A Scoping Review of Strategies for the Prevention of Hip Fracture in Elderly Nursing Home Residents

Background

Elderly nursing home residents are at increased risk of hip fracture; however, the efficacy of fracture prevention strategies in this population is unclear.

Objective

We performed a scoping review of randomized controlled trials of interventions tested in the long-term care (LTC) setting, examining hip fracture outcomes.

Methods

We searched for citations in 6 respective electronic searches, supplemented by hand searches. Two reviewers independently reviewed all citations and full-text papers; consensus was achieved on final inclusion. Data was abstracted in duplicate.

Findings

We reviewed 22,349 abstracts or citations and 949 full-text papers. Data from 20 trials were included: 7 - vitamin D (n = 12,875 participants), 2 - sunlight exposure (n = 522), 1 - alendronate (n = 327), 1 - fluoride (n = 460), 4 – exercise or multimodal interventions (n = 8,165), and 5 - hip protectors (n = 2,594). Vitamin D, particularly vitamin D₃ ≥800 IU orally daily, reduced hip fracture risk. Hip protectors reduced hip fractures in included studies, although a recent large study not meeting inclusion criteria was negative. Fluoride and sunlight exposure did not significantly reduce hip fractures. Falls were reduced in three studies of exercise or multimodal interventions, with one study suggesting reduced hip fractures in a secondary analysis. A staff education and risk assessment strategy did not significantly reduce falls or hip fractures. In a study underpowered for fracture outcomes, alendronate did not significantly reduce hip fractures in LTC.

Conclusions

The intervention with the strongest evidence for reduction of hip fractures in LTC is Vitamin D supplementation; more research on other interventions is needed.     

Quantification of Mineralized Bone Response to Prostate Cancer by Noninvasive In Vivo μCT and Non-Destructive Ex Vivo μCT and DXA in a Mouse Model

Background

To compare nondestructive in vivo and ex vivo micro-computed tomography (μCT) and ex vivo dual-energy-X-ray-absorptiometry (DXA) in characterizing mineralized cortical and trabecular bone response to prostate cancer involving the skeleton in a mouse model.

Methodology/Principal Findings

In vivo μCT was performed before and 10 weeks after implantation of human prostate cancer cells (MDA-PCa-2b) or vehicle into SCID mouse femora. After resection, femora were imaged by nondestructive ex vivo specimen μCT at three voxel sizes (31 µ, 16 µ, 8 µ) and DXA, and then sectioned for histomorphometric analysis of mineralized bone. Bone mineral density (BMD), trabecular parameters (number, TbN; separation, TbSp; thickness, TbTh) and mineralized bone volume/total bone volume (BV/TV) were compared and correlated among imaging methods and histomorphometry. Statistical tests were considered significant if P<0.05. Ten weeks post inoculation, diaphyseal BMD increased in the femur with tumor compared to the opposite femur by all modalities (p<0.005, n = 11). Diaphyseal BMD by in vivo μCT correlated with ex vivo 31 and 16 µm μCT and histomorphometry BV/TV (r = 0.91–0.94, P<0.001, n = 11). DXA BMD correlated less with bone histomorphometry (r = 0.73, P<0.001, n = 11) and DXA did not distinguish trabeculae from cortex. By in vivo and ex vivo μCT, trabecular BMD decreased (P<0.05, n = 11) as opposed to the cortex. Unlike BMD, trabecular morphologic parameters were threshold-dependent and when using “fixed-optimal-thresholds,” all except TbTh demonstrated trabecular loss with tumor and correlated with histomorphometry (r = 0.73–0.90, P<0.05, n = 11).

Conclusions/Significance

Prostate cancer involving the skeleton can elicit a host bone response that differentially affects the cortex compared to trabeculae and that can be quantified noninvasively in vivo and nondestructively ex vivo.     

Adding VFA to DXA Identifies Fracture Risk in a Way Not Duplicated by Other Measures

Objective: Published studies have demonstrated that adding vertebral fracture assessment (VFA) to dual-energy X-ray absorptiometry (DXA) identifies more patients with increased fracture risk than DXA alone. But who needs VFA? This study attempts to determine if some test other than VFA could duplicate the additional information obtained by performing VFA on all first-time patients. This study looked at the Fracture Risk Assessment Tool (FRAX), height loss, age, documented back pain, and nonvertebral fragility fractures.Methods: VFA was performed on 1,259 (all) DXA patients at their first visit from March 2010 through September 2013. All DXA and VFA results were read by the same International Society for Clinical Densitometry–certified clinician.Results: By DXA alone, 44% were osteoporosis. Adding VFA increased clinical osteoporosis by 36% of the original total patients. Eighty-three “normal bone mineral density” patients were changed to clinical osteoporosis. FRAX identified 53% of the patients with diagnosis changes. Historical height loss was not reliable. Increasing age correlated only weakly with clinical osteoporosis.Conclusion: These are modest numbers from a nonacademic referral practice and may not be typical of other populations. Thirty-six percent of our patients were misclassified by DXA alone, with fragility fractures already taken into account for T-scores of -1.5 and lower. FRAX, height loss, age, back pain, and fragility fractures all failed to identify many of the patients identified by VFA. Seeing the lateral spine images obtained by VFA influenced patients and families. VFA on all first-time patients should be reconsidered.Abbreviations:BMD = bone mineral density; DXA = dual-energy X-ray absorptiometry; FRAX = Fracture Risk Assessment Tool; HL = height loss; ISCD = International Society for Clinical Densitometry; VF = vertebral fracture; VFA = vertebral fracture assessment     

An ACACB Variant Implicated in Diabetic Nephropathy Associates with Body Mass Index and Gene Expression in Obese Subjects

Acetyl coenzyme A carboxylase B gene (ACACB) single nucleotide polymorphism (SNP) rs2268388 is reproducibly associated with type 2 diabetes (T2DM)-associated nephropathy (DN). ACACB knock-out mice are also protected from obesity. This study assessed relationships between rs2268388, body mass index (BMI) and gene expression in multiple populations, with and without T2DM. Among subjects without T2DM, rs2268388 DN risk allele (T) associated with higher BMI in Pima Indian children (n = 2021; p-additive = 0.029) and African Americans (AAs) (n = 177; p-additive = 0.05), with a trend in European Americans (EAs) (n = 512; p-additive = 0.09), but not Germans (n = 858; p-additive = 0.765). Association with BMI was seen in a meta-analysis including all non-T2DM subjects (n = 3568; p-additive = 0.02). Among subjects with T2DM, rs2268388 was not associated with BMI in Japanese (n = 2912) or EAs (n = 1149); however, the T allele associated with higher BMI in the subset with BMI≥30 kg/m² (n = 568 EAs; p-additive = 0.049, n = 196 Japanese; p-additive = 0.049). Association with BMI was strengthened in a T2DM meta-analysis that included an additional 756 AAs (p-additive = 0.080) and 48 Hong Kong Chinese (p-additive = 0.81) with BMI≥30 kg/m² (n = 1575; p-additive = 0.0033). The effect of rs2268388 on gene expression revealed that the T risk allele associated with higher ACACB messenger levels in adipose tissue (41 EAs and 20 AAs with BMI>30 kg/m²; p-additive = 0.018) and ACACB protein levels in the liver tissue (mixed model p-additive = 0.03, in 25 EA bariatric surgery patients with BMI>30 kg/m² for 75 exams). The T allele also associated with higher hepatic triglyceride levels. These data support a role for ACACB in obesity and potential roles for altered lipid metabolism in susceptibility to DN.     

Microdamage Caused by Fatigue Loading in Human Cancellous Bone: Relationship to Reductions in Bone Biomechanical Performance

Vertebral fractures associated with osteoporosis are often the result of tissue damage accumulated over time. Microscopic tissue damage (microdamage) generated in vivo is believed to be a mechanically relevant aspect of bone quality that may contribute to fracture risk. Although the presence of microdamage in bone tissue has been documented, the relationship between loading, microdamage accumulation and mechanical failure is not well understood. The aim of the current study was to determine how microdamage accumulates in human vertebral cancellous bone subjected to cyclic fatigue loading. Cancellous bone cores (n = 32) from the third lumbar vertebra of 16 donors (10 male, 6 female, age 76±8.8, mean ± SD) were subjected to compressive cyclic loading at σ/E₀ = 0.0035 (where σ is stress and E₀ is the initial Young’s modulus). Cyclic loading was suspended before failure at one of seven different amounts of loading and specimens were stained for microdamage using lead uranyl acetate. Damage volume fraction (DV/BV) varied from 0.8±0.5% (no loading) to 3.4±2.1% (fatigue-loaded to complete failure) and was linearly related to the reductions in Young’s modulus caused by fatigue loading (r² = 0.60, p<0.01). The relationship between reductions in Young’s modulus and proportion of fatigue life was nonlinear and suggests that most microdamage generation occurs late in fatigue loading, during the tertiary phase. Our results indicate that human vertebral cancellous bone tissue with a DV/BV of 1.5% is expected to have, on average, a Young’s modulus 31% lower than the same tissue without microdamage and is able to withstand 92% fewer cycles before failure than the same tissue without microdamage. Hence, even small amounts of microscopic tissue damage in human vertebral cancellous bone may have large effects on subsequent biomechanical performance.     

Reconstructive Treatment of Ruptured Intracranial Spontaneous Vertebral Artery Dissection Aneurysms: Long-Term Results and Predictors of Unfavorable Outcomes

Introduction

Few studies focused on predictors of unfavorable outcomes (modified Rankin Scale, 2–6) after reconstructive treatment of the ruptured intracranial spontaneous vertebral artery dissection aneurysms (ris-VADAs), which was evaluated based on 57 reconstructed lesions in this study.

Methods

Results of 57 consecutive patients (M:F = 29∶28; median age, 48 years; range, 27 to 69 years) harboring 57 ris-VADAs, which were treated with coils combined with single stent(n = 32), double overlapping stents (n = 16), and triple overlapping stents (n = 9) between October 2000 to March 2011, were retrospectively reviewed and analyzed.

Results

The available (n = 54) mean durations of angiographic and clinical follow-ups were 27 months (range, 12 to 78) and 62 months (range, 12 to 132), respectively. The involvement of PICA (p = 0.004), size of lesions (p = 0.000), quantity of stent (p = 0.001), and coil type (p = 0.002) affected the immediate obliteration grade, which was only risk factor for angiographic recurrences (p = 0.031). Although the post-treatment outcomes did not differ between single stent and multiple stents (p = 0.434), 5 angiographic recurrences, 1 rebleeding and 1 suspected rebleeding, all occurred in partial obliteration after single-stent-assisted coiling. Progressive thrombosis and in-stent obliteration were not detected on follow-up angiograms. Older age (odds ratio [OR] = 1.090; 95% confidence interval [CI], 1.004–1.184; p = 0.040) and unfavorable Hunt-Hess scale (OR = 4.289; 95%CI, 1.232–14.933; p = 0.022) were independent predictors of unfavorable outcomes in the reconstructed ris-VADAs.

Conclusions

Immediate obliteration grade was only risk factor for angiographic recurrence after reconstructive treatment. Unfavorable Hunt-Hess grade and older age were independent predictors of unfavorable outcomes in ris-VADAs.     

Accelerated Postero-Lateral Spinal Fusion by Collagen Scaffolds Modified with Engineered Collagen-Binding Human Bone Morphogenetic Protein-2 in Rats

Bone morphogenetic protein-2 (BMP-2) is a potent osteoinductive cytokine that plays a critical role in bone regeneration and repair. However, its distribution and side effects are major barriers to its success as therapeutic treatment. The improvement of therapy using collagen delivery matrices has been reported. To investigate a delivery system on postero-lateral spinal fusion, both engineered human BMP-2 with a collagen binding domain (CBD-BMP-2) and collagen scaffolds were developed and their combination was implanted into Sprague-Dawley (SD) rats to study Lumbar 4–5 (L4–L5) posterolateral spine fusion. We divided SD rats into three groups, the sham group (G1, n = 20), the collagen scaffold-treated group (G2, n = 20) and the BMP-2-loaded collagen scaffolds group (G3, n = 20). 16 weeks after surgery, the spines of the rats were evaluated by X-radiographs, high-resolution micro-computed tomography (micro-CT), manual palpation and hematoxylin and eosin (H&E) staining. The results showed that spine L4–L5 fusions occurred in G2(40%) and G3(100%) group, while results from the sham group were inconsistent. Moreover, G3 had better results than G2, including higher fusion efficiency (X score, G2 = 2.4±0.163, G3 = 3.0±0, p<0.05), higher bone mineral density (BMD, G2: 0.3337±0.0025g/cm3, G3: 0.4353±0.0234g/cm3. p<0.05) and more bone trabecular formation. The results demonstrated that with site-specific collagen binding domain, a dose of BMP-2 as low as 0.02mg CBD-BMP-2/cm³ collagen scaffold could enhance the posterolateral intertransverse process fusion in rats. It suggested that combination delivery could be an alternative in spine fusion with dramatically decreased side effects caused by high dose of BMP-2.     

Sleep Deprivation Impairs Consolidation of Cued Fear Memory in Rats

Post-learning sleep facilitates negative memory consolidation and also helps preserve it over several years. It is believed, therefore, that sleep deprivation may help prevent consolidation of fearful memory. Its effect, however, on consolidation of negative/frightening memories is not known. Cued fear-conditioning (CuFC) is a widely used model to understand the neural basis of negative memory associated with anxiety disorders. In this study, we first determined the suitable circadian timing for consolidation of CuFC memory and changes in sleep architecture after CuFC. Thereafter, we studied the effect of sleep deprivation on CuFC memory consolidation. Three sets of experiments were performed in male Wistar rat (n = 51). In experiment-I, animals were conditioned to cued-fear by presenting ten tone-shock paired stimuli during lights-on (7 AM) (n = 9) and lights-off (7 PM) (n = 9) periods. In experiment-II, animals were prepared for polysomnographic recording (n = 8) and changes in sleep architecture after CuFC was determined. Further in experiment-III, animals were cued fear-conditioned during the lights-off period and were randomly divided into four groups: Sleep-Deprived (SD) (n = 9), Non-Sleep Deprived (NSD) (n = 9), Stress Control (SC) (n = 9) and Tone Control (n = 7). Percent freezing amount, a hallmark of fear, was compared statistically in these groups. Rats trained during the lights-off period exhibited significantly more freezing compared to lights-on period. In CuFC trained animals, total sleep amount did not change, however, REM sleep decreased significantly. Further, out of total sleep time, animals spent proportionately more time in NREM sleep. Nevertheless, SD animals exhibited significantly less freezing compared to NSD and SC groups. These data suggest that sleep plays an important role in the consolidation of cued fear-conditioned memory.     

C-Reactive Protein,Erythrocyte Sedimentation Rate and Orthopedic Implant Infection

Background

C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) have been shown to be useful for diagnosis of prosthetic hip and knee infection. Little information is available on CRP and ESR in patients undergoing revision or resection of shoulder arthroplasties or spine implants.

Methods/Results

We analyzed preoperative CRP and ESR in 636 subjects who underwent knee (n = 297), hip (n = 221) or shoulder (n = 64) arthroplasty, or spine implant (n = 54) removal. A standardized definition of orthopedic implant-associated infection was applied. Receiver operating curve analysis was used to determine ideal cutoff values for differentiating infected from non-infected cases. ESR was significantly different in subjects with aseptic failure infection of knee (median 11 and 53.5 mm/h, respectively, p = <0.0001) and hip (median 11 and 30 mm/h, respectively, p = <0.0001) arthroplasties and spine implants (median 10 and 48.5 mm/h, respectively, p = 0.0033), but not shoulder arthroplasties (median 10 and 9 mm/h, respectively, p = 0.9883). Optimized ESR cutoffs for knee, hip and shoulder arthroplasties and spine implants were 19, 13, 26, and 45 mm/h, respectively. Using these cutoffs, sensitivity and specificity to detect infection were 89 and 74% for knee, 82 and 60% for hip, and 32 and 93% for shoulder arthroplasties, and 57 and 90% for spine implants. CRP was significantly different in subjects with aseptic failure and infection of knee (median 4 and 51 mg/l, respectively, p<0.0001), hip (median 3 and 18 mg/l, respectively, p<0.0001), and shoulder (median 3 and 10 mg/l, respectively, p = 0.01) arthroplasties, and spine implants (median 3 and 20 mg/l, respectively, p = 0.0011). Optimized CRP cutoffs for knee, hip, and shoulder arthroplasties, and spine implants were 14.5, 10.3, 7, and 4.6 mg/l, respectively. Using these cutoffs, sensitivity and specificity to detect infection were 79 and 88% for knee, 74 and 79% for hip, and 63 and 73% for shoulder arthroplasties, and 79 and 68% for spine implants.

Conclusion

CRP and ESR have poor sensitivity for the diagnosis of shoulder implant infection. A CRP of 4.6 mg/l had a sensitivity of 79 and a specificity of 68% to detect infection of spine implants.     

Urinary Collagen Fragments Are Significantly Altered in Diabetes: A Link to Pathophysiology

Background

The pathogenesis of diabetes mellitus (DM) is variable, comprising different inflammatory and immune responses. Proteome analysis holds the promise of delivering insight into the pathophysiological changes associated with diabetes. Recently, we identified and validated urinary proteomics biomarkers for diabetes. Based on these initial findings, we aimed to further validate urinary proteomics biomarkers specific for diabetes in general, and particularity associated with either type 1 (T1D) or type 2 diabetes (T2D).

Methodology/Principal Findings

Therefore, the low-molecular-weight urinary proteome of 902 subjects from 10 different centers, 315 controls and 587 patients with T1D (n = 299) or T2D (n = 288), was analyzed using capillary-electrophoresis mass-spectrometry. The 261 urinary biomarkers (100 were sequenced) previously discovered in 205 subjects were validated in an additional 697 subjects to distinguish DM subjects (n = 382) from control subjects (n = 315) with 94% (95% CI: 92–95) accuracy in this study. To identify biomarkers that differentiate T1D from T2D, a subset of normoalbuminuric patients with T1D (n = 68) and T2D (n = 42) was employed, enabling identification of 131 biomarker candidates (40 were sequenced) differentially regulated between T1D and T2D. These biomarkers distinguished T1D from T2D in an independent validation set of normoalbuminuric patients (n = 108) with 88% (95% CI: 81–94%) accuracy, and in patients with impaired renal function (n = 369) with 85% (95% CI: 81–88%) accuracy. Specific collagen fragments were associated with diabetes and type of diabetes indicating changes in collagen turnover and extracellular matrix as one hallmark of the molecular pathophysiology of diabetes. Additional biomarkers including inflammatory processes and pro-thrombotic alterations were observed.

Conclusions/Significance

These findings, based on the largest proteomic study performed to date on subjects with DM, validate the previously described biomarkers for DM, and pinpoint differences in the urinary proteome of T1D and T2D, indicating significant differences in extracellular matrix remodeling.     

Spermine and Citrate as Metabolic Biomarkers for Assessing Prostate Cancer Aggressiveness

Separating indolent from aggressive prostate cancer is an important clinical challenge for identifying patients eligible for active surveillance, thereby reducing the risk of overtreatment. The purpose of this study was to assess prostate cancer aggressiveness by metabolic profiling of prostatectomy tissue and to identify specific metabolites as biomarkers for aggressiveness. Prostate tissue samples (n = 158, 48 patients) with a high cancer content (mean: 61.8%) were obtained using a new harvesting method, and metabolic profiles of samples representing different Gleason scores (GS) were acquired by high resolution magic angle spinning magnetic resonance spectroscopy (HR-MAS). Multivariate analysis (PLS, PLS-DA) and absolute quantification (LCModel) were used to examine the ability to predict cancer aggressiveness by comparing low grade (GS = 6, n = 30) and high grade (GS≥7, n = 81) cancer with normal adjacent tissue (n = 47). High grade cancer tissue was distinguished from low grade cancer tissue by decreased concentrations of spermine (p = 0.0044) and citrate (p = 7.73·10⁻⁴), and an increase in the clinically applied (total choline+creatine+polyamines)/citrate (CCP/C) ratio (p = 2.17·10⁻⁴). The metabolic profiles were significantly correlated to the GS obtained from each tissue sample (r = 0.71), and cancer tissue could be distinguished from normal tissue with sensitivity 86.9% and specificity 85.2%. Overall, our findings show that metabolic profiling can separate aggressive from indolent prostate cancer. This holds promise for the benefit of applying in vivo magnetic resonance spectroscopy (MRS) within clinical MR imaging investigations, and HR-MAS analysis of transrectal ultrasound-guided biopsies has a potential as an additional diagnostic tool.     

Prognostic Significance of E-Cadherin Expression in Hepatocellular Carcinoma: A Meta-Analysis

Backgrounds

Hepatocellular Carcinoma (HCC) is one of the most common malignancy of liver and HCC-related morbidity and mortality remains at high level. Researchers had investigated whether and how reduced E-cadherin expression impacted the prognosis of patients with HCC but the results reported by different teams remain inconclusive.

Methods

A systematic literature search was performed in all available databases to retrieve eligible studies and identify all relevant data, which could be used to evaluate the correlation between reduced E-cadherin expression and clinicopathological features and prognosis for HCC patients. A fixed or random effects model was used in this meta-analysis to calculate the pooled odds ratios (OR) and weighted mean differences (WMD) with 95% confidence intervals (CI).

Results

Total 2439 patients in thirty studies matched the selection criteria. Aggregation of the data suggested that reduced E-cadherin expression in HCC patients correlated with poor 1-, 3- and 5-year overall survival. The combined ORs were 0.50 (n = 13 studies, 95% CI: 0.37–0.67, Z = 4.49, P<0.00001), 0.39 (n = 13 studies, 95% CI: 0.28–0.56, Z = 5.12, P<0.00001), 0.40 (n = 11 studies, 95% CI: 0.25–0.64, Z = 3.82, P = 0.0001), respectively. Additionally, the pooled analysis denoted that reduced E-cadherin expression negatively impacts recurrence-free survival (RSF) with no significant heterogeneity. The pooled ORs for 1-, 3- and 5- year RSF affected by down-regulated E-cadherin were 0.73 (n = 6 studies, 95% CI: 0.54–1.00, Z = 1.95, P = 0.05), 0.70 (n = 6 studies, 95% CI: 0.52–0.95, Z = 2.32, P = 0.02), 0.66 (n = 5 studies, 95% CI: 0.48–0.90, Z = 2.64, P = 0.008). And what’s more, reduced E-cadherin expression tended to be significantly associated with metastasis (OR = 0.31, 95% CI: 0.16–0.60, Z = 3.50, P = 0.0005), vascular invasion (OR = 0.76, 95% CI: 0.59–0.98, Z = 2.14, P = 0.03), advanced differentiation grade (OR = 0.31, 95% CI: 0.21–0.45, Z = 6.04, P<0.00001) and advanced TMN stage (T3/T4 versus T1/T2) (OR = 0.61,95% CI:0.38–0.98, Z = 2.05, P = 0.04).

Conclusions

Reduced E-cadherin expression indicates a poor prognosis for patients with HCC, and it may have predictive potential for prognosis of HCC patients.     

A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels

The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10⁻⁸). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10⁻¹⁹ for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10⁻⁸, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10⁻⁶, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10⁻³, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.     

Incident Hip Fractures among Community Dwelling Persons with Alzheimer’s Disease in a Finnish Nationwide Register-Based Cohort

Background

Previous cohort studies have shown that persons with Alzheimer’s disease (AD) have a higher risk of hip fractures but recent data from large representative cohorts is scarce.

Methods

We investigated the association between AD and prevalent and incident hip fractures in an exposure-matched cohort study conducted in Finland 2002–2009 (the Medication and Alzheimer’s disease in 2005 study; MEDALZ-2005). The study population included all community-dwelling persons with verified AD diagnosis in Finland on December 31, 2005 and one matched comparison person per AD case (N = 56,186, mean age 79.9 (SD 6.8) years, range 42–101 years). The diagnosis of AD was extracted from a special reimbursement register. Data on hip fractures during 2002–2009 was extracted from the Finnish National hospital discharge register. Analyses of incident hip fractures (n = 2,861) were restricted to years 2006–2009.

Results

Persons with AD were twice as likely to have previous hip fracture in 2005 (odds ratio, 95% confidence interval 2.00, 1.82–2.20) than matched aged population without AD. They were also more likely to experience incident hip fracture during the four-year follow-up (hazard ratio, 95% confidence interval 2.57, 2.32–2.84, adjusted for health status, psychotropic drug and bisphosphonate use). The AD-associated risk increase decreased linearly across age groups. Although people with AD had higher risk of hip fractures regardless of sex, the risk increase was larger in men than women.

Conclusion

Findings from our nationwide study are in line with previous studies showing that persons with AD, regardless of sex or age, have higher risk of hip fracture in comparison to general population. Although there was some suggestion of effect modification by age or sex, AD was consistently associated with doubling of the risk of incident hip fracture.     

Mitochondrial DNA (mtDNA) Haplogroups Influence the Progression of Knee Osteoarthritis. Data from the Osteoarthritis Initiative (OAI)

Objective

To evaluate the influence of the mtDNA haplogroups on knee osteoarthritis progression in Osteoarthritis Initiative (OAI) participants through longitudinal data from radiographs and magnetic resonance imaging (MRI).

Methods

Four-year knee osteoarthritis progression was analyzed as increase in Kellgren and Lawrence (KL) grade, in addition to increase in OARSI atlas grade for joint space narrowing (JSN), osteophytes and subchondral sclerosis in the tibia medial compartment of 891 Caucasian individuals from the progression subcohort. The influence of the haplogroups on the rate of structural progression was also assessed as the four-year change in minimum joint space width (mJSW in millimetres) in both knees of (n = 216) patients with baseline unilateral medial-tibiofemoral JSN. Quantitative cartilage measures from longitudinal MRI data were those related to cartilage thickness and volume with a 24 month follow-up period (n = 381).

Results

During the four-year follow-up period, knee OA patients with the haplogroup T showed the lowest increase in KL grade (Hazard Risk [HR] = 0.499; 95% Confidence Interval [CI]: 0.261–0.819; p<0.05) as well as the lowest cumulative probability of progression for JSN (HR = 0.547; 95% CI: 0.280–0.900; p<0.05), osteophytes (HR = 0.573; 95% CI: 0.304–0.893; p<0.05) and subchondral sclerosis (HR = 0.549; 95% CI: 0.295–0.884; p<0.05). They also showed the lowest decline in mJSW (standardized response means (SRM) = −0.39; p = 0.037) in those knees without baseline medial JSN (no-JSN knees). Normalized cartilage volume loss was significantly lower in patients carrying the haplogroup T at medial tibia femoral (SRM = −0.33; p = 0.023) and central medial femoral (SRM = −0.27; p = 0.031) compartments. Cartilage thickness loss was significantly lower in carriers of haplogroup T at central medial tibia-femoral (SRM = −0.42; p = 0.011), medial tibia femoral (SRM = −0.32; p = 0.018), medial tibia anterior (SRM = +0.31; p = 0.013) and central medial femoral (SRM = −0.19; p = 0.013) compartments.

Conclusions

Mitochondrial genome seems to play a role in the progression of knee osteoarthritis. mtDNA variation could improve identification of patients predisposed to faster or severe progression of the disease.     

Statins and Hip Fracture Prevention – A Population Based Cohort Study in Women

Objective

To study the association of long-term statin use and the risk of low-energy hip fractures in middle-aged and elderly women.

Design

A register-based cohort study.

Setting

Finland.

Participants

Women aged 45–75 years initiating statin therapy between 1996 and 2001 with adherence to statins ≥80% during the subsequent five years (n = 40 254), a respective cohort initiating hypertension drugs (n = 41 610), and women randomly selected from the population (n = 62 585).

Main Outcome Measures

Incidence rate of and hazard ratio (HR) for low-energy hip fracture during the follow-up extending up to 7 years after the 5-year exposure period.

Results

Altogether 199 low-energy hip fractures occurred during the 135 330 person-years (py) of follow-up in the statin cohort, giving an incidence rate of 1.5 hip fractures per 1000 py. In the hypertension and the population cohorts, the rates were 2.0 per 1000 py (312 fractures per 157 090 py) and 1.0 per 1000 py (212 fractures per 216 329 py), respectively. Adjusting for a propensity score and individual variables strongly predicting the outcome, good adherence to statins for five years was associated with a 29% decreased risk (HR 0.71; 95% CI 0.58–0.86) of a low-energy hip fracture in comparison with adherent use of hypertension drugs. The association was of the same magnitude when comparing the statin users with the population cohort, the HR being 0.69 (0.55–0.87). When women with poor (<40%), moderate (40 to 80%), and good adherence (≥80%) to statins were compared to those with good adherence to hypertension drugs (≥80%) or to the population cohort, the protective effect associated with statin use attenuated with the decreasing level of adherence.

Conclusions

5-year exposure to statins is associated with a reduced risk of low-energy hip fracture in women aged 50–80 years without prior hospitalizations for fractures.     

Consequences of Repeated Blood-Brain Barrier Disruption in Football Players

The acknowledgement of risks for traumatic brain injury in American football players has prompted studies for sideline concussion diagnosis and testing for neurological deficits. While concussions are recognized etiological factors for a spectrum of neurological sequelae, the consequences of sub-concussive events are unclear. We tested the hypothesis that blood-brain barrier disruption (BBBD) and the accompanying surge of the astrocytic protein S100B in blood may cause an immune response associated with production of auto-antibodies. We also wished to determine whether these events result in disrupted white matter on diffusion tensor imaging (DT) scans. Players from three college football teams were enrolled (total of 67 volunteers). None of the players experienced a concussion. Blood samples were collected before and after games (n = 57); the number of head hits in all players was monitored by movie review and post-game interviews. S100B serum levels and auto-antibodies against S100B were measured and correlated by direct and reverse immunoassays (n = 15 players; 5 games). A subset of players underwent DTI scans pre- and post-season and after a 6-month interval (n = 10). Cognitive and functional assessments were also performed. After a game, transient BBB damage measured by serum S100B was detected only in players experiencing the greatest number of sub-concussive head hits. Elevated levels of auto-antibodies against S100B were elevated only after repeated sub-concussive events characterized by BBBD. Serum levels of S100B auto-antibodies also predicted persistence of MRI-DTI abnormalities which in turn correlated with cognitive changes. Even in the absence of concussion, football players may experience repeated BBBD and serum surges of the potential auto-antigen S100B. The correlation of serum S100B, auto-antibodies and DTI changes support a link between repeated BBBD and future risk for cognitive changes.     

FRAX?: Prediction of Major Osteoporotic Fractures in Women from the General Population: The OPUS Study

Purposes

The aim of this study was to analyse how well FRAX® predicts the risk of major osteoporotic and vertebral fractures over 6 years in postmenopausal women from general population.

Patients and methods

The OPUS study was conducted in European women aged above 55 years, recruited in 5 centers from random population samples and followed over 6 years. The population for this study consisted of 1748 women (mean age 74.2 years) with information on incident fractures. 742 (43.1%) had a prevalent fracture; 769 (44%) and 155 (8.9%) of them received an antiosteoporotic treatment before and during the study respectively. We compared FRAX® performance with and without bone mineral density (BMD) using receiver operator characteristic (ROC) c-statistical analysis with ORs and areas under receiver operating characteristics curves (AUCs) and net reclassification improvement (NRI).

Results

85 (4.9%) patients had incident major fractures over 6 years. FRAX® with and without BMD predicted these fractures with an AUC of 0.66 and 0.62 respectively. The AUC were 0.60, 0.66, 0.69 for history of low trauma fracture alone, age and femoral neck (FN) BMD and combination of the 3 clinical risk factors, respectively. FRAX® with and without BMD predicted incident radiographic vertebral fracture (n = 65) with an AUC of 0.67 and 0.65 respectively. NRI analysis showed a significant improvement in risk assignment when BMD is added to FRAX®.

Conclusions

This study shows that FRAX® with BMD and to a lesser extent also without FN BMD predict major osteoporotic and vertebral fractures in the general population.     

Role of IL1A rs1800587, IL1B rs1143627 and IL1RN rs2234677 Genotype Regarding Development of Chronic Lumbar Radicular Pain; a Prospective One-Year Study

Previous studies indicate that lumbar radicular pain following disc herniation may be associated with release of several pro-inflammatory mediators, including interleukin-1 (IL1). In the present study, we examined how genetic variability in IL1A (rs1800587 C>T), IL1B (rs1143627 T>C) and IL1RN (rs2234677 G>A) influenced the clinical outcome the first year after disc herniation. Patients (n = 258) with lumbar radicular pain due to disc herniation were recruited from two hospitals in Norway. Pain and disability were measured by visual analogue scale (VAS) and Oswestry Disability Index (ODI) over a 12 month period. The result showed that patients with the IL1A T allele, in combination with the IL1RN A allele had more pain and a slower recovery than other patients (VAS p = 0.049, ODI p = 0.059 rmANOVA; VAS p = 0.003, ODI p = 0.050 one-way ANOVA at 12 months). However, regarding the IL1B/IL1RN genotype, no clear effect on recovery was observed (VAS p = 0.175, ODI p = 0.055 rmANOVA; VAS p = 0.105, ODI p = 0.214 one-way ANOVA at 12 months). The data suggest that the IL1A T/IL1RN A genotype, but not the IL1B T/IL1RN A genotype, may increase the risk of a chronic outcome in patients following disc herniation.     

Predicting Cortical Bone Strength from DXA and Dental Cone-Beam CT

Objective

This study compared the capabilities of dual-energy X-ray absorptiometry (DXA) and dental cone-beam computed tomography (CBCT) for predicting the cortical bone strength of rat femurs and tibias.

Materials and Methods

Specimens of femurs and tibias obtained from 14 rats were first scanned with DXA to obtain the areal bone mineral density (BMD) of the midshaft cortical portion of the bones. The bones were then scanned using dental CBCT to measure the volumetric cortical bone mineral density (vCtBMD) and the cross-sectional moment of inertia (CSMI) for calculating the bone strength index (BSI). A three-point bending test was conducted to measure the fracture load of each femur and tibia. Bivariate linear Pearson analysis was used to calculate the correlation coefficients (r values) among the CBCT measurements, DXA measurements, and three-point bending parameters.

Results

The correlation coefficients for the associations of the fracture load with areal BMD (measured using DXA), vCtBMD (measured using CBCT), CSMI (measured using CBCT), and BSI were 0.585 (p = 0.028) and 0.532 (p = 0.050) (for the femur and tibia, respectively), 0.638 (p = 0.014) and 0.762 (p = 0.002), 0.778 (p = 0.001) and 0.792 (p<0.001), and 0.822 (p<0.001) and 0.842 (p<0.001), respectively.

Conclusions

CBCT was found to be superior to DXA for predicting cortical bone fracture loads in rat femurs and tibias. The BSI, which is a combined index of densitometric and geometric parameters, was especially useful. Further clinical studies are needed to validate the predictive value of BSI obtained from CBCT and should include testing on human cadaver specimens.