Background and aims: There is evidence that distinct genetic polymorphisms of LRP5 are associated with low Bone Mineral Density (BMD) and the risk of fracture. However, relationships between LRP5 polymorphisms and micro- and macroarchitectural bone characteristics assessed by pQCT have not been studied. The aim of the present study was to investigate the association of Ala1330Val and Val667Met polymorphisms in LRP5 gene with volumetric BMD (υBMD) and macro-architectural bone parameters in a population-based sample of men and women. Methods: We studied 959 participants of the InCHIANTI study (451 men and 508 women, age range: 21–94 yrs). Trabecular υBMD (υBMDt, mg/cm3), cortical υBMD (υBMDc, mg/cm3), cortical bone area (CBA, mm2) and cortical thickness (Ct.Th, mm) at the level of the tibia were assessed by peripheral quantitative computed tomography (pQCT). Ala1330Val and Val667Met genotypes were determined on genomic DNA by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: In age-adjusted analyses both LRP 1330-valine and LRP 667-metionin variants were associated with lower υBMDt in men (p<0.05), and lower υBMDt (p<0.05), Ct.Th (p<0.05) and CBA (p<0.05) in women. After adjusting for multiple confounders, only the association of LRP5 1330-valine and 667-metionin with CBA remained statistically significant (p=0.04 and p=0.01, respectively) in women. Conclusion: These findings suggest that both Ala1330Val and Val667Met LRP5 polymorphisms may affect the determination of geometric bone parameters in women.

BACKGROUND AND AIMS:In advanced age, the influence of vertebral fractures on quality of life extends well beyond the usual sequelae of osteoporosis. In order to intercept older subjects' distress associated with the clinical, functional, social and psychological consequences of the disease, we developed and validated a multidimensional instrument (the triple-Q questionnaire) tailored to older women with osteoporotic fractures. We also examined specific aspects of the questionnaire correlated with bone mineral density.METHODS:100 osteoporotic women with vertebral fractures and 100 controls aged >65 years, underwent a thorough examination, which also included X-ray of the thoraco-lumbar spine, hip densitometry, the triple-Q questionnaire, and five referral instruments evaluating function, cognition, perception of general health, mood and pain.RESULTS:The questionnaire was repeatable and able to discriminate between older women with and without vertebral fractures. There was a strong association between referral instrument scores and the corresponding single domain score of the questionnaire. Femoral BMD was also associated with scores indicating fear of falling, fear of fracture, and pain.CONCLUSIONS:The questionnaire intercepted the influence of osteoporosis on the quality of life of elderly women with vertebral fractures. Subjects who suffered from severe pain and were more fearful of falling were most likely to be severely osteoporotic.

It is now recognized that quantitative ultrasound (QUS) measures may predict osteoporotic fracture risk independently of bone mineral density. Although many studies have examined genetic and environmental components of bone mineral density and calcaneal QUS measures, few of them were addressed to phalangeal QUS phenotypes, and none to graphic trace parameters. This study aims to evaluate the relative contribution of genetics in the expression of phalangeal QUS traits in the adult healthy population of a Sardinian genetic isolate. Our sample includes 6056 men and women aged 30-103 years, from 43 extended pedigrees recruited in 10 villages of Ogliastra region in occasion of a large epidemiologic survey. Amplitude-dependent speed of sound (AD-SoS), fast wave amplitude (FWA), signal dynamic (SDy), bone transmission time (BIT) and ultrasound bone profile index (UBPI) were obtained from the non-dominant hand using the IGEA DBM Sonic Bone Profiler (TM). These phenotypes were first regressed on age, anthropometric and bioimpedance measures, serum calcium, phosphorus and alkaline phosphatase, alcohol and caffeine consumption, smoking status, exercise and also months since menopause and estrogens use in women. Adjusted QUS parameters were then analyzed by univariate and bivariate variance component models to obtain heritability estimates and genetic and environmental correlations. QUS parameters were correlated to age, anthropometric and bioimpedance measures, serum phosphorus, alkaline phosphatase and to reproductive history and menopause in women. All phenotypes demonstrated substantial heritabilities ranging from 0.29 +/- 0.03 for SDy to 0.55 +/- 0.03 for FWA. Proportion of variance due to all covariates ranged from 36% for SDy to 59% for BTT. Many significant genetic and environmental correlations were found between the different QUS measures. In this study, genetic factors appear to play a relevant role in determining hand QUS measures even when taking into account various important environmental factors. Furthermore, the modest genetic correlations may imply the existence of partially unique sets of genes affecting different QUS traits, thus suggesting that QUS parameters measure different properties of bone tissue. (C) 2009 Elsevier Inc. All rights reserved.

Families affected by Paget’s disease of bone frequently harbor mutations in the SQSTM1/p62 gene. In this multicentric study we collected 345 sporadic and 12 familial PDB cases throughout Italy, identifying 12 different mutations, 5 of which are newly reported and 3, D335E, A381V, and Y383X, external to the UBA domain. Subjects with truncating mutations, E396X, showed a significantly younger age at clinical diagnosis, while the Y383X subjects had a higher average number of affected skeletal sites. All the mutants exhibited the CGTG-H2 haplotype. In two pairs and one triad of unrelated Italian PDB families from different Italian regions, we detected a common SQSTM1/p62 mutation for each P392L, M404V, and G425R group. Since the CGTG-H2 haplotype frequency was also high in normal subjects, and genetic influence due to migratory fluxes of different ethnic groups exists in the Italian population, to refine the search for a more geographically specific founder effect, we extended the haplotype analysis in these families using polymorphic microsatellite repeat markers, within and flanking the SQSTM1/p62 locus, from chromosome 5q35, other than the exon 6 and 3′UTR polymorphisms. All mutant carriers from two of the three M404V families and from the G425R families exhibited common extended chromosome 5q35 haplotypes, IT01 and IT02, respectively, which may be reflecting influences of past migrations. This may be helpful in estimating the true rate of de novo mutations. We confirm the data on the existence of both a mutational hotspot at the UBA domain of SQSTM1/p62 and a founder effect in the PDB population.

Recent results suggest that ultrastructural bone phenotypes, such as the cortical canal network and the osteocyte lacunar system, could be directly linked to the mechanical failure behavior of bone tissue. Moreover, we recently established a synchrotron radiation (SR)-based computed tomography (CT) method, allowing volumetric quantitative morphometry of bone ultrastructure and microdamage (Figure), where microdamage is believed to be a precursor of mechanical failure. Consequently, the aim of this study was to investigate quantitatively the eect of the canal network on microcrack initiation, propagation, and accumulation in two inbred strains of mice, C57BL/6 (B6) and C3H/He (C3H). We hypothesize that dierences in the canal network will help to better predict microdamage in cortical bone. Seven femora each from 16-week-old female B6 and C3H mice were embedded at both ends into polymethyl methacrylate (PMMA) cement. Additionally, a round notch was created in the proximal quadrant of the mid-diaphysis, where microcracks initiated and propagated while the bone was loaded using image-guided failure assessment (IGFA). During compression at 1% apparent strain, a high-resolution 3D image (700 nm nominal resolution) was acquired using SR CT. For morphometry, the canal network (Ca) and microcracks (Cr) were extracted as two separate phases. For each phase, a set of morphometrical indices were measured, such as canal volume density (Ca.V/Ct.V), canal unit volume (Ca.V/N.Ca), and crack number density (N.Cr/Ct.V) , where Ct.V, N.Ca and N.Cr refer to cortical bone volume, number of canals and number of cracks, respectively. Relationships between Ca and Cr indices were computed by linear regression analysis. Results from linear regression analysis involving both mouse strains showed that cannular indices were strongly associated to microcrack behavior. Canal volume density (R = 0.64, p , 0.005) and canal unit volume (R = 0.75, p , 0.001) both predicted the number of microcracks per unit volume of cortical bone. Classical morphometric indices correlated only moderately with the number of microcracks (data not shown here), where cortical thickness (R = 0.45) showed the highest correlation among them. In conclusion, we showed for the first time how bone ultrastructure predicts number of microcracks and consequently how bone ultrastructure contributes to bone strength. These new findings shed new light on the complex relation between bone quality and bone competence and might help to better understand human bone diseases like osteoporosis. Figure: Canal network (tubes in red), osteocyte lacunae (prolate ellipsoids in yellow) and microcrack (green cleft) within murine cortical bone (semitransparent shell in blue) of the femoral mid-diaphysis. Disclosures: Philipp Schneider, None.

The aim of this cross-sectional study was to study the value of five different quantified ultrasound (QUS) parameters-amplitude-dependent speed of sound (AD-SoS), Ultrasound Bone Profile Index (UBPI), fast-wave amplitude (FWA), bone transmission time (BTT) and signal dynamic (SDY)-measured at the phalanges of the hand in discriminating women with vertebral fracture and their relationship with some determinants of bone mass, in particular age and gonadal status compared with lumbar spine and hip dual-energy x-ray absorptiometry (DXA). We included 791 women aged 35-84 y, divided into pre-menopause, early menopause and late postmenopause groups on the basis of gonadal status and years since menopause (YSM). The presence of vertebral fracture was evaluated radiographically. All QUS parameters were very sensitive to changes in early postmenopause, with a doubled decrease in early postmenopausal with respect to late postmenopause. In particular AD-SoS and BTT decreases were markedly high in the early postmenopause group. In the late menopause group, similar decreases were observed for AD-SoS, UBPI and hip bone mineral density (BMD). In the multiple logistic model, DXA and QUS significantly discriminate women with and without fractures (p < 0.0001); odds ratio (OR) was higher at lumbar spine BMD (OR 4.01), FWA (OR 3.88), AD-SoS (OR 3.81) and total hip BMD (OR 3.77). Even adjusting the logistic model for age, height, weight, lumbar spine and total hip BMD, all QUS parameters remained significantly predictive of vertebral fracture. AD-SoS showed the best performances both in terms of OR and ROC analysis. QUS parameters show a different behavior in evaluating the effect on bone mass of the time since menopause; AD-SoS and BTT showed a high sensitivity to first changes in bone tissue after menopause. After correction for potential confounders, AD-SoS showed the same ability of lumbar spine BMD in discriminating women with or without vertebral fractures and in the prediction of fracture risk.

Both atherosclerosis and osteoporosis are responsible for significant morbidity and mortality, are independent predictors of cardiovascular disease (CVD) events, and may share common regulatory mechanisms as well as histopathology.Abdominal aortic calcification (AAC), an indication of atherosclerosis, is significantly associated with both cardiovascular heart disease and stroke. The increased risk of cardiovascular disease mortality associated with moderate to severe AAC is similar to the increased risk of hip fracture in the presence of a moderate to severe vertebral fracture. A negative association between bone mineral density (BMD) and AAC severity has been also demonstrated.Several non-invasive methods are available to investigate the presence and the severity of osteoporosis. With some of these is possible to measure aortic calcification and bone mass in the same exam. A new method for the evaluation of aorta calcification by dual X-Ray absorptiometry (DXA) has been recently suggested: the Instant Vertebral Assessment (IVA), which offers the possibility to obtain in the same scan an assessment of vertebral fracture and AAC. Therefore, a single IVA exam could assist in stratifying patients into high and low risk groups for two highly prevalent and significant health care problems.

In the last 25 years, several non-invasive techniques based on the attenuation of ionising radiation have been developed to quantify bone mineral density in the axial and peripheral skeleton. They represent valid methods for determination of BMD and explain about 60-80% of the variation in bone strength. However, they provide only limited information on bone structure and on bone material properties. Quantitative ultrasound (QUS) methods have been introduced for the assessment of skeletal status in osteoporosis; the physical interaction of ultrasound and bone is complex, and not completely understood; however, it is considered that QUS provides information both on bone mass and structure. QUS, because of the lack of ionising radiation, relative portability of the equipment, ease of use, and low cost, has seen marked success around the world, though it has been approved only in 1999 by FDA for clinical use in USA. The relative contribution to bone assessment of both ultrasound and the current gold standard method for bone assessment, dual x-ray absorptiometry (DXA), is still to be determined; nevertheless, QUS has demonstrated that it is able to detect bone fragility as well as DXA. Further studies needed on the diagnosis of osteoporosis using ultrasound, because current diagnostic threshold designed by the World Health Organization, cannot be always applied to QUS parameters. A better option for QUS would be to report results in terms of fracture risk, keeping in mind that a risk estimate depends not only on QUS or DXA measurement, but also on clinical risk factors.

Fragility fractures in men represent a major health problem, and this prompts a necessity for reliable tools for the identification of men at risk of fracture. In order to assess the ability of dual-energy X-ray absorptiometry (DXA) and quantitative ultrasound (QUS) in the prediction of fracture risk in men and whether their combination might be useful in a clinical setting, we studied 401 men (age range 45–82 years, mean 60.3±12.5), of whom 133 had osteoporotic fractures and 268 did not. In all subjects we measured bone mineral density at the lumbar spine (BMD-LS) and at the femur, calculating thereafter the standard femoral subregions: neck (BMD-FN), total hip (BMD-T), trochanter (BMD-TR), intertrochanter (BMD-ITR), and Ward’s triangle (BMD-W), by DXA. We also performed ultrasound parameters at the calcaneus: speed of sound (SOS), broadband ultrasound attenuation (BUA) and Stiffness, by Achilles plus, and at the phalanxes: amplitude dependent speed of sound (AD-SoS) and the parameters of the graphic trace: bone transmission time (BTT), fast wave amplitude (FWA), signal dynamic (SDy) and ultrasound bone profile index (UBPI), by Bone Profiler. All DXA and QUS parameters, apart from FWA, were significantly (P<0.001) lower in patients with a history of fracture. BMD at the proximal femur showed the best ability in discriminating men with or without fractures. QUS at the heel showed discriminatory ability significantly better than QUS at the fingers. By logistic regression analysis, adjusted for age and BMI, BMD-T showed the best association with fragility fracture [odds ratio (OR)=3.43, 95% confidence interval (CI)=2.47–4.77]. Among QUS parameters, the highest value of the OR was shown by stiffness (OR=3.18, CI=2.27–4.48). FWA and SDy were not associated with fragility fractures in men. If DXA and QUS were combined, the prediction of the OR of fragility fracture events in men increases; in fact Stiffness was able to increase the OR when added to BMD-LS (OR=5.44, CI=3.16–10.13) and BMD-T (OR=6.08, CI=2.63–14.27). SOS and BUA showed a similar pattern. AD-SoS improved the prediction of fracture only when combined with BMD-LS (OR=4.36, CI=1.99–9.57). If BMD-LS and BMD-FN or BMD-T were combined, the value of the OR increases (OR=4.59, CI=2.27–9.25 and OR=4.68, CI=2.24–9.76), respectively. Our study supports the effectiveness of QUS in the identification of osteoporotic fractures in men. QUS seems to play an independent and complementary role, with respect to DXA, in order to enhance the power for predicting osteoporotic fractures in men.

L'osteoporosi è una malattia caratterizzata da riduzione della massa ossea, deterioramento microarchitettonico del tessuto osseo e conseguente aumento della fragilità ossea e della predisposizione alle fratture. Questa definizione, stabilita nella consensus conference di Copenhagen (1990)1 e confermata in quella di Hong Kong (1993)2, sottolinea come la fragilità ossea che caratterizza l'osteoporosi sia la conseguenza non solo della riduzione della massa ossea, ma anche del danno architettonico che ne deriva. Viene inoltre precisato come l'osteoporosi divenga clinicamente rilevante solo quando il paziente presenti una frattura. L'osteoporosi, più che una malattia, deve essere considerata una condizione a rischio al pari della ipertensione arteriosa e dell'ipercolesterolemia3. Le osteoporosi possono essere primitive o secondarie e verranno qui analizzate in dettaglio.