Genetic determinants of bone density and fracture risk: State of the art and future directions

Context: Osteoporosis is a common, highly heritable condition that causes substantial morbidity and mortality, the etiopathogenesis of which is poorly understood. Genetic studies are making increasingly rapid progress in identifying the genes involved. Evidence Acquisition and Synthesis: In this review, we will summarize the current understanding of the genetics of osteoporosis based on publications from PubMed from the year 1987 onward. Conclusions: Most genes involved in osteoporosis identified to date encode components of known pathways involved in bone synthesis or resorption, but as the field progresses, new pathways are being identified. Only a small proportion of the total genetic variation involved in osteoporosis has been identified, and new approaches will be required to identify most of the remaining genes.

Partial intervertebral fusion secures successful outcomes after thoracoscopic anterior scoliosis correction: A low-dose computed tomography study

Study Design Retrospective review of prospectively collected data. Objectives To analyze intervertebral (IV) fusion after thoracoscopic anterior spinal fusion (TASF) and explore the relationship between fusion scores and key clinical variables. Summary of Background Information TASF provides comparable correction with some advantages over posterior approaches but reported mechanical complications, and their relationship to non-union and graft material is unclear. Similarly, the optimal combination of graft type and implant stiffness for effecting successful radiologic union remains undetermined. Methods A subset of patients from a large single-center series who had TASF for progressive scoliosis underwent low-dose computed tomographic scans 2 years after surgery. The IV fusion mass in the disc space was assessed using the 4-point Sucato scale, where 1 indicates <50% and 4 indicates 100% bony fusion of the disc space. The effects of rod diameter, rod material, graft type, fusion level, and mechanical complications on fusion scores were assessed. Results Forty-three patients with right thoracic major curves (mean age 14.9 years) participated in the study. Mean fusion scores for patient subgroups ranged from 1.0 (IV levels with rod fractures) to 2.2 (4.5-mm rod with allograft), with scores tending to decrease with increasing rod size and stiffness. Graft type (autograft vs. allograft) did not affect fusion scores. Fusion scores were highest in the middle levels of the rod construct (mean 2.52), dropping off by 20% to 30% toward the upper and lower extremities of the rod. IV levels where a rod fractured had lower overall mean fusion scores compared to levels without a fracture. Mean total Scoliosis Research Society (SRS) questionnaire scores were 98.9 from a possible total of 120, indicating a good level of patient satisfaction. Conclusions Results suggest that 100% radiologic fusion of the entire disc space is not necessary for successful clinical outcomes following thoracoscopic anterior selective thoracic fusion.

Osteopenia and rickets in the extremely low birth weight infant: A survey of the incidence and a radiological classification

A review was carried out of the radiographs of twenty-five infants with birth weights under 1000 G, who survived for more than twenty-eight days; eighteen of these had enough suitable films for a survey of the progressive bone changes which occur in these infants, including estimation of humeral cortical cross-sectional area. The incidence of the changes has been assessed and a typical progression of radiographic appearances has been shown, with a suggested system of staging. All infants showed some loss of bone mineral, with frank changes of rickets occurring in forty-four percent. Aetiological factors are mainly concerned with the difficulty of supplying and ensuring absorption of sufficient bone mineral (calcium and phosphate) and vitamin D. Liver immaturity may be another factor. Disease states additional to prematurity accentuate the problem. Rib fractures occurring around 80–90 days post-nataEy commonly draw attention to the bone disorder and are probably the major clinical factor of importance; there is a high incidence of associated lung disease of uncertain pathology. Attention is drawn to possible confusion with other bone disorders in the post-natal period.

Risk assessment of wandering behavior in mild dementia

Objective This prospective longitudinal study aims to determine the risk factors of wandering-related adverse consequences in community-dwelling persons with mild dementia. These adverse consequences include negative outcomes of wandering (falls, fractures, and injuries) and eloping behavior. Methods We recruited 143 dyads of persons with mild dementia and their caregivers from a veteran's hospital and memory clinic in Florida. Wandering-related adverse consequences were measured using the Revised Algase Wandering Scale – Community Version. Variables such as personality (Big Five Inventory), behavioral response to stress, gait, and balance (Tinetti Gait and Balance), wayfinding ability (Wayfinding Effectiveness Scale), and neurocognitive abilities (attention, cognition, memory, language/verbal skills, and executive functioning) were also measured. Bivariate and logistic regression analyses were performed to assess the predictors of these wandering-related adverse consequences. Results A total of 49% of the study participants had falls, fractures, and injuries due to wandering behavior, and 43.7% demonstrated eloping behaviors. Persistent walking (OR = 2.6) and poor gait (OR = 0.9) were significant predictors of negative outcomes of wandering, while persistent walking (OR = 13.2) and passivity (OR = 2.55) predicted eloping behavior. However, there were no correlations between wandering-related adverse consequences and participants' characteristics (age, gender, race, ethnicity, and education), health status (Charlson comorbidity index), or neurocognitive abilities. Conclusion Our results highlight the importance of identifying at-risk individuals so that effective interventions can be developed to reduce or prevent the adverse consequences of wandering.

Close Encounters of the Continuum: Speaking (to), Performing and Experiencing Gender In Janet Cardiff’s Whispering Room

This 'project' investigates Janet Cardiff's Whispering Room. It examines how Cardiff deconstructs the privileging of the visual over all other corporeal senses in her work, the Whispering Room. Using sound as a fulcrum, Cardiff explores the links between subjects, collective narratives, memories, experiences and performances. Janet Cardiff destabilizes time and space and fractures the continuum through the use of sound. My 'project' celebrates sound as a transgressive medium — sound not as a gendered medium but as a vehicle in which to speak (to) gender. It explores how sound can destabilize notions of perception and reception and question art and museal practices. In the process this 'project' reveals the complexity of interpreting and representing art as an object. My aim is to reflect the very intertextual and expressionist collage that Cardiff has created in Whispering Room in my own text. Cardiff solicits the viewer's intimacy and participation. Whispering Room is a physical yet metonymic space in which Cardiff creates a place for performatvity, experience, memory, desire and speech, thus she opens up a space for the utterance and performance of the viewer. Viewers construct and create meaning/s for themselves within this mnemonic space by digging up their own memories, desires and reveries. The strength of Cardiff's work is that it relies on a viewer to perform, a body to trigger the pseudo-spectacle and a voice to interrupt the whispers. One might ask of Whispering Room where the illusionistic space begins and where the physical space ends. This 'project' investigates how in Whispering Room there is no one experience but many experiences.

Can we safely deform a plate to fit every bone? Population-based fit assessment and finite element deformation of a distal tibial plate

Anatomically precontoured plates are commonly used to treat periarticular fractures. A well-fitting plate can be used as a tool for anatomical reduction of the fractured bone. Recent studies highlighted that some plates fit poorly for many patients due to considerable shape variations between bones of the same anatomical site. While it is impossible to design one shape that fits all, it is also burdensome for the manufacturers and hospitals to produce, store and manage multiple plate shapes without the certainty of utilization by a patient population. In this study, we investigated the number of shapes required for maximum fit within a given dataset, and if they could be obtained by manually deforming the original plate. A distal medial tibial plate was automatically positioned on 45 individual tibiae, and the optimal deformation was determined iteratively using finite element analysis simulation. Within the studied dataset, we found that: (i) 89% fit could be achieved with four shapes, (ii) 100% fit was impossible through mechanical deformation, and (iii) the deformations required to obtain the four plate shapes were safe for the stainless steel plate for further clinical use. The proposed framework is easily transferable to other orthopaedic plates.

Mechanical testing of internal fixation devices: A theoretical and practical examination of current methods

Successful healing of long bone fractures is dependent on the mechanical environment created within the fracture, which in turn is dependent on the fixation strategy. Recent literature reports have suggested that locked plating devices are too stiff to reliably promote healing. However, in vitro testing of these devices has been inconsistent in both method of constraint and reported outcomes, making comparisons between studies and the assessment of construct stiffness problematic. Each of the methods previously used in the literature were assessed for their effect on the bending of the sample and concordant stiffness. The choice of outcome measures used in in vitro fracture studies was also assessed. Mechanical testing was conducted on seven hole locked plated constructs in each method for comparison. Based on the assessment of each method the use of spherical bearings, ball joints or similar is suggested at both ends of the sample. The use of near and far cortex movement was found to be more comprehensive and more accurate than traditional centrally calculated inter fragmentary movement values; stiffness was found to be highly susceptible to the accuracy of deformation measurements and constraint method, and should only be used as a within study comparison method. The reported stiffness values of locked plate constructs from in vitro mechanical testing is highly susceptible to testing constraints and output measures, with many standard techniques overestimating the stiffness of the construct. This raises the need for further investigation into the actual mechanical behaviour within the fracture gap of these devices.

Impact of malnutrition on 12-month mortality following acute hip fracture

Background Studies investigating the relationship between malnutrition and post-discharge mortality following acute hip fracture yield conflicting results. This study aimed to determine whether malnutrition independently predicted 12-month post-fracture mortality after adjusting for clinically relevant covariates. Methods An ethics approved, prospective, consecutive audit was undertaken for all surgically treated hip fracture inpatients admitted to a dedicated orthogeriatric unit (November 2010–October 2011). The 12-month mortality data were obtained by a dual search of the mortality registry and Queensland Health database. Malnutrition was evaluated using the Subjective Global Assessment. Demographic (age, gender, admission residence) and clinical covariates included fracture type, time to surgery, anaesthesia type, type of surgery, post-surgery time to mobilize and post-operative complications (delirium, pulmonary and deep vein thrombosis, cardiac complications, infections). The Charlson Comorbidity Index was retrospectively applied. All diagnoses were confirmed by the treating orthogeriatrician. Results A total of 322 of 346 patients were available for audit. Increased age (P = 0.004), admission from residential care (P < 0.001), Charlson Comorbidity Index (P = 0.007), malnutrition (P < 0.001), time to mobilize >48 h (P < 0.001), delirium (P = 0.003), pulmonary embolism (P = 0.029) and cardiovascular complication (P = 0.04) were associated with 12-month mortality. Logistic regression analysis demonstrated that malnutrition (odds ratio (OR) 2.4 (95% confidence interval (CI) 1.3–4.7, P = 0.007)), in addition to admission from residential care (OR 2.6 (95% CI 1.3–5.3, P = 0.005)) and pulmonary embolism (OR 11.0 (95% CI 1.5–78.7, P = 0.017)), independently predicted 12-month mortality. Conclusions Findings substantiate malnutrition as an independent predictor of 12-month mortality in a representative sample of hip fracture inpatients. Effective strategies to identify and treat malnutrition in hip fracture should be prioritized.

Improving diagnosis of tumor-induced osteomalacia with gallium-68 DOTATATE PET/CT

Context: Tumor-induced osteomalacia (TIO) is a rarely diagnosed disorder presenting with bone pain, fractures, muscle weakness, and moderate-to-severe hypophosphatemia resulting from fibroblast growth factor 23-mediated renal phosphate wasting. Tumors secreting fibroblast growth factor 23 are often small and difficult to find with conventional imaging. Objective: We studied the utility of 68Ga-DOTA-octreotate (DOTATATE) somatostatin receptor positron emission tomography (PET)/computed tomography (CT) imaging in the diagnosis of TIO. Design and Setting: A multicenter case series was conducted at tertiary referral hospitals. Patients and Methods: Six patients with TIO diagnosed between 2003 and 2012 in Australia were referred for DOTATATE PET imaging. We reviewed the clinical history, biochemistry, imaging characteristics, histopathology, and clinical outcome of each patient. Results: Each case demonstrated delayed diagnosis despite severe symptoms. DOTATATE PET/CT imaging demonstrated high uptake and localized the tumor with confidence in each case. After surgical excision, there was resolution of clinical symptoms and serum phosphate, except in one patient who demonstrated residual disease on PET/CT. All tumors demonstrated high somatostatin receptor subtype 2 cell surface receptor expression using immunohistochemistry. Conclusions: In patients with TIO, DOTATATE PET/CT can successfully localize phosphaturic mesenchymal tumors and may be a practical first step in functional imaging for this disorder. Serum phosphate should be measured routinely in patients with unexplained muscle weakness, bone pain, or stress fractures to allow earlier diagnosis of TIO. - See more at: http://press.endocrine.org/doi/abs/10.1210/jc.2012-3642#sthash.eXD0CopL.dpuf

Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

Physical activity and health in mid age and older Australian women

The US Surgeon General's report was a landmark publication in the field of physical activity and health, but was constrained by a lack of evidence relating to women. This report examines the links between physical activity and health in mid-age and older women. It includes four parts (i)recent evidence relating physical activity to the national public health priorities and reproductive health (ii)consideration of the amount of physical activity required to obtain health benefits (iii)new data from the Australian Longitudinal Study on Women's Health on activity patterns, including relationships between changes in physical activity and life events, sociodemographic characteristics and health behaviours in mid-age and older Australian women (iv)new data from the Australian Longitudinal Study on Women's Health on the relationships between physical activity and menopausal symptoms, stiff or painful joints and arthritis, anxiety and depression, memory problems, falls and fractures, general physical and psychological well-being, and healthcare costs in mid-age and older Australian women

The Exeter Contemporary flanged cemented acetabular component in primary total hip arthroplasty

Aims: We report on the outcome of the Exeter Contemporary flanged cemented all-polyethylene acetabular component with a mean follow-up of 12 years (10 to 13.9). This study reviewed 203 hips in 194 patients. 129 hips in 122 patients are still in situ; 66 hips in 64 patients were in patients who died before ten years, and eight hips (eight patients) were revised. Clinical outcome scores were available for 108 hips (104 patients) and radiographs for 103 hips (100 patients). Patients and Methods: A retrospective review was undertaken of a consecutive series of 203 routine primary cemented total hip arthroplasties (THA) in 194 patients. Results: There were no acetabular component revisions for aseptic loosening. Acetabular revision was undertaken in eight hips. In four hips revision was necessitated by periprosthetic femoral fractures, in two hips by recurrent dislocation, in one hip for infection and in one hip for unexplained ongoing pain. Oxford and Harris hip scores demonstrated significant clinical improvement (all p < 0.001). Radiolucent lines were present in 37 (36%) of the 103 acetabular components available for radiological evaluation. In 27 of these, the line was confined to zone 1. No component had migrated. Conclusion: Kaplan–Meier survivorship, with revision for aseptic loosening as the endpoint, was 100% at 12.5 years and for all causes was 97.8% (95% confidence interval 95.6 to 100) when 40 components remained at risk. The Exeter Contemporary flanged cemented acetabular component demonstrates excellent survivorship at 12.5 years. Take home message: The Exeter Contemporary flanged cemented acetabular component has excellent clinical outcomes and survivorship when used with the Exeter stem in total hip arthroplasty.