Bone composition: relationship to bone fragility and antiosteoporotic drug effects.
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ABSTRACT:
SUBMITTER: Boskey AL
PROVIDER: S-EPMC3909232 | biostudies-other | 2013
REPOSITORIES: biostudies-other
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Project description:Fourier transform infrared imaging (FTIRI) provides information on spatial distribution of the chemical composition of thin tissue specimens at ?7?µm spatial resolution. This study of 120 age- and bone mineral density (BMD)-matched patients was designed to investigate the association of FTIRI variables, measured in iliac crest biopsies, with fragility fractures at any site. An earlier study of 54 women found hip BMD to be a significant explanatory variable of fracture risk for cortical bone but not for cancellous bone. In the current study, where age and BMD were controlled through matching, no such association was observed, validating the pairing scheme. Our first study of unmatched iliac crest biopsies found increases in collagen maturity (cancellous and cortical bone) and mineral crystal size (cortical bone only) to be a significant explanatory variable of fracture when combined with other covariates. The ratio for collagen maturity has been correlated to the amount of enzymatic collagen cross-links. To assess the impact of other FTIRI variables (acid phosphate substitution, carbonate-to-phosphate ratio, and the pixel distribution [heterogeneity] of all relevant FTIRI variables), we examined biopsies from a matched case-controlled study, in which 60 women with fractures were each paired with an age- and BMD-matched female control. With the matched data set of 120 women, conditional logistic regression analyses revealed that significant explanatory variables of fracture were decreased carbonate-to-phosphate ratio in both cancellous (odds ratio [OR]?=?0.580, 95% confidence interval [CI] 0.37-0.909, p?=?0.0176) and cortical bone (OR?=?0.519, 95% CI 0.325-0.829, p?=?0.0061), and increased heterogeneity (broadened pixel distribution) of collagen maturity for cancellous bone (OR?=?1.549, 95% CI 1.002-2.396, p?=?0.0491). The observation that collagen maturity was no longer linked to fracture in age- and BMD-matched samples suggests that age-dependent variation in collagen maturity may be a more important contributory factor to fragility fractures than previously thought. © 2015 American Society for Bone and Mineral Research.
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Project description:Bone fragility is a pathological condition caused by altered homeostasis of the mineralized bone mass with deterioration of the microarchitecture of the bone tissue, which results in a reduction of bone strength and an increased risk of fracture, even in the absence of high-impact trauma. The most common cause of bone fragility is primary osteoporosis in the elderly. However, bone fragility can manifest at any age, within the context of a wide spectrum of congenital rare bone metabolic diseases in which the inherited genetic defect alters correct bone modeling and remodeling at different points and aspects of bone synthesis and/or bone resorption, leading to defective bone tissue highly prone to long bone bowing, stress fractures and pseudofractures, and/or fragility fractures. To date, over 100 different Mendelian-inherited metabolic bone disorders have been identified and included in the OMIM database, associated with germinal heterozygote, compound heterozygote, or homozygote mutations, affecting over 80 different genes involved in the regulation of bone and mineral metabolism. This manuscript reviews clinical bone phenotypes, and the associated bone fragility in rare congenital metabolic bone disorders, following a disease taxonomic classification based on deranged bone metabolic activity.
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Project description:This study sought to define the sex-difference in trabecular and cortical bone parameters in Vietnamese individuals. The study involved 1404 women and 864 men aged between 20 and 86 years who were recruited from Ho Chi Minh City, Vietnam. Trabecular and cortical volumetric BMD were measured at the proximal tibia and proximal radius at 4%, 38%, and 66% points, using a peripheral quantitative computed tomography XCT2000 (Stratec, Germany). Polar strength strain index was estimated from cortical bone parameters. Changes in bone parameters were assessed by the multiple linear regression model. Among individuals aged 20-39 years, women had significantly lower peak trabecular BMD at both the radius (40%) and tibia (16%) than men, but the age-related reduction in trabecular BMD were similar between two sexes. For cortical BMD, peak values in women and men were comparable, but the age-related diminution was greater in women than men. At any age, polar strength strain index in women was lower than men, and the difference was mainly attributable to cortical bone area and total bone mass. We conclude that in the elderly, sex-related difference in trabecular BMD is originated during growth, but sex-related difference in cortical BMD is determined by differential age-related bone loss.
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Project description:CIDR_Genetic Determinants of Bone Fragility
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Project description:We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated ?-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis.
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Project description:Brittle cornea syndrome is a rare recessively inherited disorder (a sub-type of Ehlers-Danlos syndrome) with a clinical presentation dominated by corneal fragility and deafness. There have been suggestions that it may also have a bone fragility phenotype, but there has been little detailed description. We describe two siblings with brittle cornea syndrome due to compound heterozygous mutations in ZNF469 who had sustained ten or more fractures, the majority before the age of 15. When investigated as adults they had osteopenia, with lower z-scores than their parents who each carried one mutation. A bone biopsy from one sibling showed reduced cortical porosity. Both parents, who were heterozygous mutation carriers, had also suffered fractures but had normal bone density. This data supports the view that brittle cornea syndrome may have a bone fragility phenotype.
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Project description:The impaired maturation of bone-forming osteoblasts results in reduced bone formation and subsequent bone weakening, which leads to a number of conditions such as osteogenesis imperfecta (OI). Transplantation of human fetal mesenchymal stem cells has been proposed as skeletal anabolic therapy to enhance bone formation, but the mechanisms underlying the contribution of the donor cells to bone health are poorly understood and require further elucidation. Here, we show that intraperitoneal injection of human amniotic mesenchymal stem cells (AFSCs) into a mouse model of OI (oim mice) reduced fracture susceptibility, increased bone strength, improved bone quality and micro-architecture, normalised bone remodelling and reduced TNFα and TGFβ sigalling. Donor cells engrafted into bones and differentiated into osteoblasts but importantly, also promoted endogenous osteogenesis and the maturation of resident osteoblasts. Together, these findings identify AFSC transplantation as a countermeasure to bone fragility. These data have wider implications for bone health and fracture reduction.
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Project description:Using adult identified bone mineral density (BMD) loci, we calculated genetic risk scores (GRS) to determine if they were associated with changes in BMD during childhood. Longitudinal data from the Bone Mineral Density in Childhood Study were analyzed (N = 798, 54% female, all European ancestry). Participants had up to 6 annual dual energy X-ray scans, from which areal BMD (aBMD) Z-scores for the spine, total hip, and femoral neck were estimated, as well as total body less head bone mineral content (TBLH-BMC) Z-scores. Sixty-three single-nucleotide polymorphisms (SNPs) were genotyped, and the percentage of BMD-lowering alleles carried was calculated (overall adult GRS). Subtype GRS that include SNPs associated with fracture risk, pediatric BMD, WNT signaling, RANK-RANKL-OPG, and mesenchymal stem cell differentiation were also calculated. Linear mixed effects models were used to test associations between each GRS and bone Z-scores, and if any association differed by sex and/or chronological age. The overall adult, fracture, and WNT signaling GRS were associated with lower Z-scores (eg, spine aBMD Z-score: βadult = -0.04, p = 3.4 × 10(-7) ; βfracture = -0.02, p = 8.9 × 10(-6) ; βWNT = -0.01, p = 3.9 × 10(-4) ). The overall adult GRS was more strongly associated with lower Z-scores in females (p-interaction ≤ 0.05 for all sites). The fracture GRS was more strongly associated with lower Z-scores with increasing age (p-interaction ≤ 0.05 for all sites). The WNT GRS associations remained consistent for both sexes and all ages (p-interaction > 0.05 for all sites). The RANK-RANKL-OPG GRS was more strongly associated in females with increasing age (p-interaction < 0.05 for all sites). The mesenchymal stem cell GRS was associated with lower total hip and femoral neck Z-scores, in both boys and girls, across all ages. No associations were observed between the pediatric GRS and bone Z-scores. In conclusion, adult identified BMD loci associated with BMD and BMC in the pediatric setting, especially in females and in loci involved in fracture risk and WNT signaling.
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Project description:Adolescence is a period characterized by large accumulation of bone mass. Body composition is an important determinant of bone mass. This study aimed to assess the relationship of bone mass with lean mass (LM) and fat mass (FM) in normal-weight and overweight adolescents with consideration of sex, sexual maturation and physical activity covariates. A total of 118 adolescents (60 girls and 58 boys) aged between 10 and 14 years participated in the study. Individuals were classified as normal weight or overweight according to body mass index. Bone mineral density (BMD), bone mineral content (BMC), LM, and FM were measured by dual-energy X-ray absorptiometry. In normal-weight adolescents, LM (β = 0.725, p < 0.001) and FM (β = 0.185, p = 0.019) were associated with lumbar spine BMC, whereas in overweight adolescents only LM (β = 0.736, p < 0.001) was associated with lumbar spine BMC. Furthermore, in the normal-weight group, FM and LM were associated with total body less head BMD (LM, β = 0.792, p < 0.001; FM, β = 0.257, p = 0.007) and lumbar spine BMD (LM, β = 0.553, p < 0.001; FM, β = 0.199, p < 0.035). In the overweight group, only LM was associated with total body less head BMD (β = 0.682, p < 0.001) and lumbar spine BMD (β = 0.528, p < 0.001). LM was the main predictor of bone mass in normal-weight and overweight adolescents. FM was associated with bone mass in normal-weight adolescents only. LM may be considered an important and useful marker in adolescents, when investigating bone health in this population. Activities that promote LM gain to reduce the risk of bone fractures and diseases in adulthood are recommended.
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Project description:Fragility fractures are generally associated with substantial loss in trabecular bone mass and alterations in structural anisotropy. Despite the high correlations between measures of trabecular mass and mechanical properties, significant overlap in density measures exists between individuals with osteoporosis and those who do not fracture. The purpose of this paper is to provide an analysis of trabecular properties associated with fragility fractures. While accurate measures of bone mass and 3-D orientation have been demonstrated to explain 80% to 90% of the variance in mechanical behavior, clinical and experimental experience suggests the unexplained proportion of variance may be a key determinant in separating high- and low-risk patients. Using a hierarchical perspective, we demonstrate the potential contributions of structural and tissue morphology, material properties, and chemical composition to the apparent mechanical properties of trabecular bone. The results suggest that the propensity for an individual to remodel or adapt to habitual damaging or nondamaging loads may distinguish them in terms of risk for failure.
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