Changes in gait performance over several years are associated with recurrent falls status in community-dwelling older women at high risk of fracture.

BACKGROUND: Gait analysis is a recommended geriatric assessment for falls risk and sarcopenia; however, previous research utilises measurements at a single time point only. It is presently unclear how changes in gait over several years influence risk of recurrent falls in older adults. METHODS: We investigated 135 female volunteers (mean age±SD: 76.7±5.0 years; range: 70-92 years) at high risk of fracture. Gait parameters (speed, cadence, step length, step width, swing time and double support phase) were assessed using the GAITRite Electronic Walkway System at four annual clinics over ∼3.7±0.5 years. Participants reported incident falls monthly for 3.7±1.2 years. RESULTS: Increasing gait speed (odds ratio: 0.96; 95% confidence interval 0.93, 0.99) and step length (0.87; 0.77, 0.98) from baseline to final follow-up was associated with reduced likelihood of being a recurrent faller over the study period. No significant associations were observed for baseline gait parameters (all P≥0.05). At the second follow-up (2.8±0.6 years), an increase in swing time (0.65; 0.43, 0.98) was associated with reduced likelihood, while an increase in double support phase (1.31; 1.04, 1.66) was associated with increased likelihood, for being a recurrent faller in the subsequent 1.3 years following this time point. CONCLUSION: Changes in gait parameters over several years are significantly associated with the likelihood of being a recurrent faller among community-dwelling older women at high risk of fracture. Further research is required to develop gait monitoring guidelines and gait parameter decline cut points that may be utilised by clinicians to identify older adults at risk of incident falls and sarcopenia.

Dominant negative MCP-1 blocks human osteoclast differentiation.

Human osteoclasts were differentiated using receptor activator of NFκB ligand (RANKL) and macrophage colony stimulating factor (M-CSF) from colony forming unit-granulocyte macrophage (CFU-GM) precursors of the myeloid lineage grown from umbilical cord blood. Gene expression profiling using quantitative polymerase chain reaction (Q-PCR) showed more than 1,000-fold induction of chemokine MCP-1 within 24 h of RANKL treatment. MCP-1 mRNA content exceeds that of other assayed chemokines (CCL1, 3, 4, and 5) at all time points up to day 14 of treatment. MCP-1 induction preceded peak induction of calcium signaling activator calmodulin 1 (CALM1) and transcription factors JUN and FOS, which were at 3 days. Key osteoclast related transcription factors NFATc1 and NFATc2 showed peak induction at 7 days, while marker genes for osteoclast function cathepsin K and tartrate resistance acid phosphatase (TRAP) were maximally induced at 14 days, corresponding with mature osteoclast function. To test whether the early and substantial peak in MCP-1 expression is part of human osteoclast differentiation events, a dominant negative inhibitor of MCP-1 (7ND) was added simultaneously with RANKL and M-CSF, resulting in blockade of CALM1, JUN and NFATc2 induction and strong inhibition of human osteoclast differentiation. These data show that a cascade of gene expression leading to osteoclast differentiation depends on intact early MCP-1 induction and signaling in human osteoclasts.

Endogenous parathyroid hormone is associated with reduced cartilage volume in vivo in a population-based sample of adult women.

OBJECTIVES: Animal and in vitro studies suggest that parathyroid hormone (PTH) may affect articular cartilage. However, little is known of the relationship between PTH and human joints in vivo. DESIGN: Longitudinal. SETTING: Barwon Statistical Division, Victoria, Australia. PARTICIPANTS: 101 asymptomatic women aged 35-49 years (2007-2009) and without clinical knee osteoarthritis, selected from the population-based Geelong Osteoporosis Study. RISK FACTORS: Blood samples obtained 10 years before (1994-1997) and stored at -80°C for random batch analyses. Serum intact PTH was quantified by chemiluminescent enzyme assay. Serum 25-hydroxyvitamin D (25(OH)D) was assayed using equilibrium radioimmunoassay. Models were adjusted for age, bone area and body mass index; further adjustment was made for 25(OH)D and calcium supplementation. OUTCOME: Knee cartilage volume, measured by MRI. RESULTS: A higher lnPTH was associated with reduced medial-but not lateral-cartilage volume (regression coefficient±SD, p value: -72.2±33.6 mm(3), p=0.03) after adjustment for age, body mass index and bone area. Further sinusoidal adjustment (-80.8±34.4 mm(3), p=0.02) and 25(OH)D with seasonal adjustment (-72.7±35.1 mm(3), p=0.04), calcium supplementation and prevalent osteophytes did not affect the results. CONCLUSIONS: A higher lnPTH might be detrimental to knee cartilage in vivo. Animal studies suggest that higher PTH concentrations reduce the healing ability of cartilage following minor injury. This may be apparent in the presence of increased loading, which occurs in the medial compartment, placing the medial cartilage at higher risk for injury.

Common variants in the region around Osterix are associated with bone mineral density and growth in childhood.

Peak bone mass achieved in adolescence is a determinant of bone mass in later life. In order to identify genetic variants affecting bone mineral density (BMD), we performed a genome-wide association study of BMD and related traits in 1518 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). We compared results with a scan of 134 adults with high or low hip BMD. We identified associations with BMD in an area of chromosome 12 containing the Osterix (SP7) locus, a transcription factor responsible for regulating osteoblast differentiation (ALSPAC: P = 5.8 x 10(-4); Australia: P = 3.7 x 10(-4)). This region has previously shown evidence of association with adult hip and lumbar spine BMD in an Icelandic population, as well as nominal association in a UK population. A meta-analysis of these existing studies revealed strong association between SNPs in the Osterix region and adult lumbar spine BMD (P = 9.9 x 10(-11)). In light of these findings, we genotyped a further 3692 individuals from ALSPAC who had whole body BMD and confirmed the association in children as well (P = 5.4 x 10(-5)). Moreover, all SNPs were related to height in ALSPAC children, but not weight or body mass index, and when height was included as a covariate in the regression equation, the association with total body BMD was attenuated. We conclude that genetic variants in the region of Osterix are associated with BMD in children and adults probably through primary effects on growth.

Annual high-dose vitamin D3 and mental well-being: randomised controlled trial.

BACKGROUND: Epidemiological evidence supports a relationship between vitamin D and mental well-being, although evidence from large-scale placebo-controlled intervention trials is lacking. AIMS: To examine if vitamin D supplementation has a beneficial effect on mood in community-dwelling older women; if a single annual large dose of vitamin D has a role in the prevention of depressive symptoms; and if there is an association between serum 25-hydroxyvitamin D levels and mental health. METHOD: A double-blind, randomised, placebo-controlled trial of women aged 70 or older (the Vital D Study: ISRCTN83409867 and ACTR12605000658617). Participants were randomly assigned to receive 500 000 IU vitamin D(3) (cholecalciferol) orally or placebo every autumn/winter for 3-5 consecutive years. The tools utilised at various time points were the General Health Questionnaire, the 12-item Short Form Health Survey, the Patient Global Impression-Improvement scale and the WHO Well-Being Index. Serum 25-hydroxyvitamin D levels were measured in a subset of 102 participants. RESULTS: In this non-clinical population, no significant differences between the vitamin D and placebo groups were detected in any of the measured outcomes of mental health. Serum 25-hydroxyvitamin D levels in the vitamin D group were 41% higher than the placebo group 12 months following their annual dose. Despite this difference, scores from the questionnaires did not differ. Furthermore, there was no interaction between those on antidepressant/anxiety medication at baseline and the treatment groups. CONCLUSIONS: The lack of improvement in indices of mental well-being in the vitamin D group does not support the hypothesis that an annual high dose of vitamin D(3) is a practical intervention to prevent depressive symptoms in older community-dwelling women.

The Cost of Osteoporosis, Osteopenia, and Associated Fractures in Australia in 2017.

Osteoporosis and osteopenia are increasingly prevalent conditions among older adults. Not only do the fractures associated with poor bone health have significant health consequences for the individual, but also their economic impact is placing increasing financial burden on governments and society. This study aimed to determine the direct economic cost of osteoporosis, osteopenia, and fractures among Australians aged 50 years and older in 2017. This study uses previous Australian data on the incidence and prevalence of osteoporosis and osteopenia together with recent Australian data on health service utilization after fracture to provide an estimate of the economic burden of osteoporosis. A bottom-up costing approach was used to determine the average direct health care and non-health care total costs of a fracture, as well as the average community health service costs of managing individuals with osteoporosis or osteopenia. The total direct cost of osteoporosis in Australia in 2017 was estimated to be $3.44 billion (AUD 2017, USD 2.77 billion). Treatment of fractures accounted for 68% of total direct costs, and non-fracture management of osteoporosis accounted for 32%. Hip fractures accounted for the highest proportion (43%) of the total direct cost of fractures, although fractures at "other" sites accounted for 38.5%. Fractures among individuals aged 70 years and older accounted for 74% of the direct costs (55% and 19% in women and men, respectively). Fracture costs in those with osteopenia accounted for 50% of direct fracture treatment costs. This up-to-date cost analysis estimated that costs in 2017 were three times higher than in 2007. These estimates will aid clinicians, policy makers, researchers, and health care organizations to acknowledge the economic importance of reducing osteoporosis-related fractures and associated costs. This provides a strong public health case to promote bone health that will assist in reducing future fracture-related costs. © 2018 American Society for Bone and Mineral Research.

Identification of a major locus for Paget's disease on chromosome 10p13 in families of British descent.

UNLABELLED: Mutations of SQSTM1 are an important cause of PDB, but other genes remain to be discovered. A major susceptibility locus for PDB was identified on chromosome 10p13 by a genome-wide linkage scan in families of British descent, which accounted for the vast majority of cases not caused by SQSTM1 mutations. INTRODUCTION: Paget's disease of bone (PDB) has a strong genetic component, and several susceptibility loci have been identified by genome-wide linkage scans. We previously identified three susceptibility loci for PDB using this approach on chromosomes 5q35, 2q36, and 10p13 in 62 families of mainly British descent, but subsequently, mutations in the SQSTM1 gene were found to be the cause of PDB in 23 families from this cohort. Here we reanalyzed the results of our genome-wide search in families from this cohort who did not have SQSTM1 mutations. MATERIALS AND METHODS: The study population consisted of 210 individuals from 39 families of predominantly British descent with autosomal dominant inheritance of PDB in whom SQSTM1 mutations had been excluded by mutation screening. The average family size was 5.44 +/- 3.98 (SD) individuals (range, 2-24 individuals). Genotyping was performed using standard techniques with 382 microsatellite markers spaced at an average distance of 9.06 cM throughout the autosomes. Multipoint linkage analysis was performed using the GENEHUNTER program under models of homogeneity and heterogeneity. RESULTS: Multipoint parametric linkage analysis under a model of homogeneity and nonparametric linkage analysis under a model of heterogeneity both showed strong evidence of linkage to a single locus on chromosome 10p13 (LOD score, +4.08) close to the marker D10S1653 at 41.43cM. No evidence of linkage was detected at the chromosome 2q36 locus previously identified in this population, and linkage to other candidate loci previously implicated in the pathogenesis of PDB was excluded. CONCLUSIONS: We conclude that there is an important susceptibility gene for PDB on chromosome 10p13 in families of British descent and find no evidence to support the existence of a susceptibility locus on chromosome 2q36 or other previously identified candidate loci for PDB in this population. The gene that lies within the 10p13 locus seems to account for the development of PDB in the vast majority of families of British descent who do not carry SQSTM1 mutations.

The Association Between Anxiety and Falls: A Meta-Analysis.

OBJECTIVES: Falls occur frequently among older adults and can lead to a range of adverse and debilitating outcomes. Although symptoms of clinical anxiety have been implicated as risk factors for falls, there is no current consensus on the empirical association between anxiety and falls. The current study aimed to address this gap in the literature by conducting a quantitative, meta-analytic review of findings from previous studies. METHOD: A systematic literature search of bibliographic databases was conducted, yielding 18 studies that fit the criteria for inclusion in the meta-analysis. RESULTS: A random-effects model of all 18 studies showed a significant overall odds ratio of 1.53 (95% CI 1.28-1.83, p < .001), indicating that elevated levels of anxiety were associated with a 53% increased likelihood of falls. A high amount of variance among effect sizes was observed. Only age was identified as a moderator of this relationship in a subgroup of the samples. CONCLUSIONS: Clinical anxiety is associated with falls, however, further research is required to elucidate the factors that might moderate or mediate this relationship, the casual pathways through which they are related, and the associations between different types of anxiety and falls.

Association of functionally different RUNX2 P2 promoter alleles with BMD.

UNLABELLED: RUNX2 gene SNPs were genotyped in subjects from the upper and lower deciles of age- and weight-adjusted femoral neck BMD. Of 16 SNPs in RUNX2 and its two promoters (P1 and P2), only SNPs in the P2 promoter were significantly associated with BMD. These P2 promoter SNPs were functionally different in gel-shift and promoter activity assays. INTRODUCTION: Specific osteoblast genes are induced by Runx2, a cell-specific transcription factor that is a candidate gene for controlling BMD. We tested the hypothesis that RUNX2 genetic variation is associated with BMD. MATERIALS AND METHODS: From a population repository of normal subjects, the age- and weight-adjusted femoral neck BMD was ranked, and the upper and lower deciles (n = 132 each) were taken to represent the adjusted extremes of the population distribution. In these 264 subjects, we identified 16 allelic variations within the RUNX2 gene and promoters (P1 and P2) through DNA sequencing and denaturing high-performance liquid chromatography. Characterization of these alleles was performed through allele-specific cloning, transfection into ROS 17/2.8 cells, luciferase reporter analysis, and electrophoretic mobility shift assays. RESULTS: Within the P2 promoter were three polymorphic nucleotides for which the minor alleles were over-represented in the upper decile of BMD (0.117 and 0.064 in the upper and lower deciles, respectively). These alleles are in near complete linkage disequilibrium with each other and represent a haplotype block that is significantly associated with increased BMD. The common and rare P2 promoter alleles were cloned upstream of luciferase, and when transfected into osteoblast-like cells, the construct representing the rare haplotype showed significantly greater P2 promoter activity than the common haplotype. CONCLUSIONS: Because the high BMD allele had higher P2 promoter activity, the data suggest that greater RUNX2 P2 promoter activity is associated with higher BMD.

Evaluation of the role of Valosin-containing protein in the pathogenesis of familial and sporadic Paget's disease of bone.

Paget's disease of bone (PDB) is a common metabolic bone disease of late onset with a strong genetic component. Rarely, PDB can occur as part of a syndrome in which the disease is accompanied by inclusion body myopathy and frontotemporal dementia (inclusion body myopathy, Paget's disease and frontotemporal dementia, IBMPFD). Recently, IBMPFD has been shown to be caused by mutations in Valosin-containing Protein (VCP), which is required for the proteasomal degradation of phosphorylated IkappaB-alpha, a necessary step in the activation of the transcription factor NF-kappaB. Here, we evaluated the role of VCP in the pathogenesis of typical PDB. We conducted mutation screening of VCP in 44 kindreds with familial Paget's disease recruited mainly through clinic referrals in the UK, Australia and New Zealand. We also performed an association study of VCP haplotypes in patients with PDB who did not have a family history of the disease (sporadic PDB). No mutations were found in VCP in three PDB families where there was evidence of allele sharing between affected subjects in the VCP critical region on chromosome 9p13. We failed to detect disease-associated mutations in any of the three exons previously reported to contain IBMPFD mutations in a further 41 PDB families. We found no evidence of allelic association between common VCP haplotypes in a case-control study of 179 sporadic PDB patients and 172 age- and sex-matched controls. Genetic variation in VCP does not appear to be a common cause of familial or sporadic PDB in the absence of myopathy and dementia.

Ubiquitin-associated domain mutations of SQSTM1 in Paget's disease of bone: evidence for a founder effect in patients of British descent.

UNLABELLED: Mutations in the UBA domain of SQSTM1 are a common cause of Paget's disease of bone. Here we show that the most common disease-causing mutation (P392L) is carried on a shared haplotype, consistent with a founder effect and a common ancestral origin. INTRODUCTION: Paget's disease of bone (PDB) is a common condition with a strong genetic component. Mutations affecting the ubiquitin-associated (UBA) domain of sequestosome 1 (SQSTM1) have recently been shown to be an important cause of PDB. The most common mutation results in a proline to leucine amino acid change at codon 392 (P392L), and evidence has been presented to suggest that there may be a recurrent mutation rather than a founder mutation on an ancestral chromosome. Because marked geographical differences exist in the prevalence of PDB, we have investigated the frequency of SQSTM1 mutations in different populations and looked for a founder effect on chromosomes bearing SQSTM1 UBA domain mutations. MATERIALS AND METHODS: We conducted mutation screening of SQSTM1 and performed haplotype analysis using the PHASE software program in 83 kindreds with familial PDB, recruited mainly through clinic referrals in the United Kingdom, Australia, and New Zealand. Similar studies were conducted in 311 individuals with PDB who did not have a family history and 375 age- and sex-matched controls from the United Kingdom. RESULTS: The proportion of patients with familial PDB who had SQSTM1 UBA domain mutations varied somewhat between referral centers from 7.1% (Sydney, Australia) to 50% (Perth, Australia), but the difference between centers was not statistically significant. Haplotype analysis in 311 British patients with PDB who did not have a family history and 375 age- and sex-matched British controls showed that two common haplotypes accounted for about 90% of alleles at the SQSTM1 locus, as defined by common single nucleotide polymorphisms (SNPs) in exon 6 (C916T, G976A) and the 3'UTR (C2503T, T2687G). These were H1 (916T-976A-2503C-2687T) and H2 (916C-976G-2503T-2687G). There was no significant difference in haplotype distribution in PDB cases and controls, but the P392L mutation was found on the H2 haplotype in 25/27 cases (93%), which is significantly more often than expected given the allele frequencies in the normal population (odds ratio, 13.2; 95% CI, 3.1-56.4; p < 0.0001). Similar findings were observed in familial PDB, where 12/13 (92%) of P392L mutations were carried on H2 (odds ratio 17.2; 95% CI, 2.2-138; p = 0.001). CONCLUSIONS: These results provide strong evidence for a founder effect of the SQSTM1 P392L mutation in PDB patients of British descent, irrespective of family history. Our results imply that these individuals share a common ancestor and that the true rate of de novo mutations may be lower than previously suspected.

Depression and bone mineral density in a community sample of perimenopausal women: Geelong Osteoporosis Study.

OBJECTIVE: Reduced bone mineral density (BMD) in women with a history of depressive disorders has been shown in some, but not all studies. This study investigated the association between self-reported depression and BMD in an age-stratified community sample of perimenopausal women residing in the South-Eastern region of Australia. DESIGN: Symptoms of depression in the year between July 2000 and July 2001 were ascertained by a self-report questionnaire based on Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria. Women in the perimenopausal group who had undergone a BMD total hip and spine assessment within the 12-month period after the depression assessment were included in the analysis, resulting in a sample of 78 women aged 45 to 60 years. RESULTS: In this sample, 14 women were identified as depressed. There was no difference in age, hormone therapy (HT) use, or unadjusted BMD at the total hip or spine between the depressed and nondepressed women (P = 0.14, 0.89, 0.57, and 0.70, respectively), but the depressed women tended to be heavier [depressed (median weight, interquartile range = 80 kg, 66-94) vs nondepressed (72 kg, 61-80) P = 0.06]. Whereas there was no significant difference in age-, HT-, and weight-adjusted BMD at the spine [depressed (mean +/- SE = 1.21 +/- 0.05) vs nondepressed (1.28 +/- 0.03 g/cm(2)) P = 0.18], adjusted BMD at the total hip for the depressed women was 7.8% lower than for the nondepressed [depressed (mean +/- SE = 0.957 +/- 0.038) vs nondepressed (1.038 +/- 0.023 g/cm(2)) P = 0.04]. CONCLUSIONS: These results suggest that in perimenopausal women, self-reported depression is associated with lower BMD at the hip.

Validity of 12-Month Falls Recall in Community-Dwelling Older Women Participating in a Clinical Trial.

Objectives. To compare 12-month falls recall with falls reported prospectively on daily falls calendars in a clinical trial of women aged ≥70 years. Methods. 2,096 community-dwelling women at high risk of falls and/or fracture completed a daily falls calendar and standardised interviews when falls were recorded, for 12 months. Data were compared to a 12-month falls recall question that categorised falls status as "no falls," "a few times," "several," and "regular" falls. Results. 898 (43%) participants reported a fall on daily falls calendars of whom 692 (77%) recalled fall(s) at 12 months. Participants who did not recall a fall were older (median 79.3 years versus 77.8 years, P = 0.028). Smaller proportions of fallers who sustained an injury or accessed health care failed to recall a fall (all P < 0.04). Among participants who recalled "no fall," 85% reported zero falls on daily calendars. Few women selected falls categories of "several times" or "regular" (4.1% and 0.4%, resp.) and the sensitivity of these categories was low (30% to 33%). Simply categorising participants into fallers or nonfallers had 77% sensitivity and 94% specificity. Conclusion. For studies where intensive ascertainment of falls is not feasible, 12-month falls recall questions with fewer responses may be an acceptable alternative.

Alleles of RUNX2/CBFA1 gene are associated with differences in bone mineral density and risk of fracture.

The aim of this study was to determine if DNA polymorphism within runt-related gene 2 (RUNX2)/core binding factor A1 (CBFA1) is related to bone mineral density (BMD). RUNX2 contains a glutamine-alanine repeat where mutations causing cleidocranial dysplasia (CCD) have been observed. Two common variants were detected within the alanine repeat: an 18-bp deletion and a synonymous alanine codon polymorphism with alleles GCA and GCG (noted as A and G alleles, respectively). In addition, rare mutations that may be related to low BMD were observed within the glutamine repeat. In 495 randomly selected women of the Geelong Osteoporosis Study (GOS), the A allele was associated with higher BMD at all sites tested. The effect was maximal at the ultradistal (UD) radius (p = 0.001). In a separate fracture study, the A allele was significantly protective against Colles' fracture in elderly women but not spine and hip fracture. The A allele was associated with increased BMD and was protective against a common form of osteoporotic fracture, suggesting that RUNX2 variants may be related to genetic effects on BMD and osteoporosis.

Prevention and treatment of glucocorticoid-induced osteoporosis: a comparison of calcitriol, vitamin D plus calcium, and alendronate plus calcium.

High-dose corticosteroids, used for many medical conditions, are associated with rapid bone loss from sites such as the vertebrae, and compression fractures can be observed within months. Recent trials suggest treatment with bisphosphonates or active vitamin D analogs can reduce bone loss and the risk of fracture associated with glucocorticoids, but few studies have directly compared such agents. We conducted a randomized, multicenter, open-label trial to compare the efficacy of alendronate, calcitriol, and simple vitamin D in prevention and treatment of glucocorticoid-induced bone loss. A total of 195 subjects (134 females and 61 males) commencing or already taking glucocorticoids were randomized to one of three groups: calcitriol, 0.5 to 0.75 microg/day; simple vitamin D (ergocalciferol, 30,000 IU weekly) plus calcium carbonate (600 mg daily); or alendronate, 10 mg/day plus calcium carbonate (600 mg daily). Over 2 years, mean lumbar bone mineral density change was +5.9% with alendronate, -0.5% with ergocalciferol, and -0.7% with calcitriol (p < 0.001). At the femoral neck, there was no significant difference in bone mineral density change between the treatments over 2 years: alendronate (+0.9%), ergocalciferol (-3.2%), and calcitriol (-2.2%). Lumbar bone loss varied according to whether patients were starting or receiving chronic glucocorticoids, and there was a significant treatment x prior glucocorticoid use interaction effect. Six of 66 calcitriol subjects, 1 of 61 ergocalciferol subjects, and 0 of 64 alendronate subjects sustained new vertebral fractures. These data do not suggest any difference between simple vitamin D and calcitriol but do show that alendronate was superior to either treatment for glucocorticoid induced bone loss.

Susceptibility to Paget's disease of bone is influenced by a common polymorphic variant of osteoprotegerin.

UNLABELLED: To clarify the role of the TNFRSF11B gene encoding osteoprotegerin (OPG), in Paget's disease of bone (PDB) we studied TNFRSF11B polymorphisms in an association study of 690 UK subjects and in a worldwide familial study of 66 kindreds. We found that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to both sporadic and familial PDB. INTRODUCTION: Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of bone turnover. Genetic factors are important in the pathogenesis of PDB, and studies have shown that inactivating mutations of the TNFRSF11B gene, encoding osteoprotegerin (OPG), cause the rare syndrome of juvenile Paget's disease. In this study, we sought to determine whether polymorphisms of the TNFRSF11B gene contribute to the pathogenesis of classical PDB. MATERIALS AND METHODS: We screened for polymorphisms of the TNFRSF11B gene by DNA sequencing of the proximal promoter, coding exons, and intron-exon boundaries in 20 PDB patients and 10 controls. Informative single nucleotide polymorphisms (SNPs), including a G1181C SNP, which predicts a lysine-asparagine substitution at codon 3 of the OPG signal peptide and haplotypes, were related to the presence of PDB in 312 cases compared with 378 controls and to transmission of PDB in 140 affected offspring from 66 kindreds with familial PDB. RESULTS AND CONCLUSIONS: The G1181 allele was significantly over-represented in PDB patients (chi(2) = 5.7, df = 1, p = 0.017, adjusted alpha = 0.024), equivalent to an odds ratio for PDB of 1.55 (95% CI: 1.11-2.16). The distribution of TNFRSF11B haplotypes significantly differed in sporadic PDB cases and controls (chi(2) = 30.2, df = 9, p < 0.001) because of over-representation of haplotypes containing the G1181 allele in cases. The family study showed that the most common haplotype containing the G1181 allele was transmitted more frequently than expected to 140 individuals with familial PDB (chi(2) = 7.35, df = 1, p < 0.01), and the transmission disequilibrium was even more pronounced in a subgroup of 78 familial PDB patients who did not carry mutations of the SQSTM1 gene (chi(2) = 8.44, df = 1, p < 0.005). We conclude that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to the development of sporadic PDB and familial PDB that is not caused by SQSTM1 mutations.

Novel UBA domain mutations of SQSTM1 in Paget's disease of bone: genotype phenotype correlation, functional analysis, and structural consequences.

UNLABELLED: Three novel missense mutations of SQSTM1 were identified in familial PDB, all affecting the UBA domain. Functional and structural analysis showed that disease severity was related to the type of mutation but was unrelated to the polyubiquitin-binding properties of the mutant UBA domain peptides. INTRODUCTION: Mutations affecting the ubiquitin-associated (UBA) domain of Sequestosome 1 (SQSTM1) gene have recently been identified as a common cause of familial Paget's disease of bone (PDB), but the mechanisms responsible are unclear. We identified three novel SQSTM1 mutations in PDB, conducted functional and structural analyses of all PDB-causing mutations, and studied the relationship between genotype and phenotype. MATERIALS AND METHODS: Mutation screening of the SQSTM1 gene was conducted in 70 kindreds with familial PDB. We characterized the effect of the mutations on structure of the UBA domain by protein NMR, studied the effects of the mutant UBA domains on ubiquitin binding, and looked at genotype-phenotype correlations. RESULTS AND CONCLUSIONS: Three novel missense mutations affecting the SQSTM1 UBA domain were identified, including a missense mutation at codon 411 (G411S), a missense mutation at codon 404 (M404V), and a missense mutation at codon 425 (G425R). We also identified a deletion leading to a premature stop codon at 394 (L394X). None of the mutations were found in controls. Structural analysis showed that M404V and G425R involved residues on the hydrophobic surface patch implicated in ubiquitin binding, and consistent with this, the G425R and M404V mutants abolished the ability of mutant UBA domains to bind polyubiquitin chains. In contrast, the G411S and P392L mutants bound polyubiquitin chains normally. Genotype-phenotype analysis showed that patients with truncating mutations had more extensive PDB than those with missense mutations (bones involved = 6.05 +/- 2.71 versus 3.45 +/- 2.46; p < 0.0001). This work confirms the importance of UBA domain mutations of SQSTM1 as a cause of PDB but shows that there is no correlation between the ubiquitin-binding properties of the different mutant UBA domains and disease occurrence or extent. This indicates that the mechanism of action most probably involves an interaction between SQSTM1 and a hitherto unidentified protein that modulates bone turnover.

Musculoskeletal deterioration in men accompanies increases in body fat.

OBJECTIVE: To examine body fat and musculoskeletal changes in men over 5 years. METHODS: Body composition was evaluated for men in the Geelong Osteoporosis Study using whole body dual energy X-ray absorptiometry (DXA) during two time-periods. DXA was performed for 1329 men (25-96 years) during 2001-2006 and for 900 men (25-98 years), 2006-2011. The masses of fat, lean, and bone were expressed relative to the square of height (kg/m2). Each compartment was also expressed as a percentage relative to body weight (%fat, %lean, %bone). RESULTS: Mean BMI increased from 26.9 kg/m2 in 2001-2006, to 27.2 kg/m2 in 2006-2011 (P = 0.04). Mean fat mass increased by 9.0% from 6.98 kg/m2 (95% CI 6.84-7.11) in 2001-2006, to 7.60 kg/m2 (7.44-7.77) in 2006-2011 (P < 0.001); mean lean mass decreased by 0.9%, from 18.92 kg/m2 (18.83-19.01) to 18.75 kg/m2 (18.64-18.86) (P = 0.02), and mean bone mass decreased 1.6% from 1.041 kg/m2 (1.034-1.047), to 1.024 kg/m2 (1.016-1.032). Mean %fat increased from 23.4% to 25.2%, mean %lean decreased from 72.6% to 70.9% and mean %bone decreased from 4.0% to 3.9% (all P < 0.05). CONCLUSIONS: An increase in BMI, which reflects a substantial increase in body fat mass and declines in both lean and bone mass was reported. This may have implications for future development of bone fragility, sarcopenia, and sarcopenic obesity.