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Protein phosphorylation regulates a wide variety of cellular processes. Thus, we hypothesize that single-nucleotide polymorphisms (SNPs) that may modulate protein phosphorylation could affect osteoporosis risk. Based on a previous conventional genome-wide association (GWA) study, we conducted a three-stage meta-analysis targeting phosphorylation-related SNPs (phosSNPs) for femoral neck (FN)-bone mineral density (BMD), total hip (HIP)-BMD, and lumbar spine (LS)-BMD phenotypes. In stage 1, 9593 phosSNPs were meta-analyzed in 11,140 individuals of various ancestries. Genome-wide significance (GWS) and suggestive significance were defined by α = 5.21 × 10(-6) (0.05/9593) and 1.00 × 10(-4), respectively. In stage 2, nine stage 1-discovered phosSNPs (based on α = 1.00 × 10(-4)) were in silico meta-analyzed in Dutch, Korean, and Australian cohorts. In stage 3, four phosSNPs that replicated in stage 2 (based on α = 5.56 × 10(-3), 0.05/9) were de novo genotyped in two independent cohorts. IDUA rs3755955 and rs6831280, and WNT16 rs2707466 were associated with BMD phenotypes in each respective stage, and in three stages combined, achieving GWS for both FN-BMD (p = 8.36 × 10(-10), p = 5.26 × 10(-10), and p = 3.01 × 10(-10), respectively) and HIP-BMD (p = 3.26 × 10(-6), p = 1.97 × 10(-6), and p = 1.63 × 10(-12), respectively). Although in vitro studies demonstrated no differences in expressions of wild-type and mutant forms of IDUA and WNT16B proteins, in silico analyses predicts that WNT16 rs2707466 directly abolishes a phosphorylation site, which could cause a deleterious effect on WNT16 protein, and that IDUA phosSNPs rs3755955 and rs6831280 could exert indirect effects on nearby phosphorylation sites. Further studies will be required to determine the detailed and specific molecular effects of these BMD-associated non-synonymous variants.

Summary Changes in areal bone mineral density (aBMD) and other predictors of bone loss were evaluated in 48 same-sex twin/age-matched sibling pairs discordant for antiepileptic drug (AED) use. AED users had reduced BMD at the hip regions. Prolonged AED users had greater aBMD loss, predicting a higher risk of bone fragility. Introduction To investigate the longitudinal associations of bone mineral measures with antiepileptic drug (AED) use, including enzyme-inducing (EIAED) and non-enzyme-inducing (NEIAED) types, and other predictors of bone loss in a study of 48 same-sex twin/age-matched sibling pairs (40 female, 8 male) discordant for AED use. Methods Using dual-energy X-ray absorptiometry (DXA), areal bone mineral density (aBMD) and content (BMC) at the hip regions, forearm, lumbar spine, and whole body were measured twice, at least 2 years apart. The mean within-pair difference (MWPD), MWPD%, and mean annual rate of aBMD change were adjusted for age, weight, and height. Predictors of bone loss were evaluated. Results AED users, compared to non-users, at baseline and follow-up, respectively, had reduced aBMD at the total hip (MWPD% 3.8, 4.4%), femoral neck (4.7, 4.5%), and trochanter regions (4.1, 4.6%) (p < 0.05). For the whole cohort, the annual rate of change in all aBMD/BMC (p > 0.05) regions did not differ within pairs. Nevertheless, EIAED users had greater aBMD loss than non-users (n = 20 pairs) at the total hip (1.7 vs. 0.3%, p = 0.013) and whole body regions (0.7% loss vs. 0.1% BMD gain, p = 0.019), which was not found in NEIAED-discordant pairs (n = 16). AED use >20 years predicted higher aBMD loss at the forearm (p = 0.028), whole body (p = 0.010), and whole body BMC (p = 0.031). Conclusions AED users had reduced aBMD at the hip regions. Prolonged users and EIAED users had greater aBMD loss, predicting a higher risk of bone fragility. Further prospective studies of AED effects on bone microarchitecture are needed.

Summary Objectives Chronic treatment with valproate (VPA) is commonly associated with weight gain, which potentially has important health implications, in particular increased central fat distribution. We utilized a VPA-discordant same-sex, twin and matched sibling pair study design to primarily examine for differences in fat distribution between patients with epilepsy treated with VPA compared to their matched twin or sibling control. Weight, blood pressure, and leptin levels were assessed. Methods Height, weight, waist and hip measurements, exercise, blood pressure (BP), and serum leptin levels were measured. Body composition was measured using dual-energy x-ray absorptiometry (DXA). Abdominal fat was expressed as a percentage of the abdominal region (AFat%); and of whole body fat (WBF); (AFat%WBF). Mean within-pair differences were assessed (VPA-user and nonuser). Restricted maximum likelihood (REML) linear mixed model analysis was fitted to examine associations of anthropometrics, zygosity, gender, menopausal status, VPA dose and duration, with weight and AFat%. Results We studied 19 pairs of VPA-discordant, gender-matched (five male, 14 female) twins and siblings. Mean (standard deviation, SD) duration of therapy for VPA users was 11.0 (7.4) years. There were no statistically significant within-pair differences in age, height, weight, body mass index (BMI), BP, leptin level, WBF, AFat%, or AFat%WBF. For pairs in which VPA-user was treated for >11 years there were statistically significant mean within-pair differences in AFat%, (+7.1%, p = 0.03, n = 10 pairs), mean BP (+11.0 mm Hg, p = 0.006, n = 8 pairs); but not in AFat%WBF. VPA duration was positively associated with weight (estimate +0.98 kg/per year of VPA, p = 0.03); VPA treatment duration and dose were not significantly associated with AFat%. Significance This study demonstrated a relationship between long-term VPA use and abdominal adiposity (AFat%), which could have significant health implications. We recommend ongoing monitoring of weight, BMI, and blood pressure for patients taking VPA.

Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10−8) level: 14q24.2 (rs227425, P-value 3.98 × 10−13, SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10−9, CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n = 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.

OBJECTIVE: The osteoporosis drug strontium ranelate dissociates bone remodelling processes. It also inhibits subchondral bone resorption and stimulates cartilage matrix formation in vitro. Exploratory studies in the osteoporosis trials report that strontium ranelate reduces biomarkers of cartilage degradation, and attenuates the progression and clinical symptoms of spinal osteoarthritis, suggesting symptom- and structure-modifying activity in osteoarthritis. We describe the rationale and design of a randomised trial evaluating the efficacy and safety of strontium ranelate in knee osteoarthritis. RESEARCH DESIGN, METHODS, AND RESULTS: This double-blind, placebo-controlled trial (98 centres, 18 countries) includes ambulatory Caucasian men and women aged ≥50 years with primary knee osteoarthritis of the medial tibiofemoral compartment (Kellgren and Lawrence grade 2 or 3), joint space width (JSW) 2.5 to 5 mm, and knee pain on most days in the previous month (intensity ≥40 mm on a visual analogue scale). Patients are randomly allocated to three groups (strontium ranelate 1 or 2 g/day, or placebo). Follow-up is expected to last 3 years. The primary endpoint is radiographic change in JSW from baseline in each group versus placebo. The main clinical secondary endpoint is WOMAC score at the knee. Safety is assessed at every visit. It is estimated that 1600 patients are required to establish statistical significance with power >90% (0.2 mm ± 10% between-group difference in change in JSW over 3 years). Recruitment started in April 2006. The results are expected in spring 2012. CLINICAL TRIAL REGISTRATION: The trial is registered on www.controlled-trials.com (number ISRCTN41323372). CONCLUSIONS: This randomised, double blind, placebo-controlled study will establish the potential of strontium ranelate in improving structure and symptoms in patients with knee osteoarthritis.

Postmenopausal women on aromatase inhibitors (AI) are at risk of aromatase inhibitor-associated bone loss (AIBL) and fractures. In 2005 Osteoporosis Australia proposed an algorithm for bisphosphonate intervention. Three hundred and three postmenopausal women with early breast cancer (EBC) were enrolled (osteoporotic, n=25; osteopaenic, n=146; normal bone mineral density (BMD), n=126). Weekly alendronate (70 mg) treatment efficacy as triggered by the algorithm in preventing bone loss was evaluated. All patients received anastrozole (1 mg daily), calcium and vitamin D. Results All osteoporotic patients received alendronate at baseline. Eleven out of the 146 (7.5%) osteopaenic patients commenced alendronate within 18 months of participation and eleven commenced after. One hundred and twenty four out of the 146 (84.9%) osteopaenic patients and all 126 with normal baseline BMD did not trigger the algorithm. At three years, lumbar spine mean BMD increased (15.6%, p

UNLABELLED: This analysis was conducted to assess the effect of high versus lower doses of ibandronate on nonvertebral fractures. The results were adjusted for clinical fracture, age, and bone density. The treatment effect was dose-dependent. Higher doses of ibandronate significantly reduced the risk of nonvertebral fractures more effectively compared with lower doses. INTRODUCTION: The objective of this study was to assess the efficacy of different doses of ibandronate on nonvertebral fractures in a pooled analysis. METHODS: Eight randomized trials of ibandronate were reviewed for inclusion. Alternative definitions of high versus low doses based on annual cumulative exposure (ACE) were explored. A time-to-event analysis was conducted using Kaplan-Meier methodology. Hazard ratios (HR) were derived using Cox regression and adjusted for covariates. RESULTS: Combining higher ACE doses of > or = 10.8 mg (150 mg once monthly, 3 mg i.v. quarterly, and 2 mg i.v. every 2 months) versus ACE doses of 5.5 mg, from two trials, resulted in an HR 0.62 (95% CI 0.396-0.974, p = 0.038). There was a dose-response trend with increasing ACE doses (7.2-12 mg) versus ACE of 5.5 mg. CONCLUSIONS: A dose-response effect on nonvertebral fractures was observed when comparing high with low ACE doses. A significant reduction in nonvertebral fractures was noted when pooling data from trials using ACE doses of > or = 10.8 mg versus ACE < or = 7.2 mg; and with ACE > or = 10.8 mg versus ACE of 5.5 mg (38% reduction). Higher ibandronate dose levels (150 mg monthly or 3 mg i.v. quarterly) significantly reduced nonvertebral fracture risk in postmenopausal women.

WNT16 is associated with bone mineral density, osteoporotic fracture and bone strength : a large-scale meta-analysis of genomewide association studies

The Drug Burden Index (DBI), a measure of an individual's exposure to anticholinergic and sedative medications, is associated with functional impairment in community-dwelling, older people. In people from residential aged care facilities (RACFs), DBI score does not appear to be associated with functional impairment, but is associated with an increased risk of falls.We investigated the associations between increasing DBI score and mortality in older adults living in RACFs.Study participants (n = 602; 70.9% female), recruited from 51 RACFs in Sydney, Australia, had a mean ± standard deviation (SD) age of 85.7 ± 6.4 years and a mean ± SD DBI score of 0.58 ± 0.64.Exposure to anticholinergic medication was 33.6% and sedative medications 41.9%. All-cause mortality after a variable follow-up time (774-1269 days) was 36.2% (n = 218), with the leading causes of death classified as stroke (n = 46; 21.1%), ischaemic heart disease/cardiovascular system (n = 44; 20.2%) and pneumonia (n = 31; 14.2%). One-year mortality multivariate models showed that the DBI categories low (n = 260; hazard ratio [HR] 1.13; 95% CI 0.82, 1.57) and high (n = 153; HR 1.19; 95% CI 0.82, 1.74) were not associated with mortality. This lack of a significant association remained after dichotomization into the anticholinergic and sedative components of the DBI.We found that with high exposure to anticholinergic and sedative medications, there was no significant association between increasing DBI score and all-cause mortality in old individuals living in RACFs. Further research into the adverse effects of medication use on the mortality of institutionalized older individuals is needed.

Objective To investigate whether protease-activated receptor 1 (PAR-1) and/or PAR-2 promotes the invasiveness/proliferation of synovial fibroblasts (SFs) and to determine the signaling mechanisms of these pathways. Methods SFs were isolated from the synovial tissue of patients with rheumatoid arthritis (RA), patients with osteoarthritis (OA), and PAR-1– or PAR-2–knockout (KO) mice. Expression of PAR-1 and PAR-2 was detected by immunofluorescence and Western blotting. The invasion and proliferation of SFs were measured by invasion assay and MTT assay, respectively. Matrix metalloproteinase 2 (MMP-2) and MMP-9 were detected by zymography, and cytokines were measured by enzyme-linked immunosorbent assay. Results PAR-1 and PAR-2 were colocalized with SFs in RA and OA synovium and, to a considerably lesser extent, in normal synovium. Inhibition of PAR-2 by small interfering RNA (siRNA) inhibited RASF invasion and proliferation, whereas blocking of PAR-1 by siRNA had the reverse effects. SFs from PAR-2–KO mice exhibited slower rates of proliferation and invasion. SFs from PAR-1–KO mice produced less MMP-2 and, in response to tumor necrosis factor α (TNFα) stimulation, had increased MMP-9 secretion when compared to SFs from wild-type and PAR-2–KO mice. Inhibition of PAR-1, but not PAR-2, stimulated the secretion of interleukin-17 (IL-17) and TNFα by RASFs. Furthermore, PAR-1 and PAR-2 had opposing effects on the activation of ERK, p38, and NF-κB. Conclusion Activation of PAR-1 stimulates MMP-2 secretion, inhibits RASF growth and invasion, and decreases production of IL-17 and TNFα by RASFs, whereas activation of PAR-2 stimulates RASF growth and invasion and increases production of TNFα. Thus, although PAR-1 and PAR-2 are coexpressed by RASFs, PAR-2 alone appears to be responsible for the aggressive properties of RASFs and is likely to contribute to the pathologic progression of RA.

Activated protein C (APC) is a natural anticoagulant that exerts anti-inflammatory and cytoprotective properties mediated through the protease activated receptor (PAR)-1. APC can also proteolytically cleave PAR-2, although subsequent function is unknown. On the basis of recent evidence that APC promotes wound healing, the aim of this study was to determine whether APC acts through PARs to heal murine excisional wounds or to regulate human cultured keratinocyte function and to determine the signaling mechanisms. Topical administration of APC accelerated wound healing in wild-type mice and, unexpectedly, in PAR-1 knockout mice. PAR-2 knockout mice healed significantly slower than wild-type mice, and healing was not altered by adding APC, indicating that APC acts through PAR-2 to heal wounds. In cultured human primary keratinocytes, APC enhanced PAR-2, stimulated proliferation, activated phosphatidylinositol 3-kinase/Src/Akt, and inhibited phosphorylated (P)-p38. Inhibiting PAR-1 or PAR-2, by small-interfering RNA or blocking antibody, reversed APC-induced keratinocyte proliferation and Akt activation. Blocking PAR-2, but not PAR-1, reversed the inhibition of P-p38 by APC. Furthermore, inhibition of P-p38 accelerated wound healing in wild-type mice. In summary, although APC acts through both PAR-1 and PAR-2 to activate Akt and to increase keratinocyte proliferation, APC-induced murine wound healing depends on PAR-2 activity and inhibition of P-p38.

This study summarizes the treatment effect of zoledronic acid infusion on lumbar spine bone mineral density in different subgroups with glucocorticoid-induced osteoporosis. Zoledronic acid is significantly more effective than risedronate in increasing lumbar spine (LS) bone mineral density (BMD) in both prevention and treatment of glucocorticoid-induced osteoporosis. Introduction In patients on glucocorticoids, a single zoledronic acid infusion significantly increased BMD versus daily oral risedronate. We assessed treatment effect on LS BMD in different patient subgroups at month 12 that contributed to the risk of osteoporosis in addition to glucocorticoids. Methods Patients randomized to a single IV infusion of zoledronic acid 5 mg or risedronate (5 mg/day) and stratified based on glucocorticoids duration [treatment (>3 months) and prevention (≤ 3 months) subpopulations]were subgrouped by age; gender; menopausal status in women; dose and duration of prednisone during the trial; and baseline serum 25-OH vitamin D, LS BMD T-score, creatinine clearance, and concomitant medication use. Results At month 12, zoledronic acid significantly increased LS BMD versus risedronate in patients ≤ 74 years (P

Antiresorptive therapies are used to increase bone strength in individuals with osteoporosis and include five principal classes of agents: bisphosphonates, estrogens, selective estrogen receptor modulators (SERMs), calcitonin and monoclonal antibodies such as denosumab. However, no head-to-head studies have compared different antiresorptive agents using fracture as an end point. Bisphosphonates, which have proven antifracture efficacy and a good safety profile, are the most widely used first-line antiresorptive therapy and are recommended for patients with osteoporosis, a prior fragility fracture or osteopenia, as well as individuals with a high risk of fracture. Denosumab, which also has good antifracture efficacy, is another possible first-line therapy, although long-term safety data are lacking. However, no single antiresorptive therapy is currently appropriate for all patients or clearly superior to other therapies. Antiresorptive agents such as estrogens, SERMs (in postmenopausal women) and calcitonin are considered to be second-line agents that are appropriate in special circumstances. Clinicians should determine the most appropriate pharmacological therapy after a careful assessment of the risk:benefit profiles of these drugs in each patient. In addition, patients should receive a detailed explanation of the treatment goals, so that the therapeutic benefit can be maximized through good compliance and persistence.

past research suggests that fall rates in older persons may differ by ethnicity. The aim of this study was to compare the incidence of falls between older male Italian-born immigrants and their Australian-born counterparts.this study analysed data from 335 Italian-born and 848 Australian-born men aged 70 years and over participating in the Concord Health and Ageing in Men Project (CHAMP). Prospective falls data were collected by 4 monthly phone calls (mean follow-up time: 26.7 months). Negative binomial regression compared falls incidence rate ratios (IRR) between the two groups of men.there were 37 (11%) Italian-born men and 185 (22%) Australian-born men who had two or more falls during follow-up (P 0.001). Negative binomial analysis demonstrated that Italian-born men had half the incidence rate of falls compared with Australian-born men (IRR = 0.51, 95% CI = 0.38-0.67). After adjustment for falls risk factors, Italian-born men remained significantly less likely to fall with a 43% lower fall rate (IRR = 0.57, 95% CI = 0.39-0.85).older male Italian-born immigrants are less likely to fall than their Australian-born counterparts. Differences in fall rates between the two groups are not explained by established falls risk factors.

ObjectiveLow back pain (LBP) is a common musculoskeletal disorder, but it is still unclear which individuals develop it. The authors examined the contribution of genetic factors, lumbar disc degeneration (LDD) and other risk factors in a female sample of the general population.Material and MethodsA cross-sectional study was conducted among 2256 women (371 and 698 monozygotic and dizygotic twin pairs and 29 sibling pairs and 60 singletons) with a mean age of 50 years (18–84). A self-reported validated questionnaire was used to collect back pain data. Risk factors including body weight, smoking, occupation, physical exercise and MRI assessed LDD were measured. Data analysis included logistic regression and variance decomposition.ResultsThe major factors associated with LBP included genetic background, with OR approximately 6 if the monozygotic co-twin had LBP, or 2.2 if she was a dizygotic co-twin. In addition, LDD and overweight were highly significantly (pConclusionsThe main risk factors for reported episodes of severe and disabling LBP in UK women include the degree of LDD as assessed by MRI, being overweight and genetic heritability.

OBJECTIVES: To evaluate the association between the Drug Burden Index (DBI), a measure of a person's total exposure to anticholinergic and sedative medications that includes principles of dose-response and maximal effect and is associated with impaired physical function in community-dwelling older people, and falls in residents of residential aged care facilities (RACFs). DESIGN: Data were drawn from participants in a randomized controlled trial that investigated falls and fractures. SETTING: RACFs in Sydney, Australia. PARTICIPANTS: Study participants (N=602; 70.9% female) were recruited from 51 RACFs. Mean age was 85.7 ± 6.4, and mean DBI was 0.60 ± 0.66. MEASUREMENTS: Medication history was obtained on each participant. Drugs were classified as anticholinergic or sedative and a DBI was calculated. Falls were measured over a 12-month period. Comorbidity, cognitive impairment (Mini-Mental State Examination) and depression (Geriatric Depression Scale) were determined. RESULTS: There were 998 falls in 330 individuals during a follow-up period of 574.2 person-years, equating to an average rate of 1.74 falls per person-year. The univariate negative binomial regression model for falls showed incidence rate ratios of 1.69 (95% confidence interval (CI)=1.22-2.34) for low DBI ( Language: en

Objectives Lumbar disc degeneration (LDD) is prevalent, age-related and contributes to low back pain. Crosssectional LDD as determined by MRI scan is known to be highly heritable. The authors postulated that the rate of progression might also be controlled by genetic factors. Methods A 10-year follow-up of MRI-determined LDD was performed in 234 pairs of twin volunteers in the UK and Australia, comprising 90 monozygotic pairs and 144 dizygotic same-sex twin pairs. Of the total sample, 95% were female. The mean age at baseline was 53.3 years (range 32.3–69.5). The rate of progression was calculated and, because the effect of age was non-linear, the sample was divided into age strata and heritability estimated for each trait’s progression. Results All MRI-determined traits worsened signifi cantly over the period of follow-up (p

Back pain is a near-universal human experience at some time during life, and neck pain is also common. The overwhelming majority of low back and cervical pain is considered to be due to unspecified mechanical factors or disc degeneration, which is a common with ageing and, hence, in people of working age. Back pain and disc disease appear to have significant heritability, based upon twin studies, but environmental factors also contribute - including physical occupational activities in some studies - although the strength of this association remains uncertain. This article examines the contribution of genetic and environmental factors to back pain and disc disease, with a specific focus on occupational exposures.

The role of anxiety in pain is less well understood than the role of depression. Based on recent conceptual thinking about worry and pain, we explored the relationship between pain status and worry about health and anxiety in 1217 community-dwelling men aged 70 years or older who participated in the baseline phase of the Concord Health and Ageing in Men Project study, a large population-based epidemiological study of healthy ageing based in Sydney, Australia. We hypothesised that worry about health would be associated with having persistent pain, and that the association would be stronger in the presence of co-existing pain-related interference with activities (intrusive pain). Of men in the study, 12.5% had persistent and intrusive pain, 22.4% were worried about their health, and 6.3% had anxiety. We found a strong association between worry about health and pain that was both persistent and intrusive, and that remained after accounting for age, number of comorbidities, depression, self-rated health status, arthritis, and gait speed (adjusted odds ratio 2.9; 95% confidence interval 1.8-4.7), P0.0001). The corresponding adjusted odds ratio for the association between anxiety and pain was 2.3 (95% confidence interval 1.0-4.8; P=0.0363). These findings suggest that at a population level, subthreshold anxiety and pain are strongly related, and worry about health occurs much more commonly than anxiety itself. To our knowledge, this is the first study to explore, specifically, the relationship between pain status and worry about health in older men. In older community-dwelling men, pain was robustly associated with worry about health, highlighting the potential importance of subthreshold anxiety-related psychological factors.

The prevalence of osteoporosis is expected to increase with the ageing of the world's population. This article reviews the epidemiology, risk factors and health burden of osteoporosis. In the Global Burden of Disease (GBD) Study 2005, osteoporosis is studied as a risk factor for fracture by considering the bone-mineral-density (BMD) measurement as the continuous exposure variable. We have performed a systematic review seeking population-based studies with BMD data measured by dual-X-ray absorptiometry (DXA). The femoral neck was selected as the unique location and all values were converted into Hologic(®) to enable inclusion of worldwide data for analysis. Provisional results on mean BMD values for different world regions are shown in age breakdowns for males and females 50 years or over, as well as mean T-scores using the young, white, female reference of National Health and Nutrition Examination Survey (NHANES) III. Results show remarkable geographical differences and a time trend towards improvement of the BMD values in Asian and European populations.

Aging alone is not the only factor accounting for poor bone health in older men. There are modifiable factors and lifestyle choices that may influence bone health and result in higher bone density and lower fracture risk even in very old men. The aim of this cross-sectional analysis was to identify the factors associated with areal bone mineral density (BMD) and their relative contribution in older men. The Concord Health and Ageing in Men Project is a population-based study in Sydney, Australia, involving 1,705 men aged 70–97. Data were collected using questionnaires and clinical assessments. BMD of the hip and spine was measured by dual X-ray absorptiometry. In multivariate regression models, BMD of the hip was associated with body weight and bone loading physical activities, but not independently with age. The positive relationship between higher BMD and recreational activities is attenuated with age. Factors independently associated with lower BMD at the hip were inability to stand from sitting, a history of kidney stones, thyroxine use, and Asian birth and at the spine, chronic obstructive pulmonary disease, paternal fracture history, and thyroxine use. Higher body weight, participation in dancing, tennis or jogging, quadriceps strength, alcohol consumption, and statin use were associated with higher hip BMD, while older age, osteoarthritis, higher body weight, and aspirin use were associated with higher spinal BMD. Maintaining body weight, physical activity, and strength were positively associated with BMD even in very elderly men. Other parameters were also found to influence BMD, and once these were included in multivariate analysis, age was no longer associated with BMD. This suggests that age-related diseases, lifestyle choices, and medications influence BMD rather than age per se.

Background: Frail older individuals living in residential aged care facilities (RACFs) have impaired physical function compared with to older people living in the community. In residents of RACFs, we aimed to produce sex-specific means and empirical norms of objective physical function measures to ascertain whether these measures are predictors of falls. Methods: Data were extracted from a large cohort study investigating fall and fracture rates in RACFs in the Northern Sydney Health Area, Australia. Results: Study participants (n = 602, 70.9% female) were recruited from 51 RACFs. Cohort means (±standard deviation) for females were for grip strength (GS) 16.8±5.3 kg, simple reaction time (RT) 384±154 ms, walking speed (WS) 0.56 ±0.20 ms−1, balance category (B) 3.8±1.1 and sit to stand category (STS) 3.6±0.5. For males, means were for GS 28.8±7.8 kg, RT 335±150 ms, WS 0.62±0.22 ms−1, B 4.1±1.1 and STS 3.7±0.5. Means of B and STS decreased significantly over the 1-year study period for males and females ( p < 0.001). Individual multivariate negative binomial regression models for each functional outcome showed having a WS −1 (IRR = 1.37, 95% Cl = 1.03—1.84), a STS score of 3 (IRR = 1.39, 95% Cl = 1.09—1.79) and B category of 3 or 5 (IRR = 1.69, 95% CI = 1.29—2.22) were significantly associated with an increased fall rate. Conclusions: This study establishes normative values for physical function tests in mobile residents of RACFs and demonstrates that walking speed, balance and sit to stand impairments are associated with falls in this group.

This study investigated whether women with cardiovascular disease (CVD) would have an increased risk of fractures as osteoporosis and CVD share many common risk factors. From February 2006 to January 2007, 17,033 women aged ≥50 years (mean 71.8, range 50–106) were recruited by 1,248 primary care practitioners and interviewed by trained nurses. For each woman, 10-year probability of a future major osteoporotic fracture was estimated using the World Health Organization Fracture Risk Assessment Tool (FRAX). The study showed that the 10-year probability of a major osteoporotic fracture was higher for 6,219 CVD women compared to 10,814 non-CVD women after adjustment for age, BMI, current smoking, and alcohol use (adjusted geometric means 14.3 and 13.8%, respectively; P < 0.001). With regard to high risk of fracture (i.e., 10-year probability ≥ 20%), the adjusted odds ratio for CVD was 1.23 (95% CI 1.13–1.35, P < 0.001). However, compared to non-CVD women, CVD women were more likely to report a previous fracture, to have a secondary osteoporosis, and to use glucocorticoids. Among the 4,678 women who were classified as having a high fracture risk, current use rate of bone-related medications (i.e., any one of bisphosphonates, raloxifene, PTH, vitamin D, calcium, or hormone therapy) was 50.2% in the CVD group and 56.9% in the non-CVD group. Women with CVD were at increased risk of fracture partly due to bone-specific risk factors such as history of previous fracture, use of glucocorticoids, and secondary osteoporosis. This risk is not being treated appropriately by primary health physicians.

OBJECTIVES: To determine the association between loss of muscle strength, mass, and quality and functional limitation and physical disability in older men. DESIGN: Cross-sectional study of older men participating in the Concord Health and Ageing in Men Project (CHAMP). SETTING: Elderly men living in a defined geographical region in Sydney, Australia. PARTICIPANTS: One thousand seven hundred five community-dwelling men aged 70 and older who participated in the baseline assessments of CHAMP. MEASUREMENTS: Upper and lower extremity strength were measured using dynamometers for grip and quadriceps strength. Appendicular skeletal lean mass was assessed using dual X-ray absorptiometry. Muscle quality was defined as the ratio of strength to mass in upper and lower extremities. For each parameter, subjects in the lowest 20% of the distribution were defined as below normal. Functional limitation was assessed according to self-report and objective lower extremity performance measures. Physical disability was measured according to self-report questionnaire. RESULTS: After adjusting for important confounders, the prevalence ratio (PR) for poor quadriceps strength and self-reported functional limitation was 1.91 (95% confidence interval (CI) 51.10-2.40); for performance-based functional limitation the PR was 1.81 (95% CI = 1.45-2.24). The adjusted PR for poor grip strength and physical disability in instrumental activities of daily living (IADLs) was 1.37 (95% CI = 1.20-1.56). The adjusted PR for low skeletal lean mass (adjusted for fat mass) and physical disability in basic activities of daily living was 2.08 (95% CI = 1.37-3.15). For muscle quality, the PR for lower extremity specific force and functional limitation and physical disability was stronger than upper extremity specific force. CONCLUSION: Muscle strength is the single best measure of age-related muscle change and is associated with physical disability in IADLs and functional limitation. J Am Geriatr Soc 58:2055-2062, 2010.

In a study of 2005 institutionalized older people, use of oral bisphosphonates was associated with a 27% reduction in risk of death compared to non-users after adjusting for potential confounders.This study investigated whether reductions in mortality reported in a trial of intravenous zoledronate after hip fracture could be seen in older people taking oral bisphosphonates.Two thousand and five institutionalized older people (mean age 85.7 years) were assessed at baseline and followed up for hip fracture and death for at least 5 years. Cox proportional hazards regression was used to estimate effects of bisphosphonates on risk of death.At baseline, 78 subjects were taking oral bisphosphonates. Over 5 years of follow-up, 1,596 participants (80%) died. Use of bisphosphonates was associated with a 27% reduction in risk of death compared to non-users after adjusting for age, gender, type of institution, immobility, number of medications, weight, cognitive function, co-morbidities, and hip fracture incidence during the follow-up period (hazard ratio 0.73; 95% CI, 0.56 to 0.94; P = 0.02).Oral bisphosphonates are associated with a reduction in the risk of death in the elderly. The mechanism of effect requires further investigation.

Objective: To determine the proportion of older Australian men who meet the Pharmaceutical Benefits Scheme (PBS) criteria for osteoporosis treatment and are receiving effective treatment. Design and setting: A population-based, cross-sectional analysis of the baseline phase of the Concord Health and Ageing in Men Project (CHAMP), a large epidemiological study focusing on the health of older men. Data were collected through questionnaires and clinical assessments. Bone mineral density (BMD) of the hip and spine was measured by dual x-ray absorptiometry (DXA). Vertebral deformities were identified from DXA lateral vertebral fracture assessment images. The study was conducted at Concord Hospital, Sydney, between January 2005 and May 2007. Participants: 1705 community-dwelling men aged 70 years or over from a defined geographical region around Concord Hospital. Main outcome measures: Prevalence of vertebral deformities; previous minimal trauma fractures; BMD T-scores – 3; falls in the previous 12 months; use of bisphosphonates and calcium and vitamin D supplements. Results: Of the 1705 men seen at baseline, 1626 completed all DXA scans and 401 (25%) met one or more of the PBS criteria for osteoporosis treatment. Ninety per cent of the men who met the PBS criteria were unaware they had osteoporosis. Of the men eligible for PBS-subsidised treatment, 39 (10%) reported use of a bisphosphonate, 56 (14%) had taken calcium supplements, and 28 (7%) had taken vitamin D supplements. Only three men had taken calcium, vitamin D and bisphosphonates in combination. Conclusions: Despite a high prevalence of osteoporosis in elderly Australian men

ObjectiveOsteoarthritis (OA) and osteoporosis are often considered to lie at opposite ends of a spectrum of bone phenotypes. Lumbar degenerative disc disease (LDD) may be associated with low back pain (LBP) and is similar in many ways to OA. LDD is reported in small studies to be associated with increased spine bone mineral density (BMD). The present work aimed to confirm this association in a large population sample using MRI and explore the relationship further, in particular to determine whether it is mediated genetically.MethodsA population based sample (N=908, age range 32–74 years) of UK female twins having MRI of the lumbar spine was used in this study. LDD traits and summary measures and their relationship with BMD at the lumbar spine and hip were examined using multivariate multiple regression and maximum likelihood based variance decomposition.ResultsThere was a significant positive correlation between LDD and BMD at the lumbar spine and hip, which remained significant after adjustment for confounders. Both traits were highly heritable and the associations between them were mediated genetically.ConclusionsA clear, significant and independent association of BMD at hip and lumbar spine with LDD was found which is, in part, genetically mediated. The association with the non-axial site, the hip, is of particular interest and suggests a systemic bone effect. This should encourage the search for pleiotropic genes to help in the understanding of the bone–cartilage relationship. Moreover, genetic variants identified could provide novel therapeutic targets in the management of LBP.

Objectives The aims of this study were to develop and evaluate a simple index for assessing the risk of fractures after a fall and to propose a selection strategy for identifying elderly individuals at high risk of both falls and fall-related fractures. Study Design and Setting Two thousand five institutionalized older men and women were assessed for clinical risk factors and then followed up for falls and fall-related fractures for up to 2 years. Results Our fracture risk index is derived from seven previously identified significant independent risk factors: weight, lower leg length, balance, cognitive function, type of institution, fracture history, and falls in the past year. The fracture rate was 6.5 times greater in the one-sixth of the falls with the highest index (9.7/100 falls) than in the lowest sixth (1.5/100 falls). Our proposed approach (based on balance, risk of falls, and the fracture risk index) selected a group of older people with high risk of both falls and fall-related fracture. The fracture incidence rate was 144% higher, and the falls incidence rate was 31% higher in the selected residents than in the remainder. Conclusion The index could help rationalize fracture prevention programs for frail older people.

BACKGROUND: frailty is a concept used to describe older people at high risk of adverse outcomes, including falls, functional decline, hospital or nursing home admission and death. The associations between frailty and use of specific health and community services have not been investigated. METHODS: the cross-sectional relationship between frailty and use of several health and community services in the last 12 months was investigated in 1,674 community-dwelling men aged 70 or older in the Concord Health and Ageing in Men study, a population-based study conducted in Sydney, Australia. Frailty was assessed using a modified version of the Cardiovascular Health Study criteria. RESULTS: overall, 158 (9.4%) subjects were frail, 679 (40.6%) were intermediate (pre-frail) and 837 (50.0%) were robust. Frailty was associated with use of health and community services in the last 12 months, including consulting a doctor, visiting or being visited by a nurse or a physiotherapist, using help with meals or household duties and spending at least one night in a hospital or nursing home. Frail men without disability in activities of daily living were twice more likely to have seen a doctor in the previous 2 weeks than robust men (adjusted odds ratio 2.04, 95% confidence interval 1.21-3.44), independent of age, comorbidity and socio-economic status. CONCLUSION: frailty is strongly associated with use of health and community services in community-dwelling older men. The high level of use of medical services suggests that doctors and nurses could play a key role in implementation of preventive interventions.

Clinical application of techniques for assessing bone mineral density (BMD) requires accurate and precise measurements that can be related to clearly defined normal ranges. In this study we investigated the clinical interpretation of BMD values in a group of individuals measured on the same day with two different dual-energy x-ray densitometers (Lunar DPX and Hologic QDR 1000). The BMD results were analyzed as absolute values in g/cm2 and with respect to young and age-specific normals as defined by each manufacturer. Absolute BMD values measured by the two instruments were highly correlated (lumbar spine r = 0.98, femoral neck r = 0.95; p < 0.0001). In the lumbar spine, the two instruments assigned almost identical values when expressed as a percentage of age-matched values and as a percentage of young normals, despite a small but systematic difference between the values assigned for the latter index. In the femoral neck, however, there were significant differences in assignments between instruments, expressed both as a percentage of young normal (mean difference 6.2%) and with respect to age-matched values (mean difference 3.3%). In particular, in premenopausal subjects femoral neck values with the Hologic instrument were assigned significantly lower values. This study shows effective comnparability between these two instruments for absolute and relative values for the lumbar spine, as well as for absolute values at the femoral neck, but important differences for normality assignments at the femoral neck. These latter differences may produce bias in the “diagnosis” of femoral neck osteoporosis and may have important implications for clinical decision making. Until these differences are resolved, clinicians should not rely solely on femoral neck BMD measurements in clinical decision making.

Controversy exists about rates of bone mineral loss from the lumbar spine at the menopause. Cross-sectional studies of lumbar bone mineral against age have been interpreted as evidence for or against a menopause-related change in lumbar bone loss, depending on their goodness of fit to either linear or nonlinear equations. To investigate the ability of cross-sectional studies to detect accelerated lumbar bone loss at the menopause, we constructed models of different patterns of loss and evaluated the findings in cross-sectional analyses of computer-simulated populations of normal women. A sample size of >300 was needed to distinguish between linear and nonlinear patterns of bone loss with a power of 90% when the data was analyzed throughout life. Examining for differences between the slopes of the regressions of pre- and postmenopausal women was more useful for detecting nonlinear bone loss under some circumstances. A difference between slopes was apparent in studies containing 100 subjects if lumbar bone density (BMD) was assumed to be unchanged prior to the menopause, but a larger study size was needed (> 1000) if BMD was assumed to fall before the menopause. We also measured lumbar BMD by dual photon absorptiometry in 141 normal females. When the data was analyzed against age throughout life, a nonlinear pattern of bone loss was found, and comparison of preand postmenopausal subjects showed a significant difference in the slopes of the linear regressions. Our patient data support the concept of a relatively stable lumbar BMD prior to the menopause with a rapid but transient decline postmenopausally. The modeling studies emphasize the importance of an adequate study size in cross-sectional studies to identify accelerated lumbar bone loss at the menopause.

Osteoporotic fractures are more common in women than men. Although accelerated bone loss following the menopause is recognized as of major importance, it is generally considered that a lower peak adult bone mass in females also contributes to their increased risk of osteoporosis in later life. To examine potential sex differences in peak adult bone mass we studied 29 pairs of dizygotic twins of differing within-pair sex in whom the female twin was premenopausal (mean age 37 years, range 21-55). Bone mineral density (BMD, g/cm2) was measured at the lumbar spine and femoral neck by dual-photon absorptiometry; 22 pairs also had BMD measured in the distal and 21 pairs in the ultradistal radius by single-photon absorptiometry. There was no significant difference in usual dietary calcium intake or tobacco consumption between the twin pairs. Consistent with accepted dogma, BMD at both radial sites were higher (+27%) in the males than their female cotwins. In contrast, there was no sex difference (male versus female) in BMD (mean +/- SEM) in the femoral neck (0.96 +/- 0.02 versus 0.97 +/- 0.03), and surprisingly, the females had a greater lumbar spine BMD than their male cotwins (1.19 +/- 0.03 versus 1.26 +/- 0.03, p less than 0.05). This difference was observed despite the fact that the males were taller (p = 0.033). If the femoral neck BMD values in the females were corrected for this difference in BMI, their values (0.99 +/- 0.03 g/cm2) were significantly higher than those in their male cotwin (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Bone density measurements are currently being performed throughout the world in the diagnosis and management of osteoporosis as well as in research into this major health problem. However, it is not clear to what extent bone mineral density (BMD) values determined by dual-photon absorptiometry at one center can be applied to another. This is particularly relevant for the quantitative comparison of results from studies carried out in different laboratories. Furthermore, many centers now acquiring densitometers may not have the resources to determine their own normal range, relying instead on a "normal" range provided by the manufacturer. The question of the comparability of BMD data obtained in different centers was examined by comparing the normal range for the lumbar spine and proximal femur in 203 normal white Australian women and 892 normal white U.S. women, obtained using the same model densitometer. The two populations were compared according to decade. From superimposition of the Australian individual values on the North American normal ranges, only minor differences between the two populations were seen at any of the sites measured at any decade. None of these minor differences were statistically significant. This study shows a close similarity between BMD values in both the proximal femur and lumbar spine in normal white women in Australia and North America, provided the same model densitometer is used. Thus data obtained from different centers in populations with similar ethnic composition may be compared directly. These findings provide for the first time a sound basis for the quantitative comparison of the at times conflicting studies carried out in widely differing settings around the world.

article i nfo This meta-analysis pooled data from the four phase III clinical trials of ibandronate to assess the relationship between ibandronate dose, changes in bone mineral density, and rates of both clinical and non-vertebral fractures. Individual patient data from the intent-to-treat population of the BONE, IV fracture prevention, MOBILE, and DIVA studies were included for analysis. The relationship between ibandronate dose and bone mineral density at both the lumbar spine and at the total hip was assessed qualitatively. The relationship between lumbar spine bone mineral density and clinical fracture rate, and the relationship between total hip bone mineral density and non-vertebral fracture rate, were assessed both qualitatively and using mathematical models. A total of 8710 patients were included in this analysis. Both lumbar spine and total hip bone mineral density were observed to increase with increasing ibandronate dose. The incidence of all clinical fractures was observed to decrease as lumbar spine bone mineral density increased. A statistically significant inverse linear relationship was observed between percent change in lumbar spine bone mineral density and the rate of clinical fractures (P=0.005). A non-significant curvilinear relationship was observed between percent change in total hip bone mineral density and non-vertebral fracture rate. Increased ibandronate exposure is associated with increasing gains in the lumbar spine bone mineral density and decreasing clinical fracture rates. A non-linear relationship may exist between increases in the total hip bone mineral density and non- vertebral fracture rate.

Introduction: Glucocorticoids have major effects on bone metabolism, leading to accelerated osteoporosis and fracture. Methods: This review will attempt to summarize current knowledge about their effects in light of new information and important remaining questions, especially with respect to management of this common clinical problem. Results: Glucocorticoids affect bone through multiple pathways, influencing both bone formation and bone resorption. Evidence from randomised trials suggests that postmenopausal women receiving glucocorticoids are at greatest risk of rapid bone loss and consequent fracture and should be actively considered for prophylaxis. Based upon available evidence, the rank order of choice for prophylaxis would be a bisphosphonate followed by vitamin D. For established glucocorticoid induced osteoporosis, parathyroid hormone followed by a bisphosphonate appears useful. Conclusions: Glucocorticoid-induced bone loss can be effectively prevented or reversed.

Objective: To determine the impact of awareness-raising strategies of calcium and vitamin D supplements in the active management of bone health of older people living in nursing care facilities in Australia. Design: We compared data drawn from two prospective cohort studies that have evaluated falls and fractures in older people living in hostels (intermediate care facilities): the FREE study (conducted from 1996–2002, n = 1107) and the ongoing FREEDOM study (commenced in 2006, n = 1284 screened individuals). Both studies recruited older people living in a large number of nursing care facilities in northern Sydney (Australia). Results: We found a small but significant increase in both calcium and vitamin D supplementation in the FREEDOM study participants compared to those in the FREE study. Calcium alone increased from 6.2% to 10.5% (P = 0.0002), vitamin D alone from 5.8% to 7.9% (P = 0.04) and the combined use of calcium and vitamin D increased from 1.6% to 11.9% (P

Intrusive pain is likely to have a serious impact on older people with limited ability to respond to additional stressors. Frailty is conceptualised as a functional and biological pattern of decline accumulating across multiple physiological systems, resulting in a decreased capacity to respond to additional stressors. We explored the relationship between intrusive pain, frailty and comorbid burden in 1705 community-dwelling men aged 70 or more who participated in the baseline phase of the CHAMP study, a large epidemiological study of healthy ageing based in Sydney, Australia. 9.4% of men in the study were frail (according to the commonly-used Cardiovascular Health Study frailty criteria).Using a combination of self-report and clinical measures, we found an association between frailty and intrusive pain that remained after accounting for demographic characteristics, number of comorbidities, self-reported depressed mood and arthritis (adjusted odds ratio 1.7 (95% confidence interval (CI) 1.1-2.7), p=0.0149). The finding that adjusting for depressed mood, but not a history of arthritis, attenuated the relationship between frailty and intrusive pain points to a key role for central mechanisms. Additionally, men with the highest overall health burden (frail plus high comorbid burden) were most likely to report intrusive pain (adjusted odds ratio 3.0 (95% CI 1.6-5.5), p=0.0004). These findings provide support for the concept that intrusive pain is an important challenge for older men with limited capacity to respond to additional physical stressors. To our knowledge, this is the first study to explore specifically the relationship between pain and frailty.

OBJECTIVES: To investigate which factors best predict whether a fall will result in a fracture. DESIGN: Prospective cohort. SETTING: Residential care facilities. PARTICIPANTS: One thousand three hundred forty-two older men and women (mean age 86.0) who had a fall. MEASUREMENTS: Clinical risk factors and bone fragility by calcaneus broadband ultrasound attenuation (BUA) were assessed at baseline, and falls and fall-related fractures were recorded for up to 2 years. All fractures were validated using X-ray reports. RESULTS: During a median follow-up of 1.97 years, 6,646 falls resulted in 308 fractures. Fracture rates were 6.7, 4.8, and 3.1 per 100 falls for BUA in the lowest (10.5-39.7 dB/MHz), middle (39.8-58.9 dB/MHz), and highest (>/=58.9dB/MHz) tertiles, respectively. In multivariate analysis, the odds ratio for any fracture was 1.17 (95% confidence interval=1.08-1.27; P Language: en

OBJECTIVE: To develop screening tools for predicting falls in nursing home and intermediate-care hostel residents who can and cannot stand unaided. DESIGN AND SETTING: Prospective cohort study in residential aged care facilities in northern Sydney, New South Wales, June 1999 - June 2003. PARTICIPANTS: 2005 people aged 65-104 years (mean +/- SD, 85.7 +/- 7.1 years). MAIN OUTCOME MEASURES: Demographic, health, and physical function assessment measures; number of falls over a 6-month period; validity of the screening models. RESULTS: Ability to stand unaided was identified as a significant event modifier for falls. In people who could stand unaided, having either poor balance or two of three other risk factors (previous falls, nursing home residence, and urinary incontinence) increased the risk of falling in the next 6 months threefold (sensitivity, 73%; specificity, 55%). In people who could not stand unaided, having any one of three risk factors (previous falls, hostel residence, and using nine or more medications) increased the risk of falling twofold (sensitivity, 87%; specificity, 29%). CONCLUSIONS: These two screening models are useful for identifying older people living in residential aged care facilities who are at increased risk of falls. The screens are easy to administer and contain items that are routinely collected in residential aged care facilities in Australia. Language: en

Background: Activated protein C (APC) is derived from its precursor, protein C (PC). Originally thought to be synthesised exclusively by the liver, recent reports have shown that PC is also produced by endothelial cells, smooth muscle cells, keratinocytes and some leukocytes. Objective: To provide an update on the emerging therapeutic effects of APC. Results/conclusion: APC functions as an anticoagulant with cytoprotective, anti-inflammatory and antiapoptotic properties. In vitro and preclinical data have revealed that APC exerts its protective effects via an intriguing mechanism requiring endothelial protein C receptor and protease activated receptor-1. Approved as a therapeutic agent for severe sepsis, APC is emerging as a potential treatment for a number of autoimmune and inflammatory diseases including spinal cord injury, asthma, chronic wounds and possibly rheumatoid arthritis. The future therapeutic uses of APC look very promising.

Epidemiological studies on ageing have tended to focus on women, a phenomenon recognized by sociologists as the feminization of ageing. However, a large percentage of older people are men. For example, in Australia, 44% of those aged 65 and over are male, as are 39% of those aged 75 years and over. Furthermore, the 5–7 year shorter life expectancy for men than women and higher death rates at all ages, including older ages, suggest that more detailed study of the health of older men is essential. Probably the best known study of the health of ageing in men is the Massachusetts Male Aging Study. However, at baseline, men in the Massachusetts Male Aging Study were relatively young, with a mean age of 58 years (range: 40–70 years). The recently established European Male Ageing Study also involves mostly younger men (range: 45–79 years). The Concord Health and Ageing in Men Project (CHAMP) was established to investigate health in old men, defined as age 70 years and over. There is no upper age limit for recruitment into CHAMP. CHAMP is funded by the National Health and Medical Research Council of Australia. Current funding is for baseline assessments and a two-year followup assessment. Additional funding will be sought to allow biennial assessments for at least 10 years. Recruitment of study subjects mainly occurred during 2005 and 2006, with the first follow-up assessments in early 2007. What does it cover?

Corticosteroid osteoporosis is a common clinical problem with the risk of fracture, highest in postmenopausal women. The first choice for prevention is a potent oral bisphosphonate such as alendronate or risedronate. In patients intolerant of oral bisphosphonates, intravenous bisphosphonates should be used. Prophylactic therapy should be continued whilst patients continue significant doses of corticosteroid therapy. In patients receiving chronic low-dose corticosteroids where the BMD is substantially reduced, other therapies such as PTH should be considered, followed by a bisphosphonate.

Summary Objective To investigate whether absence of secondary hyperparathyroidism in the presence of hypovitaminosis D has altered bone turnover, fracture risk and mortality. Design A prospective cohort study. Patients A total of 1280 older men and women living in residential care facilities. Measurements We measured baseline serum 25-hydroxyvitamin D (25OHD), serum intact PTH, serum amino-terminal propeptide of type I collagen (PINP) and serum carboxy-terminal telopeptide of type I collagen (CTX-I). Deaths and fractures were recorded prospectively. Results Hypovitaminosis D (25OHD 7·0 pmol/l) in the presence of hypovitaminosis D were common in this sample with a prevalence of 77·5% and 53·3%, respectively. In the presence of hypovitaminosis D, residents showing a hyperparathyroid response (n = 406) had significantly higher serum bone turnover markers than individuals with serum PTH levels ≤ 7·0 pmol/l (termed ‘low vitamin D, normal PTH’, n = 463). After adjusting for risk factors, mortality was significantly higher in the secondary hyperparathyroidism group than in the ‘low vitamin D, normal PTH’ group [hazard ratio (HR) = 1·35, 95% confidence interval (CI) 1·12–1·64; P = 0·002]. All residents with serum PTH levels ≤ 7·0 pmol/l (n = 603) were similar with regard to both bone turnover and mortality, independent of their actual vitamin D status. Conclusion Absence of secondary hyperparathyroidism in the presence of hypovitaminosis D appears to be common in the frail elderly and is associated with longer survival, similar to that observed in vitamin D-replete elderly subjects.

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 similar to 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 (Delta BMD) was expressed as percent of gain or loss per year. Intraclass correlation coefficients for ABMD were calculated for MZ and DZ pairs. Genetic model-fitting analysis was conducted to partition the total variance of ABMD 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 Delta BMD 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 +/- 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 ABMD were 0.38, 0.49, and 0.44 for the lumbar spine, total forearm, and whole body, respectively. However, the genetic effect on ABMD 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 similar to 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.

Philip SambrookUniversity of Sydney, SydneyAbstract: Osteoporosis is a chronic condition that generally requires long-term therapy for fracture risk reduction to become apparent. Although the bisphosphonates have made a major contribution to how clinicians manage osteoporosis, compliance with therapy has generally been less in the real-world setting than seen in clinical trials. Less-frequently administered dosage regimens or nonoral routes may enhance compliance and so maximize the therapeutic benefit of bisphosphonates. Ibandronate is a nitrogen-containing bisphosphonate, whose high potency allows it to be administered orally or intravenously with extended dosing intervals. This paper will review the role of intravenous ibandronate in the treatment of postmenopausal osteoporosis.Keywords: osteoporosis, bisphosphonates, intravenous, fracture

The possibility that specific environmental factors such as smoking and estrogen use modify the genetic influences (gene–environment interaction) on bone mineral density (BMD) has not been explored in genetic epidemiological studies such as twin studies. The aim of this study was to look for evidence of gene–environment interaction in BMD determination by analyzing data collected on a large number of healthy female twins. BMD of the hip, distal forearm and lumbar spine were measured by dual-energy X-ray absorptiometry on 287 identical and 265 nonidentical volunteer female twin pairs. The environmental factors examined were hormone replacement therapy (HRT) and smoking. In genetic modeling analysis using path analysis, there was evidence of ‘HRT-specific’ genetic component of BMD variance at the forearm (50% of total variance) but not at the hip. At the lumbar spine the magnitude of the genetic component of variance in HRT users (> 60-month HRT use) was less than the genetic component of variance for little or no exposure to HRT (48% vs. 84%). There was no evidence of gene–environment interaction for smoking. The main evidence for gene–environment interaction was the finding that forearm BMD variance was influenced by a significant HRT-specific genetic component. There was also evidence that in HRT users, the genetic component of total variance for lumbar BMD was lower.

When subjects are selected on the basis of fall risk alone, therapies for osteoporosis have not been effective. In a prospective study of elderly subjects at high risk of falls, we investigated the influence of bone strength and fall risk on fracture.At baseline we assessed calcaneal bone ultrasound attenuation (BUA) as well as quantitative measures of fall risk in 2005 subjects in residential care. Incident falls and fractures were recorded (median follow-up 705 days).A total of 6646 fall events and 375 low trauma fracture events occurred. The fall rate was 214 per 100 person years and the fracture rate 12.1 per 100 person years. 82% of the fractures could be attributed to falls. Although fracture rates increased with decreasing BUA (incidence rate ratio 1.94 for lowest vs. highest BUA tertile, p0.002), incident falls also affected fracture incidence. Subjects who fell frequently (3.15 falls/per person year) were 3.35 times more likely to suffer a fracture than those who did not fall. Some fall risk factors such as balance were associated with the lowest fracture risk lowest in the worst performing group. Multivariate analysis revealed higher fall rate, history of previous fracture, lower BUA, lower body weight, cognitive impairment and better balance as significant independent risk factors for fracture.In the frail elderly, both skeletal fragility and fall risk including the frequency of exposure to falls are important determinants of fracture risk.