De-stabilizing innate immunity in COVID-19: effects of its own positive feedback and erratic viraemia on the alternative pathway of complement.

Complement provides powerful, fast responses in the human circulation to SARS-CoV-2 (COVID-19 virus) infection of the lower respiratory tract. COVID-19 effects were investigated in a revised human Mass Action model of complement's alternative pathway (AP) responses. Bursts of newly circulating virions increased the fission of Complement protein C3 into C3a and C3b via stimulation of the lectin pathway or inhibited complement factor H.

An atlas of genetic influences on osteoporosis in humans and mice.

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.

Femoral neck cortical bone in female and male hip fracture cases: Differential contrasts in cortical width and sub-periosteal porosity in 112 cases and controls.

Objectives: To quantitate differences between cases of hip fracture and controls in cortical width around the mid-femoral neck in men and women.

Methods: Over 5 years, 64 (14 male) participants over age 55 (mean 79) years, who had never taken bone-active drugs and suffered intra-capsular hip fracture treated by arthroplasty, donated their routinely discarded distal intra-capsular femoral neck bone for histomorphometry. After embedding, complete femoral neck cross sections from the cut surface near the narrowest part of the neck were stained with von Kossa and cortical width was measured radially every 5 degrees of arc.

Degenerative inter-vertebral disc disease osteochondrosis intervertebralis in Europe: prevalence, geographic variation and radiological correlates in men and women aged 50 and over.

Objectives: To assess the prevalences across Europe of radiological indices of degenerative inter-vertebral disc disease (DDD); and to quantify their associations with, age, sex, physical anthropometry, areal BMD (aBMD) and change in aBMD with time.

Methods: In the population-based European Prospective Osteoporosis Study, 27 age-stratified samples of men and women from across the continent aged 50+ years had standardized lateral radiographs of the lumbar and thoracic spine to evaluate the severity of DDD, using the Kellgren-Lawrence (KL) scale. Measurements of anterior, mid-body and posterior vertebral heights on all assessed vertebrae from T4 to L4 were used to generate indices of end-plate curvature.

Role of cortical bone in hip fracture.

In this review, I consider the varied mechanisms in cortical bone that help preserve its integrity and how they deteriorate with aging. Aging affects cortical bone in two ways: extrinsically through its effects on the individual that modify its mechanical loading experience and 'milieu interieur'; and intrinsically through the prolonged cycle of remodelling and renewal extending to an estimated 20 years in the proximal femur. Healthy femoral cortex incorporates multiple mechanisms that help prevent fracture.

Focal osteoporosis defects play a key role in hip fracture.

Background: Hip fractures are mainly caused by accidental falls and trips, which magnify forces in well-defined areas of the proximal femur. Unfortunately, the same areas are at risk of rapid bone loss with ageing, since they are relatively stress-shielded during walking and sitting. Focal osteoporosis in those areas may contribute to fracture, and targeted 3D measurements might enhance hip fracture prediction.

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 ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic 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.

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902).

The fragile elderly hip: mechanisms associated with age-related loss of strength and toughness.

Every hip fracture begins with a microscopic crack, which enlarges explosively over microseconds. Most hip fractures in the elderly occur on falling from standing height, usually sideways or backwards. The typically moderate level of trauma very rarely causes fracture in younger people.

A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus.

Background: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk.

Aim: To identify CNVs associated with osteoporotic bone fracture risk.

Risedronate slows or partly reverses cortical and trabecular microarchitectural deterioration in postmenopausal women.

During early menopause, steady-state bone remodeling is perturbed; the number of basic multicellular units (BMUs) excavating cavities upon the endosteal surface exceeds the number (generated before menopause) concurrently refilling. Later in menopause, steady-state is restored; the many BMUs generated in early menopause refill as similarly large numbers of BMUs concurrently excavate new cavities. We hypothesized that risedronate reduces the number of cavities excavated.

Similarities and differences between sexes in regional loss of cortical and trabecular bone in the mid-femoral neck: the AGES-Reykjavik longitudinal study.

The risk of hip fracture rises rapidly with age, and is notably higher in women. After falls and prior fragility fractures, the main clinically recognized risk factor for hip fracture is reduced bone density. To better understand the extent to which femoral neck density and structure change with age in each sex, we carried out a longitudinal study in subjects not treated with agents known to influence bone mineral density (BMD), to investigate changes in regional cortical thickness, as well as cortical and trabecular BMD at the mid-femoral neck.

Fourier transform infrared imaging of femoral neck bone: reduced heterogeneity of mineral-to-matrix and carbonate-to-phosphate and more variable crystallinity in treatment-naive fracture cases compared with fracture-free controls.

After the age of 60 years, hip fracture risk strongly increases, but only a fifth of this increase is attributable to reduced bone mineral density (BMD, measured clinically). Changes in bone quality, specifically bone composition as measured by Fourier transform infrared spectroscopic imaging (FTIRI), also contribute to fracture risk. Here, FTIRI was applied to study the femoral neck and provide spatially derived information on its mineral and matrix properties in age-matched fractured and nonfractured bones.

Osteocyte recruitment declines as the osteon fills in: interacting effects of osteocytic sclerostin and previous hip fracture on the size of cortical canals in the femoral neck.

There is little information on the distribution of osteocytes within the individual cortical osteon, but using direct 3-D imaging in a single subject, Hannah et al. found a gradient with a two-fold higher density of cells adjacent to the cement line compared to near the canal. Since a limiting factor for bone formation might be the availability of osteoblasts due to their recruitment as osteocytes, we studied distributions of osteonal osteocytes in frozen sections of the femoral neck cortex.

Distribution of cortical bone in the femoral neck and hip fracture: a prospective case-control analysis of 143 incident hip fractures; the AGES-REYKJAVIK Study.

In this prospective nested case-control study we analyzed the circumferential differences in estimated cortical thickness (Est CTh) of the mid femoral neck as a risk factor for osteoporotic hip fractures in elderly women and men. Segmental QCT analysis of the mid femoral neck was applied to assess cortical thickness in anatomical quadrants. The superior region of the femoral neck was a stronger predictor for hip fracture than the inferior region, particularly in men.

Sclerostin and the regulation of bone formation: Effects in hip osteoarthritis and femoral neck fracture.

Remodeling imbalance in the elderly femoral neck can result in thin cortices and porosity predisposing to hip fracture. Hip osteoarthritis protects against intracapsular hip fracture. By secreting sclerostin, osteocytes may inhibit Wnt signaling and reduce bone formation by osteoblasts.

Changing structure of the femoral neck across the adult female lifespan.

The anatomic distribution of cortical and cancellous bone in the femoral neck may be critical in determining resistance to fracture. We investigated the effects of aging on femoral neck bone in women. In this cross-sectional study, we used clinical multidetector computed tomography (MDCT) of the hips to investigate aging effects in 100 female volunteers aged 20 to 90 years.

The effect of including quantitative heel ultrasound in models for estimation of 10-year absolute risk of fracture.

The role of quantitative ultrasound (QUS) in clinical practice is debatable. An unanswered question is that whether combining QUS and BMD measurements could improve the prediction of fracture risk. We examined this in a sample of men and women in the European Prospective Investigation into Cancer (EPIC)-Norfolk who had both heel QUS and hip DXA between 1995 and 1997 and were followed for any incident fracture up to 2007.

Femoral neck trabecular bone: loss with aging and role in preventing fracture.

Hip fracture risk rises 100- to 1000-fold over six decades of age, but only a minor part of this increase is explained by declining BMD. A potentially independent cause of fragility is cortical thinning predisposing to local crushing, in which bone tissue's material disintegrates at the microscopic level when compressed beyond its capacity to maintain integrity. Elastic instability or buckling of a much thinned cortex might alternatively occur under compression.

Estimation of absolute fracture risk among middle-aged and older men and women: the EPIC-Norfolk population cohort study.

While estimates of relative risks associated with risk factors such as age and bone mineral density (BMD) may be of interest for etiologic and comparative purposes, clinical questions such as who might benefit most from preventive interventions or BMD monitoring depend on estimates of absolute fracture risk. The European prospective investigation into cancer (EPIC)-Norfolk study included 25,311 participants (11,476 men) aged 4,079 years in 1993-1997. All participants were followed for osteoporotic fractures to March 2007.