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. Results: Images from 10 132 participants (56% female, mean age 63.9 years) passed quality checks. Overall, 47% of men and women had DDD grade 3 or more in the lumbar spine and 36% in both thoracic and lumbar spine. Risk ratios for DDD grades 3 and 4, adjusted for age and anthropometric determinants, varied across a three-fold range between centres, yet prevalences were highly correlated in men and women. DDD was associated with flattened, non-ovoid inter-vertebral disc spaces. KL grade 4 and loss of inter-vertebral disc space were associated with higher spine aBMD. Conclusion: KL grades 3 and 4 are often used clinically to categorize radiological DDD. Highly variable European prevalences of radiologically defined DDD grades 3+ along with the large effects of age may have growing and geographically unequal health and economic impacts as the population ages. These data encourage further studies of potential genetic and environmental causes.

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 in silico 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. Viral reproduction sub-models incorporated smoothly exponential or step-wise exponential growth. Starting complement protein concentrations were drawn randomly from published normal male or female ranges and each infection model run for 10 days. C3 and factor B (FB) syntheses driven by Lectin Pathway stimulation led to declining plasma C3 and increasing FB concentrations. The C3-convertase concentration, a driver of viral elimination, could match viral growth over three orders of magnitude but near-complete exhaustion of circulating C3 was more prevalent with step-wise than with 'smooth' increases in viral stimulation. C3 exhaustion could be prolonged. Type 2 Diabetes and hypertension led to greatly increased peak C3-convertase concentrations, as did short-term variability of COVID-19 viraemia, pulmonary capillary clotting and secondary acidosis. Positive feedback in the AP greatly extends its response range at the expense of stability.

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. Ten-year absolute risk of fracture in men and women were calculated using the baseline survivor function in multivariable Cox proportional-hazards models adjusting for age, sex, history of fractures, body mass index, smoking, and alcohol intake. In comparison of those without history of fracture versus those with history of fracture, the 10-year absolute risk of any fracture in men ranged from 1.0 vs. 1.2% at age 40 years to 3.0 vs. 4.4% at age 75 years. The respective estimates in women ranged from 0.7 vs. 1.0% at age 40 years to 9.3 vs. 17.2% at age 75 years. Statistically significant interaction between age and sex was found (P < 0.001), which contributed to the differences in predicted absolute fracture risks for men and women at different ages. Our study shows the need for population-specific data to develop efficient well calibrated algorithms for assessment of fracture risk. The interaction observed between sex and age points to the need for further prospective studies among men.

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 ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.

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

In the version of this article initially published, in Fig. 5a, the data in the right column of 'DAAM2 gRNA1' were incorrectly plotted as circles indicating 'untreated' rather than as squares indicating 'treated'. The error has been corrected in the HTML and PDF versions of the article.

Geographical variation in DXA bone mineral density in young European men and women. Results from the Network in Europe on Male Osteoporosis (NEMO) study.

UNLABELLED: We collected population-based young normal hip and spine BMD data from 17 centres across Europe to assess between centre differences and to compare reference values with the US NHANES-III data. There was strong evidence of between country heterogeneity, but not between centres within countries. Hip BMD mean values were lower in European women, but SD's differed little from the NHANES-III USA results in both sexes. It may be necessary to adjust NHANES-III based T-scores by adding/subtracting a country-specific adjustment factor. INTRODUCTION: It remains unclear whether young normal BMD reference values specific to an American population can be validly used for T-score calculation in Europeans. METHODS: We collected population based BMD data from 1163 men and 329 women aged 19-29 years from 17 centres across Europe to compare mean and SD values with the NHANES-III study USA results. BMD(g/cm2) was measured at the hip and spine using DXA densitometers cross-calibrated with the European Spine Phantom (ESP). The only exclusions were for technically inadequate scans. A linear regression model was used to derive reference values. To allow for direct comparison with published NHANES III study data, the cross-calibrated BMD values were converted using the ESP equations to Hologic QDR 1000 units. RESULTS: In men, the overall mean(SD) BMD values expressed in Hologic-QDR1000 units of measurement, were: femoral neck 0.912(0.132); trochanter 0.793(0.124); and L2-L4 spine 1.027(0.123). The respective estimates in women were: 0.826(0.115); 0.670(0.093); and 0.983(0.107). However the I2 statistic for heterogeneity indicated moderate to strong evidence of between-centre heterogeneity. There was, however, no significant heterogeneity observed between centres within countries, suggesting that this variation arose from national differences. Compared to the NHANES III population-based US data, the mean values in women were significantly lower at both sites due to some lower national European means. However, at all sites and in both sexes the SD's were very similar between the US and Europe. There was some evidence that recruiting volunteers resulted in biased values in women. CONCLUSION: Our T-score normal values for the lumbar spine (L2-L4) should be more reliable for spine-specific risk assessment than some non-representative normal ranges, and should be evaluated for that purpose in Europe. If T-scores are to be used to compare individual data with ranges seen in normal young subjects of the same nationality, it may be necessary to adjust femoral NHANES III-based T-scores by adding (or subtracting) a country-specific adjustment factor. In risk assessment it is probably sufficient to use NHANES III-based hip T-scores, as supplied for the hip by densitometer manufacturers, interpreting them in light of recent international meta-analysis data on the relationship between BMD and fracture risk.

Large-scale analysis of association between polymorphisms in the transforming growth factor beta 1 gene (TGFB1) and osteoporosis: the GENOMOS study.

INTRODUCTION: The TGFB1 gene which encodes transforming growth factor beta 1, is a strong candidate for susceptibility to osteoporosis and several studies have reported associations between bone mineral density (BMD), osteoporotic fractures and polymorphisms of TGFB1, although these studies have yielded conflicting results. METHODS: We investigated associations between TGFB1 polymorphisms and BMD and fracture in the GENOMOS study: a prospective multicenter study involving 10 European research studies including a total of 28,924 participants. Genotyping was conducted for known TGFB1 polymorphisms at the following sites: G-1639-A (G-800-A, rs1800468), C-1348-T (C-509-T, rs1800469), T29-C (Leu10Pro, rs1982073), G74-C (Arg25Pro, rs1800471) and C788-T (Thr263Ile, rs1800472). These polymorphisms were genotyped prospectively and methodology was standardized across research centers. Genotypes and haplotypes were related to BMD at the lumbar sine and femoral neck and fractures. RESULTS: There were no significant differences in either women or men at either skeletal site for any of the examined polymorphisms with the possible exception of a weak association with reduced BMD (-12 mg/cm2) in men with the T-1348 allele (p<0.05). None of the haplotypes was associated with BMD and none of the polymorphisms or haplotypes significantly affected overall risk of fractures, however, the odds ratio for incident vertebral fracture in carriers of the rare T788 allele was 1.64 (95% CI: 1.09-2.64), p<0.05. CONCLUSIONS: This study indicates that polymorphic variation in the TGFB1 gene does not play a major role in regulating BMD or susceptibility to fractures. The weak associations we observed between the C-1348-T and lumbar spine BMD in men and between C788-T and risk of incident vertebral fractures are of interest but could be chance findings and will need replication in future studies.

Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis.

CONTEXT: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population. OBJECTIVE: To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. DESIGN AND SETTING: Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. MAIN OUTCOME MEASURES: Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. RESULTS: The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20,096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31,435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. CONCLUSIONS: Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.

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. Control material (n = 48, 25 male) was available through consented post mortems prior to the year 2000. Cortical widths were averaged for circumferential octants, each representing 45 degrees of arc. Divergence of individual cortical widths from their means was also examined. RESULTS: Because sections were required to have a complete cortex, sampling was biased towards cases with sub-capital versus trans-cervical fractures. Compared to sex- and age matched controls, male cases showed larger relative differences in cortical widths than female cases. Unexpectedly, cortical widths in female but not male cases also showed marked over-representation of extremely narrow (<0.1 mm) cortical widths, located mainly posteriorly. The numbers of these very narrow cortical widths observed per subject retrospectively predicted female fracture status in logistic regression independently of mean cortical width values. Together with mean cortical width differences, the numbers of measured cortical widths <0.1 mm (out of 72 measured) raised the sensitivity of predicting fracture status in women from 48 to 80% at 80% specificity. In almost all cases, very narrow cortical widths were identified in regions enclosing a cortical pore roofed on its endosteal surface by thin structural bone defined a priori as trabecular. CONCLUSIONS: Cortical widths <0.1 mm probably reflect zones where endosteal cortex has been trabecularised through expansion of an un-refilled sub-endosteal canal close to the periosteum. Persistent cortical defects occurring near the periosteal surface, where mechanical loading exerts its greatest stresses, are likely to result in extremes of localized concentrations of stress during a fall, unknown in young normal fallers. Such defects have the potential to help explain the excess of hip fractures among elderly women. Prevention of sub-periosteal tunnelling by osteoclasts might explain in part the additional benefits, beyond an increase in bone density, of treatments that reduce excessive bone resorption or else stimulate new bone formation on previously resorbed surfaces.

A single infusion of zoledronate prevents bone loss after stroke.

BACKGROUND AND PURPOSE: Stroke is a major risk factor for hip fracture. Patients with intermediate rather than severe or mild stroke deficits at the time of hospital discharge have the most fractures. This proof-of-concept study evaluated the efficacy of a single infusion of zoledronate, an intravenous bisphosphonate, in preserving hip bone density after stroke. METHODS: In a 1-year randomized, double-blind, placebo-controlled, clinical trial, 27 newly hemiplegic patients (6 females, 21 males) with acute stroke were assigned to receive 4 mg of the intravenous zoledronate (n=14) or placebo (n=13) within 35 days. Strict inclusion criteria were followed-up to ensure recruited patients were likely to have residual functional impairment. Both groups received calcium and vitamin D supplementation. The primary outcome measure was the change in bone mineral density (BMD; Lunar Prodigy) at the hemiplegic hip during the year of investigation. RESULTS: The treatment was generally well tolerated. Mean total hip BMD was unchanged in the hemiplegic hip of the zoledronate group (mean 0.0% change), whereas in the placebo group the total hip BMD changed by -5.5%, with the greatest bone loss observed in the trochanteric subregion (mean, -8.1%). On the unaffected side the mean change in total hip BMD was +1.0% with zoledronate versus a mean change of -2.7% without. Repeated measures ANOVA confirmed the significance of the differences between groups at both hips (hemiplegic, P<0.001; unaffected, P=0.002). CONCLUSIONS: Stroke patients were protected from the deleterious effects of hemiplegia on hip bone density for at least 1 year after a single infusion of zoledronate.

More acidic dietary acid-base load is associated with reduced calcaneal broadband ultrasound attenuation in women but not in men: results from the EPIC-Norfolk cohort study.

BACKGROUND: Dietary patterns that promote mild metabolic acidosis may have a negative effect on bone density. OBJECTIVE: We investigated the relation between a measure of dietary acid-base load, potential renal acid load (PRAL), and calcaneal broadband ultrasound attenuation (BUA) after adjustment for confounders and also compared the results with different estimates of acid-base load. DESIGN: A cross-sectional study was conducted in 14 563 men and women aged 42-82 y living in Norfolk, United Kingdom, in which measures of calcaneal BUA and dietary PRAL were estimated by using the European Prospective Investigation into Cancer and Nutrition Norfolk (EPIC-Norfolk) food-frequency questionnaire. RESULTS: A more acidic dietary intake (high PRAL) was significantly associated with lower calcaneal BUA in women but not in men; there was a difference of approximately 2% in BUA between the highest and lowest quintiles of PRAL, independent of age, body mass index, smoking habit, physical activity, diagnosed osteoporosis, and history of fracture, and (in women) hormone replacement therapy. No relation was observed between history of fracture or incident fracture and PRAL. Those with the greatest PRAL had higher intakes of meat, fish, eggs, and cereal and cereal products and lower intakes of fruit and vegetables, tea, and coffee. CONCLUSION: PRAL was inversely associated with bone ultrasound measures in women, but the magnitude of the association was relatively small compared with other known risk factors. Further longitudinal studies are required to establish whether, in the long term, these small effects are important in overall fracture risk in populations.

The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis.

BACKGROUND: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear. OBJECTIVE: To evaluate the relation between VDR polymorphisms, BMD, and fractures. DESIGN: Prospective multicenter large-scale association study. SETTING: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams. PARTICIPANTS: 26,242 participants (18,405 women). MEASUREMENTS: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures. RESULTS: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model). LIMITATIONS: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis. CONCLUSIONS: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.

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. These have been described at multiple length scales from the individual bone mineral crystal to the scale of the femur itself and appear to operate hierarchically. Each cortical bone fracture begins as a sub-microscopic crack that enlarges under mechanical load, for example, that imposed by a fall. In these conditions, a crack will enlarge explosively unless the cortical bone is intrinsically tough (the opposite of brittle). Toughness leads to microscopic crack deflection and bridging and may be increased by adequate regulation of both mineral crystal size and the heterogeneity of mineral and matrix phases. The role of osteocytes in optimising toughness is beginning to be worked out; but many osteocytes die in situ without triggering bone renewal over a 20-year cycle, with potential for increasing brittleness. Furthermore, the superolateral cortex of the proximal femur thins progressively during life, so increasing the risk of buckling during a fall. Besides preserving or increasing hip BMD, pharmaceutical treatments have class-specific effects on the toughness of cortical bone, although dietary and exercise-based interventions show early promise.

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. In the FEMCO case-control clinical study, Cortical Bone Mapping (CBM) was applied to clinical computed tomography (CT) scans to define 3D cortical and trabecular bone defects in patients with acute hip fracture compared to controls. Direct measurements of trabecular bone volume were then made in biopsies of target regions removed at operation. METHODS: The sample consisted of CT scans from 313 female and 40 male volunteers (158 with proximal femoral fracture, 145 age-matched controls and 50 fallers without hip fracture). Detailed Cortical Bone Maps (c.5580 measurement points on the unfractured hip) were created before registering each hip to an average femur shape to facilitate statistical parametric mapping (SPM). Areas where cortical and trabecular bone differed from controls were visualised in 3D for location, magnitude and statistical significance. Measures from the novel regions created by the SPM process were then tested for their ability to classify fracture versus control by comparison with traditional CT measures of areal Bone Mineral Density (aBMD). In women we used the surgical classification of fracture location ('femoral neck' or 'trochanteric') to discover whether focal osteoporosis was specific to fracture type. To explore whether the focal areas were osteoporotic by histological criteria, we used micro CT to measure trabecular bone parameters in targeted biopsies taken from the femoral heads of 14 cases. RESULTS: Hip fracture patients had distinct patterns of focal osteoporosis that determined fracture type, and CBM measures classified fracture type better than aBMD parameters. CBM measures however improved only minimally on aBMD for predicting any hip fracture and depended on the inclusion of trabecular bone measures alongside cortical regions. Focal osteoporosis was confirmed on biopsy as reduced sub-cortical trabecular bone volume. CONCLUSION: Using 3D imaging methods and targeted bone biopsy, we discovered focal osteoporosis affecting trabecular and cortical bone of the proximal femur, among men and women with hip fracture.

Infant growth influences proximal femoral geometry in adulthood.

UNLABELLED: The relationship between early growth and adult femoral geometry has not been studied previously. In 333 adults, we were able to show that infant weight predicts femoral width and cross-sectional moment of inertia but not femoral neck length. These results support the hypothesis that growth in early life leads to persisting differences in proximal femoral geometry. INTRODUCTION: Both femoral geometry and bone mass have been shown independently to predict both hip strength and fracture risk. Whereas growth during intrauterine and early postnatal life has been shown to influence adult bone mass, the relationship between growth in early life and adult femoral geometry has not been described previously. MATERIALS AND METHODS: We studied the relationship between growth during early life, adult hip geometry, and proximal femur bone mass in a sample of 333 men and women (60-75 years of age), for whom birth weight and weight at 1 year of age were recorded. Hip geometry was derived using Hip Structure Analysis software from proximal femur DXA scans (Hologic QDR 1000). RESULTS: There were significant (p < 0.002) relationships between weight at age 1 year and measures of femoral width as well as intertrochanteric (IT) cross-sectional moment of inertia (CSMI), but not with femoral neck length. The relationships with measures of femoral width but not CSMI remained after adjusting for adult body weight and were independent of proximal femoral BMC. CONCLUSIONS: These results support the hypothesis that different patterns of growth in utero and during the first year of life lead to persisting differences in proximal femoral geometry, thereby mediating in part the effects of early growth on risk of hip fracture in adulthood.

Reduced vitamin D in acute stroke.

BACKGROUND AND PURPOSE: Stroke leads to a reduction in bone mineral density, altered calcium homeostasis, and an increase in hip fractures. Vitamin D deficiency is well documented in long-term stroke survivors and is associated with post-stroke hip fractures. Less is known regarding levels in acute stroke. METHODS: We compared the serum 25-dihydroxyvitamin D levels of 44 patients admitted to an acute stroke unit with first-ever stroke with results obtained by measuring 96 healthy ambulant elderly subjects every 2 months for 1 year. Statistical Z scores of serum vitamin D were then calculated after seasonal adjustment for the month of sampling. RESULTS: The mean Z score of vitamin D in acute stroke was -1.4 SD units (95% CI, -1.7, -1.1), with 77% of patients falling in the insufficient range. CONCLUSIONS: Reduced vitamin D was identified in the majority of patients with acute stroke throughout the year and may have preceded stroke. Vitamin D is a potential risk marker for stroke, and the role of vitamin D repletion in enhancing musculoskeletal health after stroke needs to be explored.

Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study.

BACKGROUND: Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes. METHODS AND FINDINGS: Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm2 (CI, 16 to 34 mg/cm2) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm2 (CI, 1 to 42 mg/cm2), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses. CONCLUSIONS: Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.

Relation between age, femoral neck cortical stability, and hip fracture risk.

BACKGROUND: Hip fracture risk rises 100 to 1000-fold over 60 years of ageing. Loss of resistance to bending is not a major feature of normal ageing of the femoral neck. Another cause of fragility is local buckling or elastic instability. Bones adapt to their local experience of mechanical loading. The suggestion that bipedalism allows thinning of the underloaded superolateral femoral neck cortex arises from the failure of walking to transmit much mechanical load to this region. We aimed to measure whether elastic instability increases greatly with age since it might trigger hip fracture in a sideways fall. METHODS: We measured with computed tomography the distribution of bone in the mid-femoral neck of 77 proximal femurs from people who died suddenly aged 20-95 years. We then calculated the critical stress, from the geometric properties and density of the cortical zone most highly loaded in a sideways fall, as a threshold for elastic instability. FINDINGS: With normal ageing, this thin cortical zone in the upper femoral neck became substantially thinner. Relative to mean values at age 60 years, female cortical thickness declined by 6.4% (SD 1.1) per decade (p<0.0001), and critical stress by 13.2% (4.3) per decade (p=0.004) in the superoposterior octant compressed most in a sideways fall. Similar, but significantly smaller, effects were evident in men (p=0.004). This thinning compromised the capacity of the femur to absorb energy independently of osteoporosis. Patients with hip fracture had further reduced stability. INTERPRETATION: As women age, hip fragility increases because underloading of the superolateral cortex leads to atrophic thinning. Because walking does not sufficiently load the upper femoral neck, the fragile zones in healthy bones may need strengthening, for example with more well targeted exercise.

Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation.

Osteocytes are the most abundant cells in bone and are ideally located to influence bone turnover through their syncytial relationship with surface bone cells. Osteocyte-derived signals have remained largely enigmatic, but it was recently reported that human osteocytes secrete sclerostin, an inhibitor of bone formation. Absent sclerostin protein results in the high bone mass clinical disorder sclerosteosis. Here we report that within adult iliac bone, newly embedded osteocytes were negative for sclerostin staining but became positive at or after primary mineralization. The majority of mature osteocytes in mineralized cortical and cancellous bone was positive for sclerostin with diffuse staining along dendrites in the osteocyte canaliculi. These findings provide for the first time in vivo evidence to support the concept that osteocytes secrete sclerostin after they become embedded in a mineralized matrix to limit further bone formation by osteoblasts. Sclerostin did not appear to influence the formation of osteocytes. We propose that sclerostin production by osteocytes may regulate the linear extent of formation and the induction or maintenance of a lining cell phenotype on bone surfaces. In doing so, sclerostin may act as a key inhibitory signal governing skeletal microarchitecture.