary, health, lifestyle and anthropometric data were collected and included as potential predictors of vitamin D status in ordinal regression models. RESULTS: Median serum 25(OH)D concentrations were 27, 45, 43 and 33 nmol/L during spring, summer, autumn and winter, respectively. The prevalence of vitamin D deficiency according to North American Institute of Medicine guidelines [serum 25(OH)D <30 nmol/L] varied significantly with season with the highest prevalence observed in spring (51%) and the lowest prevalence observed in autumn (23%; P < 0.001). Reported median (inter-quartile range) dietary intakes of vitamin D were very low at 2.9 (1.2-3.3) µg/day. In multivariate ordinal regression models, non-users of either prescribed or non-prescribed vitamin D preparations and winter and spring blood sampling were associated with lower 25(OH)D concentrations. Dietary vitamin D intake, disability score and disease count were not independently associated with vitamin D status in the cohort. CONCLUSION: There is an alarming high prevalence of vitamin D deficiency (<30 nmol/L) in 85-year-olds living in North East England at all times of the year but particularly during winter and spring. Use of vitamin D containing preparations (both supplements and medications) appeared to be the strongest predictor of 25(OH)D concentrations in these very old adults.

FRAX-based assessment and intervention thresholds--an exploration of thresholds in women aged 50 years and older in the UK.

UNLABELLED: Under current guidelines, based on prior fracture probability thresholds, inequalities in access to therapy arise especially at older ages (≥70 years) depending on the presence or absence of a prior fracture. An alternative threshold (a fixed threshold from the age of 70 years) reduces this disparity, increases treatment access and decreases the need for bone densitometry. INTRODUCTION: Several international guidelines set age-specific intervention thresholds at the 10-year probability of fracture equivalent to a woman of average BMI with a prior fracture. At older ages (≥70 years), women with prior fracture selected for treatment are at lower average absolute risk than those selected for treatment in the absence of prior fracture, prompting consideration of alternative thresholds in this age group. METHODS: Using a simulated population of 50,633 women aged 50-90 years in the UK, with a distribution of risk factors similar to that in the European FRAX derivation cohorts and a UK-matched age distribution, the current NOGG intervention and assessment thresholds were compared to one where the thresholds remained constant from 70 years upwards. RESULTS: Under current thresholds, 45.1% of women aged ≥70 years would be eligible for therapy, comprising 37.5% with prior fracture, 2.2% with high risk but no prior fracture and 5.4% selected for treatment after bone mineral density (BMD) measurement. Mean hip fracture probability was 11.3, 23.3 and 17.6%, respectively, in these groups. Under the alternative thresholds, the overall proportion of women treated increased from 45.1 to 52.9%, with 8.4% at high risk but no prior fracture and 7.0% selected for treatment after BMD measurement. In the latter group, the mean probability of hip fracture was identical to that observed in women with prior fracture (11.3%). The alternative threshold also reduced the need for BMD measurement, particularly at older ages (>80 years). CONCLUSIONS: The alternative thresholds equilibrate fracture risk, particularly hip fracture risk, in those with or without prior fracture selected for treatment and reduce BMD usage at older ages.

Magnitude of fragility fracture risk in the very old--are we meeting their needs? The Newcastle 85+ Study.

UNLABELLED: Fractures due to osteoporosis are common in older people. This study assessed the management of osteoporosis in a group of 85-year-olds and found both assessment and current treatment to be suboptimal. INTRODUCTION: Fragility fractures are a major cause of excess mortality, substantial morbidity, and health and social service expenditure in older people. However, much less is known about fracture risk and its management in the very old, despite this being the fastest growing age group of our population. METHODS: Cross-sectional analysis of people who reached the age of 85 during the year of 2006 was carried out. Data were gathered by general practice record review (GPRR) and a multidimensional health assessment (MDHA). RESULTS: Seven hundred thirty-nine individuals were recruited. Mean age was 85.55 years (SD 0.44), and 60.2% were female; 33.7% (n = 249) had experienced one or more fragility fractures (F 45.2% vs M 16.3% p < 0.001); in total, 332 fractures occurred in these 249 individuals. A formal documented diagnosis of osteoporosis occurred in 12.4%, and 38% of individuals had experienced a fall in the last 12 months. When the fracture risk assessment tool (FRAX) and National Osteoporosis Guideline Group (NOGG) guidelines were applied, osteoporosis treatment would be recommended in 35.0%, with a further 26.1% identified as needing bone mineral density (BMD) measurement and 38.9% not requiring treatment or BMD assessment. Women were more likely than men to need treatment (47.4 vs 16.3%, p < 0.001, odds ratio (OR) 4.62 (3.22-5.63)) and measurement of BMD (40.0 vs 5.1%, p < 0.001, OR 12.4 (7.13-21.6)). Of the 259 individuals identified as requiring treatment, only 74 (28.6%) were on adequate osteoporosis treatment. CONCLUSION: The prevalence of high fracture risk in the very old is much higher than the documented diagnosis of osteoporosis or the use of adequate treatments.

Efficacy and safety of strontium ranelate in the treatment of osteoporosis in men.

CONTEXT: Strontium ranelate reduces vertebral and nonvertebral fracture risk in postmenopausal osteoporosis. OBJECTIVE: The objective of this study was to determine the efficacy and safety of strontium ranelate in osteoporosis in men over 2 years (main analysis after 1 year). DESIGN: This was an international, unbalanced (2:1), double-blind, randomized placebo-controlled trial (MALEO [MALE Osteoporosis]). SETTING: This international study included 54 centers in 14 countries. PARTICIPANTS: PARTICIPANTS were 261 white men with primary osteoporosis. INTERVENTION: Strontium ranelate at 2 g/d (n = 174) or placebo (n = 87) was administered. MAIN OUTCOME MEASURES: Lumbar spine (L2-L4), femoral neck, and total hip bone mineral density (BMD), biochemical bone markers, and safety were measured. RESULTS: Baseline characteristics were similar in both groups in the whole population (age, 72.9 ± 6.0 years; lumbar spine BMD T-score, -2.7 ± 1.0; femoral neck BMD T-score, -2.3 ± 0.7). Men who received strontium ranelate over 2 years had greater increases in lumbar spine BMD than those who received placebo (relative change from baseline to end, 9.7% ± 7.5% vs 2.0% ± 5.5%; between-group difference estimate (SE), 7.7% (0.9%); 95% confidence interval, 5.9%-9.5%; P < .001). There were also significant between-group differences in relative changes in femoral neck BMD (P < .001) and total hip BMD (P < .001). At the end of treatment, mean levels of serum cross-linked telopeptides of type I collagen, a marker of bone resorption, were increased in both the strontium ranelate group (10.7% ± 58.0%; P = .022) and the placebo group (34.9% ± 65.8%; P < .001). The corresponding mean changes of bone alkaline phosphatase, a marker of bone formation, were 6.4% ± 28.5% (P = .005) and 1.9% ± 25.4% (P = .505), respectively. After 2 years, the blood strontium level (129 ± 66 µmol/L) was similar to that in trials of postmenopausal osteoporosis. Strontium ranelate was generally well tolerated. CONCLUSIONS: The effects of strontium ranelate on BMD in osteoporotic men were similar to those in postmenopausal osteoporotic women, supporting its use in the treatment of osteoporosis in men.

Femoral neck shaft angle in men with fragility fractures.

Introduction. Femoral neck shaft angle (NSA) has been reported to be an independent predictor of hip fracture risk in men. We aimed to assess the role of NSA in UK men. Methods. The NSA was measured manually from the DXA scan printout in men with hip (62, 31 femoral neck and 31 trochanteric), symptomatic vertebral (91), and distal forearm (67) fractures and 389 age-matched control subjects. Age, height, weight, and BMD (g/cm(2): lumbar spine, femoral neck, and total femur) measurements were performed. Results. There was no significant difference in mean NSA between men with femoral neck and trochanteric hip fractures, so all further analyses of hip fractures utilised the combined data. There was no difference in NSA between those with hip fractures and those without (either using the combined data or analysing trochanteric and femoral neck shaft fractures separately), nor between fracture subjects as a whole and controls. Mean NSA was smaller in those with vertebral fractures (129.2° versus 131°: P = 0.001), but larger in those with distal forearm fractures (129.8° versus 128.5°: P = 0.01). Conclusions. The conflicting results suggest that femoral NSA is not an important determinant of hip fracture risk in UK men.

Suppression of bone turnover by B-cell depletion in patients with rheumatoid arthritis.

UNLABELLED: The role of B cells in inflammatory bone formation and resorption is controversial. We investigated this in patients with rheumatoid arthritis (RA) treated with rituximab, a B-cell depleting antibody. We found a significant suppression in bone turnover, possibly a direct effect or as a consequence of a reduction in inflammation and disease activity. INTRODUCTION: RA is the most prevalent inflammatory joint disease, in which B cells play an important role. However, the role of B cells in bone turnover is controversial and RA subjects treated with rituximab, a B-cell depleting monoclonal antibody, provide an ideal model for determining the role of B cells in inflammatory bone resorption. METHODS: Serum from 46 RA patients, collected pre- and post-rituximab therapy, was analysed for biomarkers of bone turnover (procollagen type I amino-terminal propeptide [P1NP], osteocalcin, ß-isomerised carboxy-terminal telopeptide of type 1 collagen [ßCTX] and osteoprotegerin [OPG]). RESULTS: A significant decrease in bone resorption was observed 6 months after rituximab (median change ßCTX -50 ng/L, 95%CI -136, -8 p < 0.001, this equates to -37%; 95%CI -6, -49), mirrored by a reduction in disease activity. Similarly, there was a significant increase in P1NP, a marker of bone formation (median change P1NP 5.0 µg/L, 95%CI -1.0, 11.2, p = 0.02; 13%; 95%CI -3, 39), but no significant change in osteocalcin or OPG levels. The percentage change from baseline of ßCTX in a subgroup of patients (not on prednisolone or bisphosphonate) was significantly correlated with the percentage reduction in DAS28 score (r (s) = 0.570, p = 0.014). CONCLUSIONS: In conclusion, we have found that B-cell depletion increases bone formation and decreases bone resorption in RA patients; this may be a direct effect on osteoblasts and osteoclasts, respectively, and be at least partially explained by the decreased inflammation and disease activity.

National Osteoporosis Society's Position statement on hormone replacement therapy in the prevention and treatment of osteoporosis.

Hormone replacement therapy (HRT) has been shown to increase bone density, reduce the risk of fracture and can successfully relieve menopausal symptoms. From a time when HRT was the major therapeutic option for the management of osteoporosis, women and their clinicians now have a range of treatments available. Following the publication of the Women's Health Initiative (WHI) and the Million Women Study highlighting potential side-effects, such as breast cancer, heart disease and stroke, many doctors and women are now reluctant to use HRT. The National Osteoporosis Society felt that the role of HRT in the management of osteoporosis needed to be clarified. Using the Charity's expert clinical and scientific advisers, and through public consultation with members and key stakeholders, a Position Statement has been published. We conclude that HRT has a role to play in the management of osteoporosis in postmenopausal women below the age of 60 years. The key recommendations of the Position Statement are presented in this paper.

Plasma vitamin D and cytokines in periodontal disease and postmenopausal osteoporosis.

BACKGROUND AND OBJECTIVE: Osteoporosis and periodontal disease are chronic diseases, in the pathogenesis of which plasma osteoprotogerin (OPG) and RANKL are important. The study aimed to investigate the relationship between periodontal disease and plasma cytokines, vitamin D and bone mineral density in postmenopausal women with and without osteoporosis. MATERIAL AND METHODS: One hundred and eighty-five postmenopausal women with osteoporosis and 185 age- and sex-matched control subjects were recruited. Periodontal disease was subdivided into active or past periodontal disease. Osteoprotegerin, RANKL, 25-hydroxyvitamin D3 (25OHD), biochemical markers of bone turnover (serum C-terminal telopeptide, CTX), anthropometry and bone mineral density were measured. RESULTS: A significantly higher proportion of the women with osteoporosis had active or past periodontal disease or both compared with control subjects (87.6 vs. 37.8%, p < 0.001). Plasma 25OHD was significantly lower (p < 0.001) and RANKL and OPG significantly higher in the women with osteoporosis than in control subjects (p < 0.0001). RANKL, OPG and CTX were significantly higher in women with active periodontal disease than in those without (p < 0.001), as were OPG and CTX in past periodontal disease (p < 0.001). In active and past periodontal disease, 25OHD was significantly lower (p < 0.001). Multiple logistic regression analysis showed that periodontal disease was best predicted by RANKL, 25OHD, C-terminal telopeptide and weight, r² = 10.4%. CONCLUSION: Periodontal disease is more common in women with osteoporosis and is associated with lower vitamin D and higher concentrations of RANKL and OPG. Raised cytokines may provide the underlying mechanism that links these two conditions.

Proceedings of the Rank Forum on Vitamin D.

The Rank Forum on Vitamin D was held on 2nd and 3rd July 2009 at the University of Surrey, Guildford, UK. The workshop consisted of a series of scene-setting presentations to address the current issues and challenges concerning vitamin D and health, and included an open discussion focusing on the identification of the concentrations of serum 25-hydroxyvitamin D (25(OH)D) (a marker of vitamin D status) that may be regarded as optimal, and the implications this process may have in the setting of future dietary reference values for vitamin D in the UK. The Forum was in agreement with the fact that it is desirable for all of the population to have a serum 25(OH)D concentration above 25 nmol/l, but it discussed some uncertainty about the strength of evidence for the need to aim for substantially higher concentrations (25(OH)D concentrations>75 nmol/l). Any discussion of 'optimal' concentration of serum 25(OH)D needs to define 'optimal' with care since it is important to consider the normal distribution of requirements and the vitamin D needs for a wide range of outcomes. Current UK reference values concentrate on the requirements of particular subgroups of the population; this differs from the approaches used in other European countries where a wider range of age groups tend to be covered. With the re-emergence of rickets and the public health burden of low vitamin D status being already apparent, there is a need for urgent action from policy makers and risk managers. The Forum highlighted concerns regarding the failure of implementation of existing strategies in the UK for achieving current vitamin D recommendations.

A lifecourse study of bone resorption in men ages 49-51years: the Newcastle Thousand Families cohort study.

It has been suggested that bone health in adulthood is programmed by development in utero. Most previous investigations addressing this topic have focussed on bone mineral density or content, rather than other indicators of bone health, such as biochemical markers of bone turnover. This study investigated whether potential predictors, from different stages of life, influence bone resorption in men aged 49-51years in the Newcastle Thousand Families birth cohort. The cohort originally consisted of all 1142 births in the city of Newcastle upon Tyne, UK in May and June 1947. Detailed information was collected prospectively during childhood, including birth weight and socio-economic circumstances. At 49-51years of age, 574 study members completed a detailed 'Health and Lifestyle' questionnaire, including the European Prospective Investigation of Cancer (EPIC) food frequency questionnaire and 412 study members attended for clinical examination, including 172 men in whom bone resorption was assessed by measurement of serum beta C-telopeptide of type 1 collagen (CTX). A significant trend was seen between increasingly disadvantaged socio-economic status at birth and increased bone resorption (p=0.04, r-squared 2.6%). However, birth weight, standardised for sex and gestational age, was not associated with serum CTX (p=0.77, r-squared 0.05%). Significant trends were also seen between increasing total energy intake (p=0.03, r-squared 2.9%), dietary intake of saturated fat (p=0.02, r-squared 2.6%), protein (p=0.04, r-squared 2.5%) and carbohydrates (p=0.04, r-squared 2.6%) and higher serum CTX. However, on adjustment for total energy intake, none of the other dietary variables was significant at the univariate level maintained significance. Our findings suggest that early socio-economic disadvantage and later dietary factors may be associated with increased bone resorption in middle aged men. However, as little of the variance in serum CTX was explained by the variables included within this investigation, further longitudinal studies, with sufficient statistical power, are required to assess predictors of bone resorption in adulthood and their relative importance.