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Objective: To evaluate fractures and falls in epilepsy patients taking antiepileptic drugs (AED) and to assess their awareness of AED-related bone health, falls, and fracture risk., Methods: A cross-sectional study was conducted in epilepsy patients taking AEDs and in nonepileptic non-AED users. Information on falls and fracture history was collected., Results: A total of 150 AED users were compared with 506 non-AED users. Users had greater odds of fracture at spine (odds ratio [OR] 3.92; confidence interval [CI] 1.08-14.16; p = 0.037), clavicle (OR 3.75; CI 1.24-11.34; p = 0.019), and ankle sites (OR 2.34; CI 1.01-5.42; p = 0.048), increased odds for osteoporosis (OR 4.62; CI 1.40-15.30; p = 0.012), and fracture occasions (OR 2.64; CI 1.29-5.43; p = 0.008). We estimate that with every year of AED use the odds of fractures increase by 4%-6%, or 40% per decade for any fracture (OR 1.40; CI 1.02-1.91) and 60% for seizure-related fractures (OR 1.63; CI 1.10-2.37). Non-seizure-related fractures (69% of cumulative fractures) occurred more than seizure-related fractures during therapy. Female users, compared to female nonusers, had more non-seizure falls (31% vs 17%, p = 0.027) and multiple falls (18% vs 5%, p = 0.028) in the preceding year. Fewer than 30% of epilepsy patients knew of the association of AED use with increased risk for fractures, decreased bone mineral density, or falls., Conclusions: Epilepsy patients taking AEDs had a higher risk of fractures, which was highest in those with longer-term AED exposure. Female AED users had a higher prevalence of falls than matched nonusers. Awareness among epilepsy patients regarding risks of falling and fractures was low.

Significant relationships exist between areal bone mineral density (BMD) derived from dual energy X-ray absorptiometry (DXA) and bone strength. However, the predictive validity of BMD for osteoporotic vertebral fractures remains suboptimal. The diagnostic sensitivity of DXA in the lumbar spine may be improved by assessing BMD from lateral-projection scans, as these might better approximate the objective of measuring the trabecular-rich bone in the vertebral body, compared to the commonly-used posterior-anterior (PA) projections. Nowadays, X-ray micro-computed tomography (μCT) allows non-destructive three-dimensional structural characterization of entire bone segments at high resolution. In this study, human lumbar cadaver spines were examined ex situ by DXA in lateral and PA projections, as well as by μCT, with the aims (1) to investigate the ability of bone quantity measurements obtained by DXA in the lateral projection and in the PA projection, to predict variations in bone quantity measurements obtained by μCT, and (2) to assess their respective capabilities to predict whole vertebral body strength, determined experimentally. Human cadaver spines were scanned by DXA in PA projections and lateral projections. Bone mineral content (BMC) and BMD for L2 and L3 vertebrae were determined. The L2 and L3 vertebrae were then dissected and entirely scanned by μCT. Total bone volume (BV(tot)=cortical+trabecular), trabecular bone volume (BV), and trabecular bone volume fraction (BV/TV) were calculated over the entire vertebrae. The vertebral bodies were then mechanically tested to failure in compression, to determine ultimate load. The variables BV(tot), BV, and BV/TV measured by μCT were better predicted by BMC and BMD measured by lateral-projection DXA, with higher R(2) values and smaller standard errors of the estimate (R(2)=0.65-0.90, SEE=11%-18%), compared to PA-projection DXA (R(2)=0.33-0.53, SEE=22%-34%). The best predictors of ultimate load were BV(tot) and BV assessed by μCT (R(2)=0.88 and R(2)=0.81, respectively), and BMC and BMD from lateral-projection DXA (R(2)=0.82 and R(2)=0.70, respectively). Conversely, BMC and BMD from PA-projection DXA were lower predictors of ultimate load (R(2)=0.49 and R(2)=0.37, respectively). This ex vivo study highlights greater capabilities of lateral-projection DXA to predict variations in vertebral body bone quantity as measured by μCT, and to predict vertebral strength as assessed experimentally, compared to PA-projection DXA. This provides basis for further exploring the clinical application of lateral-projection DXA analysis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Chronic low back pain (CLBP) experienced in middle-age may have important implications for vertebral bone health, although this issue has not been investigated as a primary aim previously. This study investigated the associations between CLBP and dual energy X-ray absorptiometry (DXA)-derived vertebral bone mineral measures acquired from postero-anterior and lateral-projections, among community-dwelling, middle-aged adults., Methods: Twenty-nine adults with CLBP (11 male, 18 female) and 42 adults with no history of LBP in the preceding year (17 male, 25 female) were evaluated. Self-reported demographic and clinical data were collected via questionnaires. Areal bone mineral density (aBMD) was measured in the lumbar spine by DXA. Apparent volumetric (ap.v) BMD in the lumbar spine was also calculated. Multiple linear regression models were used to examine associations between study group (CLBP and control) and vertebral DXA variables by gender, adjusting for height, mass and age., Results: There was no difference between groups by gender in anthropometrics or clinical characteristics. In the CLBP group, the mean (SD) duration of CLBP was 13.3 (10.4) years in males and 11.6 (9.9) years in females, with Oswestry Disability Index scores of 16.2 (8.7)% and 15.4 (9.1)%, respectively. Males with CLBP had significantly lower adjusted lateral-projection aBMD and lateral-projection ap.vBMD than controls at L3 with mean differences (standard error) of 0.09 (0.04) g/cm2 (p = 0.03) and 0.02 (0.01) g/cm3 (p = 0.04). These multivariate models accounted for 55% and 53% of the variance in lateral-projection L3 aBMD and lateral-projection L3 ap.vBMD., Conclusions: CLBP in males is associated with some lumbar vertebral BMD measures, raising important questions about the mechanism and potential clinical impact of this association.

Although a strong relationship exists between areal bone mineral density (aBMD) derived from dual-energy X-ray absorptiometry (DXA) and bone strength, the predictive validity of aBMD for osteoporotic vertebral fractures remains suboptimal. The diagnostic sensitivity of DXA may be improved by assessing aBMD within vertebral subregions, rather than relying on an estimate derived from the total area of the vertebra. The objective of this study was to validate a method of measuring subregional vertebral aBMD in vitro using lateral-projection DXA against subregional volumetric BMD (vBMD) measured with peripheral quantitative computed tomography (pQCT). A mixed set of 49 lumbar and thoracic vertebrae from 25 donors were scanned using lateral-projection DXA and pQCT. aBMD and apparent vBMD were measured in 7 vertebral regions (1 total area and 6 subregions) from the lateral DXA scan. vBMD was calculated in anatomically equivalent regions from pQCT scan data, using a customised software program designed to increase efficiency of the analysis process. Significant differences in densitometric parameters between subregions were observed by DXA and pQCT (P < 0.01). Subregional vBMD derived from pQCT was explained by a significant proportion of the variance in DXA-derived aBMD (R (2) = 0.51-0.67, P < 0.05) and apparent vBMD (R (2) = 0.64-0.75, P < 0.05). These results confirm the validity of measuring aBMD in vertebral subregions using lateral-projection DXA. The clinical significance should now be explored.

Summary: Patients treated with intravenous zoledronic acid 5 mg for osteoporosis may experience post-dose influenza-like symptoms. Oral acetaminophen/paracetamol or ibuprofen administered 4 h post-infusion reduced the proportion of patients with increased oral temperature and worsening post-infusion symptom scores vs. placebo, thus providing an effective strategy for the treatment of such symptoms., Introduction: Once-yearly intravenous zoledronic acid 5 mg is a safe and effective treatment for postmenopausal osteoporosis. This study assessed whether transient influenza-like post-dose symptoms associated with intravenous infusion of zoledronic acid can be reduced by post-dose administration of acetaminophen/paracetamol or ibuprofen., Methods: In an international, multicenter, randomized, double-blind, double-dummy parallel-group study, bisphosphonate-naïve postmenopausal women with osteopenia (n = 481) were randomized to receive zoledronic acid 5 mg + acetaminophen/paracetamol (n = 135), ibuprofen (n = 137) or placebo (n = 137), or placebo + placebo (n = 72). Acetaminophen/paracetamol and ibuprofen were administered every 6 h for 3 days beginning 4 h post-infusion., Results: The proportion of patients with increased oral temperature (≥1°C above 37.5°C) and with worsening post-infusion symptom scores over 3 days was significantly lower in patients receiving ibuprofen (36.8% and 48.5%) or acetaminophen/paracetamol (37.3% and 46.3%) vs. those receiving placebo (63.5% and 75.9%, respectively; all p < 0.0001) compared with background rates of 11.1% and 16.7%, respectively, in the absence of any active treatment. Overall incidence of adverse events was comparable for patients receiving acetaminophen/paracetamol or ibuprofen., Conclusion: Oral acetaminophen/paracetamol or ibuprofen effectively managed the transient influenza-like symptoms associated with zoledronic acid 5 mg.

Background: Recruitment of young people for health research by traditional methods has become more expensive and challenging over recent decades. The Internet presents an opportunity for innovative recruitment modalities., Objective: To assess the feasibility of recruiting young females using targeted advertising on the social networking site Facebook., Methods: We placed an advertisement on Facebook from May to September 2010, inviting 16- to 25-year-old females from Victoria, Australia, to participate in a health study. Those who clicked on the advertisement were redirected to the study website and were able to express interest by submitting their contact details online. They were contacted by a researcher who assessed eligibility and invited them to complete a health-related survey, which they could do confidentially and securely either at the study site or remotely online., Results: A total of 551 females responded to the advertisement, of whom 426 agreed to participate, with 278 completing the survey (139 at the study site and 139 remotely). Respondents' age distribution was representative of the target population, while 18- to 25-year-olds were more likely to be enrolled in the study and complete the survey than 16- to 17-year-olds (prevalence ratio=1.37, 95% confidence interval 1.05-1.78, P=.02). The broad geographic distribution (major city, inner regional, and outer regional/remote) and socioeconomic profile of participants matched the target population. Predictors of participation were older age, higher education level, and higher body mass index. Average cost in advertising fees per compliant participant was US $20, making this highly cost effective., Conclusions: Results demonstrate the potential of using modern information and communication technologies to engage young women in health research and penetrate into nonurban communities. The success of this method has implications for future medical and population research in this and other demographics.

Purpose: This case-control pilot study examined whether vertebral bone mineral measures were associated with the presence of chronic low back pain (CLBP) and Modic changes (MCs), and to compare psychological wellbeing and inflammation among individuals with CLBP and MCs, compared to individuals with no history of low back pain and without MCs., Methods: Eleven individuals with MRI-defined MCs in the lumbar spine and CLBP (cases) and 10 individuals with no history of CLBP or MCs (controls) responded to standard questionnaires regarding pain characteristics and psychological health. Bone mineral density (BMD) was measured with postero-anterior and lateral-projection dual energy X-ray absorptiometry (DXA) to estimate areal BMD (aBMD) and apparent volumetric BMD (ap.vBMD). High sensitivity serum C-reactive protein (hsCRP) was measured as an index of inflammation., Results: While there was no difference between the groups in measures of depression, anxiety and stress, cases reported significantly greater pain catastrophizing attitudes (P < 0.01). hsCRP concentrations did not differ between groups (P = 0.54). Among the 7 cases where MCs were identified between L3-4, significantly higher mean aBMD was observed at the affected vertebral level, compared to the adjacent, unaffected, cephalad level (P = 0.01-0.04), but not when ap.vBMD was calculated (P = 0.36)., Conclusions: Vertebral BMD is not reduced among individuals with CLBP and MCs compared to a control group, although pain catastrophizing attitudes are increased among individuals with CLBP and MCs.

Measures of dietary patterns have been increasingly used to capture the complex nature of dietary intake. Few studies have investigated the impact of specific dietary patterns on bone health. Areal bone mineral density (BMD) at the lumbar spine and total hip and total body bone mineral content (BMC) were measured using DXA in Australian women aged 18-65 y (n = 527). Dietary patterns were assessed using a 4-d food diary and factor analysis. Scores were calculated based on the amount of each food consumed in the pattern and the weightings determined by factor analysis. Analysis was conducted using generalized estimating equation methods. Factor analysis revealed 5 dietary patterns. Pattern 1 (high consumption of refined cereals, soft drinks, fried potatoes, sausages and processed meat, vegetable oils, beer, and takeaway foods and low consumption of other vegetables, vegetable dishes, tea, coffee, fruit, wholegrain breads, and breakfast cereals) were significantly inversely associated with total body BMC (g) [β = -15.4 (95% CI -27.4, -3.3), adjusted for age, height, physical activity, smoking, education, energy, and calcium intake]. Pattern 4 (high consumption of legumes, seafood, seeds, nuts, wine, rice and rice dishes, other vegetables, and vegetable dishes and low consumption of bacon and ham) were directly associated with BMD at both sites and total body BMC in adjusted models [BMC (g): β = 15.2 (95% CI 2.84, 27.6), fully adjusted model]. The remaining dietary patterns were not consistently associated with BMD or BMC. This study identified specific dietary patterns associated with BMD and total body BMC among women and provides evidence that will contribute to potential food-based strategies for improving bone health.

Background: Bisphosphonates are common first line medications used for the management of benign bone disease. One of the most devastating complications associated with bisphosphonate use is osteonecrosis of the jaws which may be related to duration of exposure and hence cumulative dose, dental interventions, medical co-morbidities or in some circumstances with no identifiable aggravating factor. While jaw osteonecrosis is a devastating outcome which is currently difficult to manage, various forms of delayed dental healing may be a less dramatic and, therefore, poorly-recognised complications of bisphosphonate use for the treatment of osteoporosis. It is hypothesised that long-term (more than 1 year's duration) bisphosphonate use for the treatment of post-menopausal osteoporosis or other benign bone disease is associated with impaired dental healing., Methods/design: A case-control study has been chosen to test the hypothesis as the outcome event rate is likely to be very low. A total of 54 cases will be recruited into the study following review of all dental files from oral and maxillofacial surgeons and special needs dentists in Victoria where potential cases of delayed dental healing will be identified. Potential cases will be presented to an independent case adjudication panel to determine if they are definitive delayed dental healing cases. Two hundred and fifteen controls (1:4 cases:controls), matched for age and visit window period, will be selected from those who have attended local community based referring dental practices. The primary outcome will be the incidence of delayed dental healing that occurs either spontaneously or following dental treatment such as extractions, implant placement, or denture use., Discussion: This study is the largest case-controlled study assessing the link between bisphosphonate use and delayed dental healing in Australia. It will provide invaluable data on the potential link between bisphosphonate use and osteonecrosis of the jaws.

Low birth weight and poor childhood growth program a variety of adult diseases including bone disorders such as osteoporosis. We have previously reported that offspring born small, as a result of uteroplacental insufficiency, have shorter femurs, lower bone mineral content and a bone strength deficit as adults. The aim of this study was to determine the effects of calcium supplementation from adolescence on growth restricted male and female offspring which have a programmed bone deficit. Bilateral uterine vessel ligation (Restricted) or sham surgery (Control) was performed on gestational day 18 in WKY rats to induce uteroplacental insufficiency and growth restriction. At 2 months pups were allocated to one of four diet groups: diet 1-constant normal calcium diet, diet 2-variable normal calcium diet, diet 3-constant high calcium diet, diet 4-variable high calcium diet. Diet groups 1 and 3 were fed their respective diets constantly for the duration of the study. In groups 2 and 4, rats were fed one diet for 5 days, followed by a switch to a low calcium diet for the next 5 days. At 6 months Dual Energy Xray Absorptiometry (DXA) and Peripheral Quantitative Computed Tomography (pQCT) were performed on the right femur. Bone turnover markers were measured at 4 months. Male and female Restricted offspring were born 14% lighter compared to Controls (p<0.05). At 6 months both male and female Restricted offspring remained smaller and had shorter femurs compared to Controls (p<0.05). Restricted males and females had reduced trabecular and cortical content compared to Controls, regardless of diet (p<0.05). Trabecular bone density was lower in Restricted females only (p<0.05). A constant high calcium diet increased cortical BMD in Restricted male and both female groups (p<0.05). Measures of bone geometry indicated that Restricted offspring have narrower bones with preservation of absolute cortical thickness (p<0.05). Importantly, the stress strain index of bone bending strength was lower in male and female Restricted offspring, regardless of diet by up to 9.0% and 7.8%, respectively. DXA results were similar to pQCT results. Being born small, due to uteroplacental insufficiency, programs reduced adult femur length, dimensions and stress strain index. Supplementation with a high calcium diet from adolescence can increase adult cortical bone density in low birth weight males and females, and normal weight females. This increase in bone density was not sufficient to rescue the bone dimension and strength deficits which were programmed in utero, suggesting that the early life environment is critical for bone programming., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Aromatase inhibitors have been increasingly used in boys with growth retardation to prolong the duration of growth and increase final height. Multiple important roles of oestrogen in males point to potential adverse effects of this strategy. Although the deleterious effects of aromatase deficiency in early childhood and adulthood are well documented, there is limited information about the potential long-term adverse effects of peripubertal aromatase inhibition. To address this issue, we evaluated short-term and long-term effects of peripubertal aromatase inhibition in an animal model. Peripubertal male Wistar rats were treated with aromatase inhibitor letrozole or placebo and followed until adulthood. Letrozole treatment caused sustained reduction in bone strength and alteration in skeletal geometry, lowering of IGF1 levels, inhibition of growth resulting in significantly lower weight and length of treated animals and development of focal prostatic hyperplasia. Our observation of adverse long-term effects after peripubertal male rats were exposed to aromatase inhibitors highlights the need for further characterisation of long-term adverse effects of aromatase inhibitors in peripubertal boys before further widespread use is accepted. Furthermore, this suggests the need to develop more selective oestrogen inhibition strategies in order to inhibit oestrogen action on the growth plate, while beneficial effects in other tissues are preserved.

Purpose: Bone disease and fractures are common with chronic antiepileptic drug (AED) therapy, but the underlying mechanisms are poorly understood. This study aimed to characterize adverse bone effects of valproate and to identify mouse strains either resistant or sensitive to these effects., Methods: Seven mouse strains (n = 40/strain; 10/diet) were screened for the effect of chronic (8 weeks) valproate treatment (0, 2, 4, and 6 g/kg food) on total bone mineral content (BMC, by dual energy x-ray absorptiometry). In a confirmatory study the effect of valproate (0 or 4 g/kg food) over 16 weeks was assessed in five of the mouse strains (n = 60/strain; 30/diet) identified in the screening phase as either sensitive or resistant. Ex vivo volumetric bone measures and structural changes were assessed using peripheral quantitative computed tomography (pQCT) and histomorphometry., Results: Chronic valproate treatment reproducibly affected bone in C3H/HeJ mice, with a 9.1% (p < 0.01) reduction in total BMC and a 10.7% (p < 0.01) reduction in trabecular volumetric density, indicating a sensitive strain to AED-induced bone loss. Histomorphometry was consistent, revealing reductions in trabecular volume (19.6%, p < 0.05) and number (14.3%, p < 0.04), and a 19.9% (p < 0.05) increase in trabecular separation. In contrast the A/J mice were reproducibly resistant to the bone effects., Conclusion: Mouse strains sensitive and resistant to the adverse bone effects of chronic valproate treatment were identified. The strain-specific effects suggest a role of genetic factors in the pathogenesis of AED-induced bone disease. This novel model provides a new, powerful tool to investigate the pathophysiology and therapy of AED-associated bone disease.

In the clinical environment dual-energy X-ray absorptiometry (DXA) is the current tool of first choice for assessing and monitoring skeletal integrity. A major drawback of standard DXA is that the bone mineral density (BMD) data cannot be used with certainty to predict who will sustain a vertebral fracture. However, measurement of BMD within vertebral subregions, instead of relying on a gross estimate of vertebral BMD, may improve diagnostic sensitivity. The aim of this article was to describe a validation study for subregional BMD measurement using lateral-projection DXA and to present preliminary data. Concurrent validity of measuring subregional BMD with DXA was established against measures of volumetric subregional BMD from peripheral quantitative computed tomography (pQCT) and subregional bone volume fraction from microCT at the L2 vertebral body in 8 cadaver spine specimens. The novel approaches for measuring subregional parameters with each imaging modality are described. Significant differences in bone parameters between vertebral subregions were observed for each imaging modality (p<0.05). Correspondence ranged from R(2)=0.01-0.79 and R(2)=0.06-0.80 between "DXA vs. pQCT" and "DXA vs. micro-CT," respectively. For both imaging modalities, correspondence with DXA was high for centrally and anteriorly positioned subregions. These data provide a basis for larger studies to examine the biological significance of heterogeneity in vertebral BMD., (The International Society for Clinical Densitometry. All rights reserved.)

Purpose: Patients taking antiepileptic drugs (AEDs) have an increased incidence of fractures. This study investigated chronic AED use and physical contributors to falls risk using an AED-discordant, twin and sibling matched-pair approach, and assessed clinically relevant subgroups: AED polytherapy; longer-duration AED; and falls history., Methods: Twenty-nine same-sex (mean age 44.9 years, 59% female), ambulatory, community-dwelling twin and sibling pairs, discordant for AED exposure (and AED-indication), were recruited. Validated clinical and laboratory tests of strength, gait, and balance were performed. Relevant AED levels, and fasting serum samples for 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and immunoreactive parathyroid hormone (iPTH) levels were taken., Results: There were significant mean within-pair differences in tests of static and dynamic balance, with the AED user having poorer balance function than the AED nonuser. No difference was seen in lower limb strength or gait measures. Increased duration of AED therapy and AED polytherapy were independent predictors of increased sway. No significant within-pair differences were seen in fasting serum levels of 1,25(OH)(2)D, 25OHD and iPTH after Bonferroni correction., Discussion: Balance performance is impaired in AED users compared to their matched nonuser siblings. Pairs where the AED users took AED polytherapy, or had a longer duration of AED use, had more impaired balance performance. These balance deficits may contribute to the increased rate of fractures in this population.

The mechanisms of how tea and epigallocatechin-3-gallate (EGCG) lower body fat are not completely understood. This study investigated long-term administration of green tea (GT), black tea (BT), or isolated EGCG (1 mg/kg per day) on body composition, glucose tolerance, and gene expression related to energy metabolism and lipid homeostasis; it was hypothesized that all treatments would improve the indicators of metabolic syndrome. Rats were fed a 15% fat diet for 6 months from 4 weeks of age and were supplied GT, BT, EGCG, or water. GT and BT reduced body fat, whereas GT and EGCG increased lean mass. At 16 weeks GT, BT, and EGCG improved glucose tolerance. In the liver, GT and BT increased the expression of genes involved in fatty acid synthesis (SREBP-1c, FAS, MCD, ACC) and oxidation (PPAR-alpha, CPT-1, ACO); however, EGCG had no effect. In perirenal fat, genes that mediate adipocyte differentiation were suppressed by GT (Pref-1, C/EBP-beta, and PPAR-gamma) and BT (C/EBP-beta), while decreasing LPL, HSL, and UCP-2 expression; EGCG increased expression of UCP-2 and PPAR-gamma genes. Liver triacylglycerol content was unchanged. The results suggest that GT and BT suppressed adipocyte differentiation and fatty acid uptake into adipose tissue, while increasing fat synthesis and oxidation by the liver, without inducing hepatic fat accumulation. In contrast, EGCG increased markers of thermogenesis and differentiation in adipose tissue, while having no effect on liver or muscle tissues at this dose. These results show novel and separate mechanisms by which tea and EGCG may improve glucose tolerance and support a role for these compounds in obesity prevention.

Summary: Vertebral fractures are a major adverse consequence of osteoporosis. In a large placebo-controlled trial in postmenopausal women with osteoporosis, strontium ranelate reduced vertebral fracture risk by 33% over 4 years, confirming the role of strontium ranelate as an effective long-term treatment in osteoporosis., Introduction: Osteoporotic vertebral fractures are associated with increased mortality, morbidity, and loss of quality-of-life (QoL). Strontium ranelate (2 g/day) was shown to prevent bone loss, increase bone strength, and reduce vertebral and peripheral fractures. The preplanned aim of this study was to evaluate long-term efficacy and safety of strontium ranelate., Methods: A total of 1,649 postmenopausal osteoporotic women were randomized to strontium ranelate or placebo for 4 years, followed by a 1-year treatment-switch period for half of the patients. Primary efficacy criterion was incidence of patients with new vertebral fractures over 4 years. Lumbar bone mineral density (BMD) and QoL were also evaluated., Results: Over 4 years, risk of vertebral fracture was reduced by 33% with strontium ranelate (risk reduction = 0.67, p < 0.001). Among patients with two or more prevalent vertebral fractures, risk reduction was 36% (p < 0.001). QoL, assessed by the QUALIOST(R), was significantly better (p = 0.025), and patients without back pain were greater (p = 0.005) with strontium ranelate than placebo over 4 years. Lumbar BMD increased over 5 years in patients who continued with strontium ranelate, while it decreased in patients who switched to placebo. Emergent adverse events were similar between groups., Conclusion: In this 4- and 5-year study, strontium ranelate is an effective and safe treatment for long-term treatment of osteoporosis in postmenopausal women.

Background: Vertebroplasty has become a common treatment for painful osteoporotic vertebral fractures, but there is limited evidence to support its use., Methods: We performed a multicenter, randomized, double-blind, placebo-controlled trial in which participants with one or two painful osteoporotic vertebral fractures that were of less than 12 months' duration and unhealed, as confirmed by magnetic resonance imaging, were randomly assigned to undergo vertebroplasty or a sham procedure. Participants were stratified according to treatment center, sex, and duration of symptoms (< 6 weeks or > or = 6 weeks). Outcomes were assessed at 1 week and at 1, 3, and 6 months. The primary outcome was overall pain (on a scale of 0 to 10, with 10 being the maximum imaginable pain) at 3 months., Results: A total of 78 participants were enrolled, and 71 (35 of 38 in the vertebroplasty group and 36 of 40 in the placebo group) completed the 6-month follow-up (91%). Vertebroplasty did not result in a significant advantage in any measured outcome at any time point. There were significant reductions in overall pain in both study groups at each follow-up assessment. At 3 months, the mean (+/-SD) reductions in the score for pain in the vertebroplasty and control groups were 2.6+/-2.9 and 1.9+/-3.3, respectively (adjusted between-group difference, 0.6; 95% confidence interval, -0.7 to 1.8). Similar improvements were seen in both groups with respect to pain at night and at rest, physical functioning, quality of life, and perceived improvement. Seven incident vertebral fractures (three in the vertebroplasty group and four in the placebo group) occurred during the 6-month follow-up period., Conclusions: We found no beneficial effect of vertebroplasty as compared with a sham procedure in patients with painful osteoporotic vertebral fractures, at 1 week or at 1, 3, or 6 months after treatment. (Australian New Zealand Clinical Trials Registry number, ACTRN012605000079640.), (2009 Massachusetts Medical Society)

Low birth weight increases the risk of developing adult onset cardiovascular and metabolic diseases. Recently being born small has also been identified as a risk factor for adverse bone growth, development and adult fracture risk. Evidence also suggests that accelerated growth in offspring of normal birth weight, following periods of slowed growth, can also independently program adult diseases. The aim of this study was to determine the relative roles of prenatal and postnatal growth restriction on adult bone characteristics and strength. Bilateral uterine vessel ligation (Restricted) or sham surgery (Control) was performed on gestational day 18 in WKY rats to induce fetal growth restriction. Control, Reduced (reduced Control litter size to match Restricted) and Restricted pups were cross-fostered onto different Control (normal lactation) or Restricted (impaired lactation) mothers 1 day after birth. Femur length, dimensions, strength, mineral content and density were quantified using DXA and pQCT analysis. Markers of bone turnover were measured in offspring at 6 months. Restricted pups were born lighter than Controls with males, not females, remaining smaller than Control-on-Control at 6 months (P<0.05). Pups born of normal weight from a reduced litter suckling on a Restricted mother (Reduced-on-Restricted) grew slowly during lactation then quicker after weaning compared to Controls (P<0.05). Cortical bone mineral content, dimensions and strength were lower in Restricted-on-Restricted and Reduced-on-Restricted offspring compared to Controls with lower density in Reduced-on-Restricted females (P<0.05). The stress strain index of bone bending strength remained lower in the Restricted male offspring when body weight adjustments were made. Cross-fostering Restricted females, but not males, onto mothers with normal lactation (Restricted-on-Control) restored growth and bone parameters to Controls (P<0.05). Being born small, or postnatal growth restriction for normal birth weight offspring followed by accelerated growth, programs bone content and strength deficits. Deficits were corrected by improving postnatal nutrition for females born small, highlighting sex specific programming outcomes and impact of postnatal nutrition. These findings suggest a link between growth restriction and adult bone health with additional studies needed to further explore this link in humans.

Background/objectives: We tested the hypothesis that the relationship between maternal 25-hydroxyvitamin D (25-(OH)D) and offspring birth size differs according to offspring vitamin D receptor (VDR) genotype (Apa1, Bsm1, Fok1 or Taq1)., Subjects/methods: Mothers of 354 singleton babies had serum 25-(OH)D concentration measured at 28-30 weeks of gestation and consented to measurement of their babies soon after birth. DNA was extracted from the babies' Guthrie cards., Results: There was evidence of effect modification by infant FokI genotype. Babies of deficient mothers had lower birth weight with FF or Ff, but not ff genotype (P-value for interaction after adjustment for potential confounding factors=0.02), but thicker subscapular and suprailiac skinfolds with ff, but not FF or Ff genotype (P=0.008 and 0.02, respectively). Sample size was insufficient to investigate effect modification by the other VDR polymorphisms., Conclusions: These preliminary findings suggest that studies of maternal vitamin D status and birth size may need to take VDR genotype into account.

Bone health is generally not considered in patients who present with chronic back pain. Nonetheless, bone health and back pain share common genetic and environmental correlates suggesting a co-dependence. Evidence exists for a relationship between back pain and impaired bone health. Here we present the evidence, theoretic framework and clinical relevance. Bone health and back pain are important determinants of musculoskeletal health. Back pain experienced in youth is a risk factor for future back pain, while suboptimal bone health during development increases the risk of skeletal fragility in later life. Generally, bone health is not considered in patients with chronic back pain who do not demonstrate other well-recognised bone health risk factors or associated conditions. Nonetheless, evidence suggests that back pain and impaired bone health share common environmental and genetic correlates, indicating that bone health ought to be considered in the context of back pain in otherwise healthy individuals. This review describes the likely mechanisms explaining the relationship between back pain and impaired bone health, evidence concerning the relationship and suggestions for future research. A narrative literature search was conducted using CINAHL, Medline, PubMed and Web of Science electronic databases. A history of back pain is associated with decreased bone mineral density in adults, yet this tends to be site-specific. No studies were identified examining this association in youth, yet the negative effects of childhood skeletal trauma and obesity on bone and spinal health provide indirect evidence for an association. Further research is required to clarify the impact of back pain on bone health at different lifespan stages using prospective cohort designs.

Background: Vertebroplasty is a promising but as yet unproven treatment for painful osteoporotic vertebral fractures. It involves radiographic-guided injection of various types of bone cement directly into the vertebral fracture site. Uncontrolled studies and two controlled quasi-experimental before-after studies comparing volunteers who were offered treatment to those who refused it, have suggested an early benefit including rapid pain relief and improved function. Conversely, several uncontrolled studies and one of the controlled before-after studies have also suggested that vertebroplasty may increase the risk of subsequent vertebral fractures, particularly in vertebrae adjacent to treated levels or if cement leakage into the adjacent disc has occurred. As yet, there are no completed randomised controlled trials of vertebroplasty for osteoporotic vertebral fractures. The aims of this participant and outcome assessor-blinded randomised placebo-controlled trial are to i) determine the short-term efficacy and safety (3 months) of vertebroplasty for alleviating pain and improving function for painful osteoporotic vertebral fractures; and ii) determine its medium to longer-term efficacy and safety, particularly the risk of further fracture over 2 years., Design: A double-blind randomised controlled trial of 200 participants with one or two recent painful osteoporotic vertebral fractures. Participants will be stratified by duration of symptoms (< and >or= 6 weeks), gender and treating radiologist and randomly allocated to either the treatment or placebo. Outcomes will be assessed at baseline, 1 week, 1, 3, 6, 12 and 24 months. Outcome measures include overall, night and rest pain on 10 cm visual analogue scales, quality of life measured by the Assessment of Quality of Life, Osteoporosis Quality of Life and EQ-5D questionnaires; participant perceived recovery on a 7-point ordinal scale ranging from 'a great deal worse' to 'a great deal better'; disability measured by the Roland-Morris Disability Questionnaire; timed 'Up and Go' test; and adverse effects. The presence of new fractures will be assessed by radiographs of the thoracic and lumbar spine performed at 12 and 24 months., Discussion: The results of this trial will be of major international importance and findings will be immediately translatable into clinical practice.

Osteoporotic fractures, falls and obesity are major health problems in developed nations. Evidence suggests that there are antenatal factors predisposing to these conditions. Data are emerging from Australia and elsewhere to suggest that maternal vitamin D status in pregnancy affects intrauterine skeletal mineralisation and skeletal growth together with muscle development and adiposity. Given that low levels of vitamin D have been documented in many urbanised populations, including those in countries with abundant sunlight, an important issue for public health is whether maternal vitamin D insufficiency during pregnancy has adverse effects on offspring health. The developing fetus may be exposed to low levels of vitamin D during critical phases of development as a result of maternal hypovitaminosis D. We hypothesise that this may have adverse effects on offspring musculoskeletal health and other aspects of body composition. Further research focused on the implications of poor gestational vitamin D nutrition is warranted as these developmental effects are likely to have a sustained influence on health during childhood and in adult life. We suggest that there is a clear rationale for randomised clinical trials to assess the potential benefits and harmful effects of vitamin D supplementation during pregnancy.

An age-related decline in balance, gait and lower-extremity muscle strength measures may lead to increased risk of falls and fractures. Previous studies have reported a possible non-linear age-related decline in these measures, but the choice of methodological approach has limited its interpretation. Healthy community-dwelling women (n=212) 21-82 years of age were evaluated for strength [Nicholas MMT (manual muscle tester)], gait [CSA (clinical stride analyser)], activity [HAP (human activity profile)] and static and dynamic balance [CBS (Chattecx balance system), LBT (Lord's balance test) and the ST (step test)]. A GAM (generalized additive model) was developed for each outcome variable to estimate the functional relationship, with age as a continuous variable. Performance was maintained until 45-55 years of age, depending on the outcome measure. Thereafter a decline in performance was evident with increasing age in all measures. Overall, a significant non-linear relationship with age was demonstrated for lower-extremity strength measures (MMT), velocity and double support duration of gait (CSA) and some clinical and laboratory balance tests [ST, LBT (eyes open) and the CBS]. Linear relationships were demonstrated by the LBT with eyes closed and activity measures. Balance, lower-extremity muscle strength and gait may decline non-linearly with age. Our study suggests possible threshold effects between age and balance, muscle strength and gait measures in women. Further research into these threshold effects may have implications for the optimal timing of exercise and other interventions to reduce the risk of falls and fractures.

Consensus guidelines for the treatment of Paget's disease of bone have been published, but it is not known how closely these reflect clinical practice. We conducted a multi-centre, stratified, retrospective review of case notes of 531 subjects treated for Paget's disease of bone between 2000 and 2005 in 29 Australian centres. The subjects received 1072 courses of bisphosphonate treatment (pamidronate 363, alendronate 324, risedronate 208, tiludronate 103, zoledronic acid 69, and etidronate 5). The most recent treatment received was oral therapy in 57% of patients (alendronate 29%, risedronate 24%, and tiludronate 4%) and intravenous in 43% (pamidronate 33%, and zoledronic acid 10%). For oral bisphosphonates, the percentages of courses which were at the recommended dosage and duration were: alendronate 33%, risedronate 60% and tiludronate 29%. Pamidronate was administered in a wide range of dosing schedules, most commonly 60 mg every 3 months (18%), 6 months (17%) or annually (12%), whereas zoledronic acid was mainly given as a 4 mg infusion (98%) as a single dose (52%) or annually (19%). Most clinicians reported taking into account symptoms, plasma alkaline phosphatase activity and anatomical location of disease in determining the need for treatment. Patient preference, intolerance of oral therapy and compliance were ranked highest in determining the choice between oral and intravenous therapy. We conclude that oral and intravenous bisphosphonate dosing regimens are both commonly used to treat Paget's disease of bone in Australia. Only a minority of courses of oral bisphosphonate treatment are at the recommended dosage and duration, and there is a lack of consensus on regimens for intravenous treatment.

In addition to its role in the storage of fat, adipose tissue acts as an endocrine organ, and it contains a functional renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) plays a key role in the RAS by converting angiotensin I to the bioactive peptide angiotensin II (Ang II). In the present study, the effect of targeting the RAS in body energy homeostasis and glucose tolerance was determined in homozygous mice in which the gene for ACE had been deleted (ACE(-/-)) and compared with wild-type littermates. Compared with wild-type littermates, ACE(-/-) mice had lower body weight and a lower proportion of body fat, especially in the abdomen. ACE(-/-) mice had greater fed-state total energy expenditure (TEE) and resting energy expenditure (REE) than wild-type littermates. There were pronounced increases in gene expression of enzymes related to lipolysis and fatty acid oxidation (lipoprotein lipase, carnitine palmitoyl transferase, long-chain acetyl CoA dehydrogenase) in the liver of ACE(-/-) mice and also lower plasma leptin. In contrast, no differences were detected in daily food intake, activity, fed-state plasma lipids, or proportion of fat excreted in fecal matter. In conclusion, the reduction in ACE activity is associated with a decreased accumulation of body fat, especially in abdominal fat depots. The decreased body fat in ACE(-/-) mice is independent of food intake and appears to be due to a high energy expenditure related to increased metabolism of fatty acids in the liver, with the additional effect of increased glucose tolerance.

Objectives: To compare alendronate 70 mg once weekly (OW) with risedronate 35 mg OW with respect to change in bone mineral density (BMD), biochemical markers and upper gastrointestinal (UGI) tolerability over 24 months., Methods: This was a 12-month extension to the Fosamax Actonel Comparison Trial international study (FACTS). Postmenopausal women with osteoporosis randomly assigned to either alendronate 70 mg OW or risedronate 35 mg OW for the 12-month base study continued taking the same double-blind study medication. Efficacy measurements were BMD at the hip trochanter, lumbar spine, total hip, and femoral neck and levels of four bone turnover markers at 24 months. The primary hypothesis was that alendronate would produce a greater mean per cent increase from baseline in hip trochanter BMD at 24 months., Results: Trochanter BMD increased significantly from baseline to month 24 in both groups, with a significantly larger increase with alendronate: adjusted mean treatment difference of 1.50% (95% confidence interval: 0.74%, 2.26%; p < 0.001). Similar results were seen at all BMD sites. Significant geometric mean per cent decreases (p < 0.001) from baseline were seen for all four bone turnover markers in both groups, with significantly larger decreases (p < 0.001) with alendronate: adjusted mean treatment differences ranged from 8.9% to 25.3%. No significant differences were seen in incidence of UGI or other adverse events., Conclusions: Alendronate 70 mg OW yielded significantly greater BMD gains and larger decreases in bone turnover marker levels than risedronate 35 mg OW over 24 months, with no difference in UGI tolerability.

In vitro studies have demonstrated that angiotensin II (ANG II) induces adipocyte hyperplasia and hypertrophy. The aim of the present study was to determine the effect of angiotensin-converting enzyme inhibition on body weight, adiposity and blood pressure in Sprague-Dawley rats. From birth half of the animals (n=15) were given water to drink, while the remainder were administered perindopril in their drinking water (2 mg/kg/day). Food intake, water intake and body weight were measured weekly. Blood pressure was measured by tail cuff plethysmography at 11-weeks. Body fat content and distribution were assessed using dual energy X-ray absorptiometry and Magnetic Resonance Imaging at 12 weeks. Animals administered with perindopril had a body fat proportion that was half that of controls. This was consistent with, but disproportionately greater than the observed differences in food intake and body weight. Perindopril treatment completely removed hypertension. We conclude that the chronic inhibition of ANG II synthesis from birth specifically reduces the development of adiposity in the rat.

Objective: The aim of this study was to determine whether a 3-year treatment with strontium ranelate could delay the progression of spinal osteoarthritis (OA)., Methods: This study was a post-hoc analysis of pooled data from the Spinal Osteoporosis Therapeutic Intervention (SOTI) and TReatment Of Peripheral OSteoporosis (TROPOS) trials performed on 1105 women with osteoporosis and concomitant radiological spinal OA at baseline, and for whom lumbar x-rays were available at baseline and over the 3-year treatment period. The presence and severity of osteophytes, disc space narrowing and sclerosis in the lumbar intervertebral spaces was graded according to a validated method, and an overall OA score was calculated for each intervertebral space. Back pain (measured on a five-point Likert scale only in SOTI) and health-related quality of life (SF-36 questionnaire) were assessed at baseline and after 3 years. Patients who suffered an incident or progressive vertebral fracture during the study were excluded from the analysis., Results: The proportion of patients with worsening overall spinal OA score was reduced by 42% in the strontium ranelate group, compared with placebo (RR, 0.58; 95% CI, 0.42 to 0.79; p = 0.0005). Significantly more patients in the strontium ranelate group experienced an improvement in back pain after 3 years, compared with placebo (p = 0.03), while no significant difference was observed in terms of health-related quality of life between these patient groups., Conclusions: The results of this post-hoc analysis suggest that strontium ranelate could reduce the progression of the radiographic features of spinal OA and back pain in women with osteoporosis and prevalent spinal OA.

To establish the effect of dietary omega-3 PUFA on angiotensin II (ANG II)-mediated hypertension, male TGR (mRen-2)27 (Ren-2) rats (animals with high ANG II activity) were maintained on a diet either deficient or sufficient in omega-3 PUFA from conception. Half the animals on each diet were treated with the angiotensin-converting enzyme inhibitor, perindopril, from birth. Ren-2 rats fed the omega-3 PUFA deficient diet were significantly more hypertensive than those fed the omega-3 PUFA sufficient diet. Perindopril reduced the blood pressure of both omega-3 PUFA-deficient and omega-3 PUFA-sufficient diet-fed Ren-2 rats. Body weight, body fat and plasma leptin were reduced by perindopril treatment but not affected by omega-3 PUFA supply. Given that the elevated blood pressure of the Ren-2 rat is mediated by ANG II, the data suggest that omega-3 PUFA may reduce hypertension via the renin-angiotensin system.

The way human adults grasp objects is typically influenced by their knowledge of what they intend to do with the objects. This influence is reflected in the end-state comfort effect: Actors adopt initially uncomfortable postures to accommodate later task demands. Although many experiments have demonstrated this effect, to the best of our knowledge its phylogenetic roots have not been investigated. In two experiments, we tested whether 9 cotton-top tamarin monkeys would show the end-state comfort effect. We did so by presenting the monkeys with a small cup containing a marshmallow. The cup was suspended in different orientations. The monkeys inhibited their natural grasping tendencies and adopted unusual grasping postures to accommodate subsequent task requirements, thus demonstrating the end-state comfort effect. This outcome provides evidence for more sophisticated motor planning than has previously been ascribed to this and related species.

Unlabelled: This longitudinal twin study was designed to assess the heritability of bone loss in peri- and postmenopausal women. A sample of 724 female twins was studied. Baseline and repeat BMD measurements were performed. Results of genetic model-fitting analysis indicated genetic effects on bone loss account for approximately 40% of the between-individual variation in bone loss at the lumbar spine, forearm, and whole body., Introduction: BMD and bone loss are important predictors of fracture risk. Although the heritability of peak BMD is well documented, it is not clear whether bone loss is also under genetic regulation. This study was designed to assess the heritability of bone loss in peri- and postmenopausal women., Materials and Methods: A sample of 724 female twins (177 monozygotic [MZ] and 185 dizygotic [DZ] pairs), 45-82 yr of age, was studied. Each individual had baseline BMD measurements at the lumbar spine, hip, forearm, and total body by DXA and at least one repeat measure, on average 4.9 yr later. Change in BMD (DeltaBMD) was expressed as percent of gain or loss per year. Intraclass correlation coefficients for DeltaBMD were calculated for MZ and DZ pairs. Genetic model-fitting analysis was conducted to partition the total variance of DeltaBMD into three components: genetic (G), common environment (C), and specific environment, including measurement error (E). The index of heritability was estimated as the ratio of genetic variance over total variance., Results: The mean annual DeltaBMD was -0.37 +/- 1.43% (SD) per year at the lumbar spine, -0.27 +/- 1.32% at the total hip, -0.77 +/- 1.66% at the total forearm, -0.36 +/- 1.56% at the femoral neck, and -0.16 +/- 0.81% at the whole body. Intraclass correlation coefficients were significantly higher in MZ than in DZ twins for all studied parameters, except at the hip sites. Results of genetic model-fitting analysis indicated that the indices of heritability for DeltaBMD were 0.38, 0.49, and 0.44 for the lumbar spine, total forearm, and whole body, respectively. However, the genetic effect on DeltaBMD at all hip sites was not significant., Conclusions: These data suggest that, although genetic effects on bone loss with aging are less pronounced than on peak bone mass, they still account for approximately 40% of the between-individual variation in bone loss for the lumbar spine, total forearm, and whole body in peri- and postmenopausal women. These findings are relevant for studies aimed at identification of genes that are involved in the regulation of bone loss.

Osteoporotic fractures are a major public health problem in most developed countries and an increasing concern in much of the developing world. This healthcare burden will increase significantly worldwide over the next 20 years due to aging of the population. Smoking is a key lifestyle risk factor for bone loss and fractures that appears to be independent of other risk factors for fracture such as age, weight, sex and menopausal status. This review discusses the effects of smoking on bone health in pre-menopausal and post-menopausal women and men. Data from twin studies and the three main published meta-analyses are presented. Possible mechanisms by which smoking affects bone mass are reviewed. Despite smoking being a major lifestyle risk factor for osteoporosis, the mechanisms underlying smoking-associated bone loss and fracture risk remain poorly understood. The effect appears dose-dependent, and may be, at least partially, reversible. However, more work is required to confirm and characterize the reversibility of smoking-associated bone defects. Finally, strategies for quitting smoking are discussed. Encouragement of lifestyle alterations, including smoking cessation, should be a major component of any bone therapeutic programme.

Once an initial vertebral fracture is sustained, the risk of subsequent vertebral fracture increases significantly. This phenomenon has been termed the "vertebral fracture cascade". Mechanisms underlying this fracture cascade are inadequately understood, creating uncertainty in the clinical environment regarding prevention of further fractures. The cascade cannot be explained by low bone mass alone, suggesting that factors independent of this parameter contribute to its aetiopathogenesis. This review explores physiologic properties that may help to explain the vertebral fracture cascade. Differences in bone properties, including bone mineral density and bone quality, between individuals with and those without osteoporotic vertebral fractures are discussed. Evidence suggests that non-bone parameters differ between individuals with and those without osteoporotic vertebral fractures. Spinal properties, including vertebral macroarchitecture, intervertebral disc integrity, spinal curvature and spinal loading are compared in these groups of individuals. Cross-sectional studies also indicate that neurophysiologic properties, particularly trunk control and balance, are affected by the presence of a vertebral fracture. This review provides a synthesis of the literature to highlight the multi-factorial aetiopathogenesis of the vertebral fracture cascade. With a more comprehensive understanding of the mechanisms underlying this clinical problem, more effective preventative strategies may be developed to offset the fracture cascade.

Introduction: Balance impairments have been identified in people with osteoporosis. Although an association between thoracic kyphosis and impaired balance has been reported, the specific role of vertebral fractures has not been considered. This study aimed to investigate the independent effects of osteoporotic vertebral fracture and thoracic kyphosis on balance characteristics in an osteoporotic population., Methods: Twenty-two individuals with osteoporosis were divided into groups with (n=10) and without (n=12) radiologically diagnosed fracture, and into groups with low (n=11) and high (n=11) thoracic kyphosis. Force-plate-derived balance parameters were recorded during three static standing tasks of 70-s duration. Balance measures were compared between fracture and kyphosis groups, and significant differences were further explored through subgroup analyses, to tease out the relationships between confounded independent variables (fracture and kyphosis) and balance measures., Results: In the anterior-posterior direction, the range and root mean square of shear forces (p=0.048 and p=0.032, respectively), and range of displacement of the centre of pressure (p=0.049) were greater in the fracture group. There were no differences between groups when comparison was based on the magnitude of thoracic kyphosis (all p>or=0.264). Analyses of subgroups supported these findings., Discussion: Vertebral fracture but not thoracic kyphosis is associated with impaired balance characteristics in the osteoporosis population. This finding has important implications for fracture prevention and conservative management regimes.

Background: Epilepsy is a common chronic neurological disorder, usually requiring long-term treatment with anti-epileptic drugs (AED). Many studies have reported that AED therapy is associated with metabolic bone disease and is a major iatrogenic risk factor for fractures. There remains uncertainty about the type(s) of bone disease due to AED treatment, and the pathogenesis of AED-associated fractures., Rationale: Deficits in bone mineral density (BMD) are widely reported in AED-treated patient populations. However, much of the research conducted to date has been limited by factors such as small sample size, potentially biased subject selection, a lack of selection of appropriate control data, and failure to take account of important confounding influences. The pathogenesis of AED-associated fractures is likely to be multifactorial, due to factors including reduced BMD, impaired bone quality (due to osteoporosis and/or osteomalacia), increased propensity to fall, and fractures associated with seizures or loss of consciousness., Recommendations: Patients receiving long-term AED should be monitored for indices of bone health, including BMD and vitamin D status. Lifestyle factors should be optimized, vitamin D status maintained, and fall prevention strategies introduced as appropriate. Good seizure control is important. The use of additional, specific osteoporosis therapy is not evidence-based in this setting, but would appear reasonable in patients with clinically significant decreases in BMD, applying current treatment guidelines for osteoporosis., Conclusion: There is a pressing need for improved understanding of the pathogenesis of AED-associated bone disease, for better definition of the risk associated with specific AED regimens, and for the development of evidence-based preventive and treatment approaches in this common but neglected disorder.

Purpose: Validation of dual-energy X-ray absorptiometry (DXA) with the Hologic QDR 4500A (QDR 4500) Fan Beam X-ray densitometer for in vivo assessment of body fat content in mice., Methods: Precision of DXA fat measurement was assessed by repeated in vivo scanning and re-positioning of different sized mice (17.6, 24.6, 34.2 g). DXA fat and total mass measurements were correlated with dissected tissue weights in 240 female adult mice of seven strains (mean weights 21.9-26.8 g). Accuracy of DXA fat tissue measurements was assessed by chemical analysis in a subgroup of 40 female decapitated mice (mean weights 19.6-28.4 g)., Results: Precision of the DXA measurements for fat mass was dependent on body weight (mean coefficient of variation, CV, 34.2 g mouse: 7.53 ± 0.13%; 24.6 g mouse: 32.16 ± 0.17%; 17.6 g mouse: 40.64 ± 0.06%). A moderate to high correlation with the dissected fat tissue weights was found for all seven strains: r = 0.52, p ≤ 0.01 (AJ) to r = 0.83, p ≤ 0.01 (CBA, both mean weight = 22 g). The correlation of DXA measurements with the chemical analysis of the carcass was good to excellent (r = 0.80, p ≤ 0.01)., Conclusion: The results demonstrate that the QDR 4500A DXA can be utilised for in vivo measurements of fat content in mice weighing as little as 20 g, with excellent correlations between tissue dissections and chemical analysis demonstrating high consistency of the measurements. DXA values were consistently slightly lower than those by direct chemical analysis; however, the limits of agreement (mean difference 0.96 g) demonstrated good concordance between the two methods., (© 2007 Asian Oceanian Association for the Study of Obesity . Published by Elsevier Ltd. All rights reserved.)

Background: The effects of systematic sports training during childhood and adolescence on subsequent growth and sexual maturation remains in dispute., Aim: The study aimed to determine whether moderate-high volumes of dance training adversely influence linear growth and sexual maturation of young girls progressing through puberty., Subjects and Methods: This 3-year mixed longitudinal study comprised 82 novice dancers and 61 controls, aged 8-11 years at baseline, who were assessed bi-annually for 3 consecutive years. A biological maturational age was determined by estimating attainment of age at peak height velocity (PHV). Body dimensions were measured by anthropometry, and exercise levels, nutritional intake and age at menarche by questionnaires., Results: Controls had significantly greater unadjusted height velocity than dancers 1 year before PHV, however there was no difference between groups in age of attainment of PHV. When controlling for maturation, lean mass, fat mass and extracurricular sport (excluding dancing), there were no group differences in absolute growth or velocity of growth in height, sitting height or leg length. Within the dancers there were no effects of years of dancing (>6.5 years) or weekly dance hours (>7 h per week) on growth velocities. No association was found between age at menarche and years or hours of dance training., Conclusion: Results suggest that moderate-high levels of dance training do not affect linear growth and maturation. Thus, girls should not be discouraged from dance participation on the basis of potential growth delays.

Context: There is inconsistent evidence that maternal 25-hydroxyvitamin D [25-(OH)D] deficiency may impair fetal growth., Objective: The objective of the study was to examine the relationship between maternal 25-(OH)D and PTH concentrations at less than 16 and 28 wk gestation and offspring birth size., Design: This was an observational study., Setting: The study was set at a hospital antenatal clinic., Participants: Women with singleton pregnancies, before 16 wk gestation, participated., Interventions: No interventions were used., Main Outcome Measure: Knee-heel length at birth was the main outcome measure., Results: Altogether 374 of 475 (79%) women completed this study. We found no evident relationship between birth size measures and maternal 25-(OH)D or PTH at recruitment (approximately 11 wk). Gestation length was 0.7 wk (95% confidence interval -1.3, -0.1) shorter and knee-heel length was 4.3 mm smaller (-7.3, -1.3) in infants of 27 mothers with low 25-(OH)D (<28 nmol/liter) at 28-32 wk vs. babies whose mothers had higher concentrations. This latter difference was reduced to -2.7 mm (-5.4, -0.1) after adjustment for gestation length, suggesting some of the apparent growth deficit is explained by shorter gestation. There was no evidence that other birth measures were affected. Maternal PTH concentration at 28-32 wk was positively related to knee-heel length, birth weight, and mid-upper arm and calf circumferences. These associations were independent of 25-(OH)D concentration., Conclusions: Low maternal 25-(OH)D in late pregnancy is associated with reduced intrauterine long bone growth and slightly shorter gestation. The long-term consequences for linear growth and health require follow-up. The positive relationship between maternal PTH and measures of infant size may relate to increased mineral demands by larger babies, but warrants further investigation.

Background: The objective of the study was to evaluate the effects of alendronic acid once weekly relative to risedronic acid once weekly on bone mineral density (BMD), markers of bone turnover and tolerability in the treatment of osteoporosis in postmenopausal women., Methods: This was a randomised, double-masked, double-dummy multicentre international study (75 centres in 27 countries in Europe, the Americas and Asia-Pacific). A total of 1303 women were screened and 936 with low bone density (T-score < or = -2.0 at the spine, hip trochanter, total hip or femoral neck) were randomised; 91% (n = 854) completed the study. Patients were randomised to treatment with either active alendronic acid 70 mg weekly (Fosamax) and placebo identical to risedronic acid weekly or active risedronic acid 35 mg weekly (Actonel) and placebo identical to alendronic acid weekly for 12 months. The primary efficacy endpoint was the percentage change from baseline in hip trochanter BMD at 12 months. Secondary endpoints included the percentage change from baseline in lumbar spine, total hip and femoral neck BMD; biochemical markers of bone turnover (including serum bone-specific alkaline phosphatase [BSAP] and urinary type I collagen N-telopeptides [NTx]); and safety and tolerability as assessed by reporting of adverse experiences., Results: Alendronic acid produced greater increases in BMD than did risedronic acid at 12 months at all sites measured. Mean percentage increases from baseline in hip trochanter BMD at month 12 were 3.56% and 2.71% in the alendronic acid and risedronic acid groups, respectively (treatment difference [95% CI]: 0.83% [0.22, 1.45; p = 0.008]). Mean percentage increases from baseline were greater with alendronic acid than risedronic acid at the lumbar spine, total hip and femoral neck BMD at month 12 (p = 0.002, p < 0.001, p = 0.039, respectively). Increases in BMD with alendronic acid compared with risedronic acid were also significantly greater at 6 months at the trochanter and total hip. There was a greater reduction in bone turnover with alendronic acid compared with risedronic acid: NTx decreased 58% with alendronic acid compared with 47% with risedronic acid at 12 months (p < 0.001); and BSAP decreased 45% with alendronic acid compared with 34% with risedronic acid at 12 months (p < 0.001). Overall tolerability and upper gastrointestinal tolerability were similar for both agents., Conclusions: Alendronic acid once weekly produced greater BMD increases at both hip and spine sites and greater reductions in bone turnover relative to risedronic acid once weekly. Both agents were well tolerated with no significant difference in upper gastrointestinal adverse experiences. Clinicians should consider these results when making treatment decisions for postmenopausal women with osteoporosis.

Introduction: Weight-bearing exercise during growth enhances peak bone mass. However, the window of opportunity for optimizing positive effects of exercise on peak bone mass remains to be fully defined. Ballet dancing provides a model of mechanical loading patterns required to site-specifically modulate bone., Methods: We assessed the effects of ballet dancing on bone mineral accrual in female non-elite dancers and normally active controls for 3 years across puberty. We recruited 82 ballet dancers and 61 controls age 8-11 years at baseline. Participants were measured over 3 consecutive years; however, the overlap in ages allowed analysis of the groups across 8-14 years of age. We annually assessed bone mineral content (BMC) at the total body (TB), including upper and lower limb regions, and biannually assessed BMC at the proximal femur and lumbar spine (LS) using dual x-ray absorptiometry (DXA). We derived TB lean mass and fat mass from DXA TB scans. Anthropometry, exercise levels, and calcium intake were also measured biannually. Maturational age was determined by age at peak height velocity (PHV). A multilevel regression model was used to determine the independent effects of body size, body composition, maturation, exercise levels, and calcium intake at each measurement occasion., Results: When adjusted for growth and maturation, dancers had significantly greater BMC at the TB, lower limbs, femoral neck (FN), and LS than controls. Excepting the FN region, these differences became apparent at 1 year post-PHV, or the peripubertal years, and by 2 years post-PHV the differences represented a cumulative advantage in dancers of 0.6-1.3% (p<0.05) greater BMC than controls. At the FN, dancers had 4% (p<0.05) greater BMC than controls in prepuberty and maintained this advantage throughout the pubertal years., Conclusions: Results from this novel population provide evidence for modest site-specific and maturity-specific effects of mechanical loading on bone.

Objectives: To determine whether vitamin D supplementation can reduce the incidence of falls and fractures in older people in residential care who are not classically vitamin D deficient., Design: Randomized, placebo-controlled double-blind, trial of 2 years' duration., Setting: Multicenter study in 60 hostels (assisted living facilities) and 89 nursing homes across Australia., Participants: Six hundred twenty-five residents (mean age 83.4) with serum 25-hydroxyvitamin D levels between 25 and 90 nmol/L., Intervention: Vitamin D supplementation (ergocalciferol, initially 10,000 IU given once weekly and then 1,000 IU daily) or placebo for 2 years. All subjects received 600 mg of elemental calcium daily as calcium carbonate., Measurements: Falls and fractures recorded prospectively in study diaries by care staff., Results: The vitamin D and placebo groups had similar baseline characteristics. In intention-to-treat analysis, the incident rate ratio for falling was 0.73 (95% confidence interval (CI)=0.57-0.95). The odds ratio for ever falling was 0.82 (95% CI=0.59-1.12) and for ever fracturing was 0.69 (95% CI=0.40-1.18). An a priori subgroup analysis of subjects who took at least half the prescribed capsules (n=540), demonstrated an incident rate ratio for falls of 0.63 (95% CI=0.48-0.82), an odds ratio (OR) for ever falling of 0.70 (95% CI=0.50-0.99), and an OR for ever fracturing of 0.68 (95% CI=0.38-1.22)., Conclusion: Older people in residential care can reduce their incidence of falls if they take a vitamin D supplement for 2 years even if they are not initially classically vitamin D deficient.

Mammographic density and bone mineral density, risk factors for breast cancer and osteoporotic fractures, respectively, are both thought to reflect cumulative exposure to estrogen and are highly heritable. We asked if there was overlap between the genes that explain their variances. We studied 63 monozygous and 71 dizygous female twin pairs ages 38 to 71 years (mean, 50 years). Absolute and percent mammographic densities were measured by a computer-assisted method, and bone mineral density was measured at the lumbar spine, femoral neck, and forearm by dual energy X-ray absorptiometry. After adjusting for age, height, and weight, the within-person and cross-trait cross-twin correlations between the mammographic density and bone mineral density measures were between -0.09 and 0.16 (SEs, 0.07-0.09) and independent of zygosity (all P > 0.05). We conclude that there is little, if any, overlap between the genetic or environmental determinants of disease risk associated with these traits.

Analysis of apparent bone mineral density (BMD) in the lumbar spine is commonly based on anteroposterior (AP) scanning using dual-energy X-ray absorptiometry (DXA). Although not widely used, clinically important information can also be derived from lateral scanning. Vertebral bone density, and therefore strength, can may vary in different subregions of the vertebral body. Therefore, subregional BMD measurements might be informative about fracture risk. However, the intrarater and interrater precision of in vivo subregional BMD assessments from lateral DXA remains unknown. Ten normal, young (mean: 24 yr) and 10 older (mean: 63 yr) individuals with low BMD were scanned on one occasion using an AP/lateral sequence. Each lateral scan was reanalyzed six times at L2 by three raters to determine the intrarater and interrater precision in selecting seven regions of interest (subregions). Precision was expressed using percentage coefficients of variation (% CV) and intraclass correlation coefficients (ICC). Intrarater precision ranged from ICC(1,1) 0.971 to 0.996 (% CV: 0.50-3.68) for the young cohort and ICC(1,1) 0.934 to 0.993 (% CV: 1.46-5.30) for the older cohort. Interrater precision ranged from ICC(2,1) 0.804 to 0.915 (% CV: 1.11-2.35) for the young cohort and ICC(2,1) 0.912 to 0.984 (% CV: 1.85-4.32) for the older cohort. Scanning a subgroup of participants twice with repositioning was used to assess short-term in vivo precision. At L2, short-term in vivo precision ranged from ICC(1,1) 0.867 to 0.962 (% CV: 3.38-9.61), at L3 from ICC(1,1) 0.961 to 0.988 (% CV: 2.02-5.57) and using an L2/L3 combination from ICC(1,1) 0.942 to 0.980 (% CV: 2.04-4.61). This study demonstrated moderate to high precision for subregional analysis of apparent BMD in the lumbar spine using lateral DXA in vivo.

Objective: The aim of this study was to assess the relative strength of the association of endogenous estradiol and androgens with bone loss at the lumbar spine and femoral neck during the menopausal transition., Design: A longitudinal study of a population-based cohort of 159 Australian-born women who at baseline had a mean age of 50.0 years (SD=2.4) and had menstruated in the prior 3 months. BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine and femoral neck on up to three occasions., Results: Of the 159 participants, 50 had two BMD measurements and 109 had a third measure. The mean time between the first and final measures for the whole group was 39 months and at the time of the final measures 49% of the participants had become postmenopausal. The mean percentage change/year in lumbar spine BMD was -0.9% (95% CI, -1.1 to -0.6) and at the femoral neck, -0.5% (95% CI, -0.7 to -0.2). A highly significant association with estradiol at the final time point was found, whereas the contribution of estradiol at baseline was negligible. The variance explained by estradiol levels was 19% and 11% for change in BMD at the LS and FN, respectively. Excluding baseline estradiol values and using the average of change in BMD at the LS and FN, the final regression equation estimated that an estradiol level of 330 pmol/l (95% CI, 274 to 386) and 245 pmol/l (95% CI, 194 to 296) is required for preservation of LS and FN BMD, respectively. A stepwise linear regression model was used to assess the effect of age, BMI, estradiol, testosterone, DHEAS, SHBG, and free testosterone index on changes in BMD and found that only the final estradiol level had a significant association with change in BMD., Conclusion: Endogenous estradiol was the only hormone among those investigated to have a significant effect on bone mineral density during the menopausal transition.

The age and developmental stage at which calcium supplementation produces the greatest bone effects remain controversial. We tested the hypothesis that calcium supplementation may improve bone accrual in premenarcheal females. Fifty-one pairs of premenarcheal female twins (27 monozygotic and 24 dizygotic; mean +/- sd age, 10.3 +/- 1.5 yr) participated in a randomized, single-blind, placebo-controlled trial with one twin of each pair receiving a 1200-mg calcium carbonate (Caltrate) supplement. Areal bone mineral density (aBMD) was measured at baseline and 6, 12, 18 and 24 months. There were no within-pair differences in height, weight, or calcium intake at baseline. Calcium supplementation was associated (P < 0.05) with increased aBMD compared with placebo, adjusted for age, height, and weight at the following time points from baseline: total hip, 6 months (1.9%), 12 months (1.6%), and 18 months (2.4%); lumbar spine, 12 months (1.0%); femoral neck, 6 months (1.9%). Adjusted total body bone mineral content was higher in the calcium group at 6 months (2.0%), 12 months (2.5%), 18 months (4.6%), and 24 months (3.7%), respectively (all P < 0.001). Calcium supplementation was effective in increasing aBMD at regional sites over the first 12-18 months, but these gains were not maintained to 24 months.

Background: The aetiology of osteoporotic vertebral fracture is multifactorial and may be conceptualised using a systems framework. Previous studies have established several correlates of vertebral fracture including reduced vertebral cross-sectional area, weakness in back extensor muscles, reduced bone mineral density, increasing age, worsening kyphosis and recent vertebral fracture. Alterations in these physical characteristics may influence biomechanical loads and neuromuscular control of the trunk and contribute to changes in subregional bone mineral density of the vertebral bodies. Methods: This review discusses factors that have received less attention in the literature, which may contribute to the development of vertebral fracture. A literature review was conducted using electronic databases including Medline, Cinahl and ISI Web of Science to examine the potential contribution of trabecular architecture, subregional bone mineral density, vertebral geometry, muscle force, muscle strength, neuromuscular control and intervertebral disc integrity to the aetiology of osteoporotic vertebral fracture. Interpretation: A better understanding of factors such as biomechanical loading and neuromuscular control of the trunk may help to explain the high incidence of subsequent vertebral fracture after sustaining an initial vertebral fracture. Consideration of these issues may be important in the development of prevention and management strategies.

Objectives: To determine the prevalence of vitamin D deficiency in older people in residential care and the influence that the level of vitamin D may have on their incidence of falls., Design: Prospective cohort., Setting: Residential care facilities for older people in several states of Australia., Participants: Six hundred sixty-seven women in low-level care and 952 women in high-level care, mean age 83.7 years., Measurements: Serum 25-hydroxyvitamin D (25D) levels and recognized risk factors for falls including current medication use, a history of previous fractures, weight, tibial length (as a surrogate for height), cognitive function, walking ability, and frequency of going outdoors were determined. The women in low-level care and high-level care were followed for an average of 145 and 168 days, respectively. Falls were recorded prospectively in diaries completed monthly by residential care staff., Results: Vitamin D deficiency (defined as a serum 25D level below 25 nmol/L) was present in 144 (22%) women in low-level care and 428 (45%) in high-level care. After excluding 358 bed-bound residents and adjusting for weight, cognitive status, psychotropic drug use, previous Colles fracture, and the presence of wandering behavior, log serum 25D level remained independently associated with time to first fall. The adjusted hazards ratio was 0.74 (95% confidence interval=0.59-0.94; P=.01), implying a 20% reduction in the risk of falling with a doubling of the vitamin D level., Conclusion: Vitamin D deficiency is common in residential care in Australia. A low level of serum vitamin D is an independent predictor of incident falls.

Objective: To investigate the effect of endogenous hormone levels on central abdominal fat during the menopausal transition in a population-based cohort of Australian-born women., Design: Prospective observational study., Setting: Population-based sample. Body composition was assessed in the Royal Melbourne Hospital, and interviews were conducted at the patient's home., Subject(s): One hundred two women from the Melbourne Women's Midlife Health Project. Data, physical measures, and blood were obtained by interview when the longitudinal study commenced (baseline) and at the time of the total body scan approximately 5 years later. Body composition was measured using dual-energy X-ray absorptiometry., Intervention(s): None., Main Outcome Measures: Total body fat and central abdominal fat., Result(s): The 102 women were either premenopausal or in the early menopausal transition at baseline. At the time of their dual-energy X-ray absorptiometry scan, 31 were in the early menopausal transition, 22 were in the late menopausal transition, and 49 were postmenopausal. Multiple regression analysis found that total percentage of body fat was associated with weight measures, whereas central abdominal fat was also positively associated with baseline free T index (FTI) and with the increase in FTI since baseline., Conclusion(s): The major hormonal change associated with central adiposity during the menopausal transition is the increase in the FTI. This effect is significant even after allowing for baseline and final weight.