Age-related Bone Fragility Research Articles

Targeting Longevity Gene SLC13A5: A Novel Approach to Prevent Age-Related Bone Fragility and Osteoporosis.

Reduced expression of the plasma membrane citrate transporter SLC13A5, also known as INDY, has been linked to increased longevity and mitigated age-related cardiovascular and metabolic diseases. Citrate, a vital component of the tricarboxylic acid cycle, constitutes 1-5% of bone weight, binding to mineral apatite surfaces. Our previous research highlighted osteoblasts' specialized metabolic pathway facilitated by SLC13A5 regulating citrate uptake, production, and deposition within bones. Disrupting this pathway impairs bone mineralization in young mice. New Mendelian randomization analysis using UK Biobank data indicated that SNPs linked to reduced SLC13A5 function lowered osteoporosis risk. Comparative studies of young (10 weeks) and middle-aged (52 weeks) osteocalcin-cre-driven osteoblast-specific Slc13a5 knockout mice (Slc13a5cKO) showed a sexual dimorphism: while middle-aged females exhibited improved elasticity, middle-aged males demonstrated enhanced bone strength due to reduced SLC13A5 function. These findings suggest reduced SLC13A5 function could attenuate age-related bone fragility, advocating for SLC13A5 inhibition as a potential osteoporosis treatment.

Effect of non-enzymatic glycation on collagen nanoscale mechanisms in diabetic and age-related bone fragility.

Age and diabetes have long been known to induce an oxidative reaction between glucose and collagen, leading to the accumulation of advanced glycation end-products (AGEs) cross-links in collagenous tissues. More recently, AGEs content has been related to loss of bone quality, independent of bone mass, and increased fracture risk with aging and diabetes. Loss of bone quality is mostly attributed to changes in material properties, structural organization, or cellular remodeling. Though all these factors play a role in bone fragility disease, some common recurring patterns can be found between diabetic and age-related bone fragility. The main pattern we will discuss in this viewpoint is the increase of fibrillar collagen stiffness and loss of collagen-induced plasticity with AGE accumulation. This study focused on recent related experimental studies and discusses the correlation between fluorescent AGEs content at the molecular and fibrillar scales, collagen deformation mechanisms at the nanoscale, and resistance to bone fracture at the macroscale.

Ageing Effects on 3-Dimensional Femoral Neck Cross-Sectional Asymmetry: Implications for Age-Related Bone Fragility in Falling

This paper explores the effects of aging on femoral neck (FN) anatomy in a study of women aged 20–90years in relation to implications for FN fracture propensity in buckling. Five hundred and four participants were scanned by Quantitative Computed Tomography and analyzed using Quantitative Computed Tomography Pro BIT (Mindways). FN cross-section was split through geometric center into superior and inferior sectors. Bone mass, structural measurements, and bone mineral density were analyzed. Buckling ratio was calculated as ratio of buckling radius to cortical thickness. Between 2nd decade and 8th decade, age-related integral bone mass reduction in superior sector was substantially larger than in inferior sector (33% compared to 21%), especially in cortical bone superiorly compared to inferiorly (53% vs 21%; p < 0.001), principally due to reduction in cortical thickness, averaged cortical thickness (56%) with little difference in density. Superior and inferior sector trabecular bone mineral density reduction was similar at 41% and 43% respectively. Differential cortical bone loss in superior sector resulted in a 59% inferior displacement (δ) of center-of-mass from geometric center. Differences in δ and averaged cortical thickness with age accounted for a 151% increase in mean superior buckling ratio from 9 to 23. Analysis confirms significant progressive age-related superior cortical bone loss as the major age effect on FN structure with relative preservation of inferior cortex probably related to maintenance of inferior sector by regular loading as a result of standing and walking. Computation of buckling ratio may allow prediction of fracture propensity in a sideways fall.

Damaged elastic bone-column buckling theory within the context of adaptive elasticity

Bone column-buckling is known as due to the loss of trabecular connectivity such that vertical weight-bearing trabeculae lose their cross attachments with each other. It has been considered as a predominant mechanism accounting for skeletal fragility disproportional to the degree of bone loss. Here, we focus our attention upon the improvement of our understanding of the relationships between bone degradation and fracture risk assessment (i.e., buckling load) which is both timely and at the core of important clinical problems such as osteoporosis and age-related bone fragility. With respect to well-known existing literature, there is a great need for a theoretical framework that provides new insights into the bending–buckling process when coupled to continuum damaged-bone adaptation. Within the limitations of our assumptions, it is clearly shown that damage occurs preferentially in regions where bone resorption activity dominates and the existence of a bone density gradient helps to maintain the stability of the bone-column deflection. For another, predicted buckling stress as a function of slenderness ratio is satisfactorily appreciated through experimental results. In our knowledge, this contribution is an original first attempt, at the scale of the single trabecula, which used adaptive elasticity in order to state an original but simplified adaptive-damage bone column buckling theory.

Skeletal stem cells and their contribution to skeletal fragility: senescence and rejuvenation.

Age-related osteoporotic fractures are major health care problem worldwide and are the result of impaired bone formation, decreased bone mass and bone fragility. Bone formation is accomplished by skeletal stem cells (SSC) that are recruited to bone surfaces from bone marrow microenvironment. This review discusses targeting SSC to enhance bone formation and to abolish age-related bone fragility in the context of using stem cells for treatment of age-related disorders. Recent studies are presented that have demonstrated that SSC exhibit impaired functions during aging due to intrinsic senescence-related changes as well as the presence of senescent microenvironment. Also, a number of approaches aiming at increasing bone formation through targeting SSC and that include systemic SSC transplantation, systemic SSC targeting using aptamers or antibodies, use of therapeutic screteome and tissue engineering approaches will be presented and discussed.

Serum Levels of Sclerostin and Dickkopf-1: Effects of Age, Gender and Fracture Status

Background: Fragility fractures, especially hip fractures, are a very common complication of osteoporosis in elderly subjects. Sclerostin (SOST) and dickkopf-1 (DKK-1) are inhibitors of the canonical wnt signalling pathway and thus could be involved in the pathogenesis of age-related bone fragility. Objective: To investigate SOST and DKK-1 in a large group of geriatric patients with hip fractures and to relate the wnt inhibitors to age and gender. Methods: This was a cross-sectional study carried out in a department of acute geriatric care in a district hospital in Upper Austria and a hospital in Vienna, Austria. A total of 256 geriatric patients (172 women and 84 men) and 67 young control subjects were selected after exclusion. Medical history was obtained, a comprehensive geriatric assessment was performed and serum levels of SOST, DKK-1 and bone formation markers were analysed. Results: DKK-1 levels increased with age and in the presence of hip fractures. In contrast, SOST levels were lower in patients with hip fractures. When compared to women, men had higher SOST levels but lower DKK-1 levels. Conclusion: Serum levels of the inhibitors of the canonical wnt signalling pathway reflect different biological events and are useful for the study of bone fragility in geriatric patients.

Age‐dependence of power spectral density and fractal dimension of bone mineralized matrix in atomic force microscope topography images: potential correlates of bone tissue age and bone fragility in female femoral neck trabeculae

There is an increasing interest in bone nano-structure, the ultimate goal being to reveal the basis of age-related bone fragility. In this study, power spectral density (PSD) data and fractal dimensions of the mineralized bone matrix were extracted from atomic force microscope topography images of the femoral neck trabeculae. The aim was to evaluate age-dependent differences in the mineralized matrix of human bone and to consider whether these advanced nano-descriptors might be linked to decreased bone remodeling observed by some authors and age-related decline in bone mechanical competence. The investigated bone specimens belonged to a group of young adult women (n = 5, age: 20-40 years) and a group of elderly women (n = 5, age: 70-95 years) without bone diseases. PSD graphs showed the roughness density distribution in relation to spatial frequency. In all cases, there was a fairly linear decrease in magnitude of the power spectra with increasing spatial frequencies. The PSD slope was steeper in elderly individuals (-2.374 vs. -2.066), suggesting the dominance of larger surface morphological features. Fractal dimension of the mineralized bone matrix showed a significant negative trend with advanced age, declining from 2.467 in young individuals to 2.313 in the elderly (r = 0.65, P = 0.04). Higher fractal dimension in young women reflects domination of smaller mineral grains, which is compatible with the more freshly remodeled structure. In contrast, the surface patterns in elderly individuals were indicative of older tissue age. Lower roughness and reduced structural complexity (decreased fractal dimension) of the interfibrillar bone matrix in the elderly suggest a decline in bone toughness, which explains why aged bone is more brittle and prone to fractures.

Solid state NMR investigation of intact human bone quality: balancing issues and insight into the structure at the organic-mineral interface.

Age-related bone fragility fractures present a significant problem for public health. Measures of bone quality are increasingly recognized to complement the conventional bone mineral density (BMD) based assessment of fracture risk. The ability to probe and understand bone quality at the molecular level is desirable in order to unravel how the structure of organic matrix and its association with mineral contribute to the overall mechanical properties. The (13)C{(31)P} REDOR MAS NMR (Rotational Echo Double Resonance Magic Angle Spinning Nuclear Magnetic Resonance) technique is uniquely suited for the study of the structure of the organic-mineral interface in bone. For the first time, we have applied it successfully to analyze the structure of intact (non-powdered) human cortical bone samples, from young healthy and old osteoporotic donors. Loading problems associated with the rapid rotation of intact bone were solved using a Finite Element Analysis (FEA) approach, and a method allowing osteoporotic samples to be balanced and spun reproducibly is described. REDOR NMR parameters were set to allow insight into the arrangement of the amino acids at the mineral interface to be accessed, and SVD (Singular Value Decomposition) was applied to enhance the signal to noise ratio and enable a better analysis of the data. From the REDOR data, it was found that carbon atoms belonging to citrate/glucosaminoglycans (GAGs) are closest to the mineral surface regardless of age or site. In contrast, the arrangement of the collagen backbone at the interface varied with site and age. The relative proximity of two of the main amino acids in bone matrix proteins, hydroxyproline and alanine, with respect to the mineral phase was analyzed in more detail, and discussed in view of glycation measurements which were carried out on the tissues. Overall, this work shows that the (13)C{(31)P} REDOR NMR approach could be used as a complementary technique to assess a novel aspect of bone quality, the organic-mineral interface structure.

Unmet needs in fracture prevention: new European guidelines for the investigation and registration of therapeutic agents

Recognition of the problem of age-related bone fragility emerged in the middle of the last century when Fuller Albright drew attention to the common occurrence of vertebral fractures in postmenopausal women [1]. With increasing numbers of individuals living into old age, hip fractures gained recognition because of the high incidence, morbidity, mortality and cost imposed by this type of fracture [2]. More recently, several insights have emerged that require attention if the burden of fractures is to be minimized. First, although vertebral and hip fractures are important, from a global perspective, 80–90% of all fragility fractures and the disutility they cause are peripheral in origin (non-hip, nonvertebral) [3, 4]. Second, over 50% of all fragility fractures arise from the larger segment of the population with osteopenia, not osteoporosis [5, 6]. These are fragility fractures, but the basis for the bone fragility is only beginning to be defined [7]. Third, with the changing demographics of the population, over 80 year olds comprise ∼10% of the population but contribute 20–25% of all fragility fractures because this segment of the population have the highest prevalence of risk factors (osteoporosis, prevalent fractures, falls) and the highest morbidity and mortality [8]. Fourth, fractures in men are common [9]. Fifth, two major impediments to fracture prevention are failure of uptake of treatments and failure of adherence to treatment in 50% within 12 months of initiating treatment [10]. These issues are compounded by corresponding deficiencies in treatment. Vertebral fracture risk reduction, although credibly reported with several agents, is only 30–50% [11]. Anti-hip fracture efficacy is also only 30– 50% and has only been reported with alendronate, risedronate [11], and zoledronate [12]. Anti-hip fracture efficacy has also been reported in a post hoc analysis with strontium ranelate [13]. Hip fracture risk reduction has been studied as a primary endpoint in only one pivotal trial and several smaller studies with risedronate [11, 14–16]. For peripheral (non-vertebral non-hip) fractures, fracture risk reduction is modest, 16 to 20%, and has been demonstrated with risedronate, PTH 1–34 and strontium ranelate [11], but planned as a primary endpoint only with strontium ranelate [13]. Peripheral fracture risk reduction has also been reported with alendronate in the FOSIT study and after pooling of patients in the fracture intervention trial (FIT 1) with those patients with osteoporosis in FIT 2 [11, 17]. Issues concerning the design and execution of trials of calcitonin, calcitriol and other vitamin metabolites make inferences concerning anti-fracture efficacy difficult. Recent studies of calcium supplementation had methodological problems, particularly compliance [18–20]. Although lower fracture rates in compliers were reported in each trial is encouraging, whether this was due to the calcium supplement is uncertain. Random allocation assures that known and unknown confounders that independently influence fracture rates are equally prevalent in placebo and calcium arms. With adherence of ∼50%, this assurance is lost. In women with osteopenia alone, only raloxifene and strontium ranelate have been reported to reduce vertebral fracture risk [21, 22]. Alendronate has also been reported to reduce vertebral fracture risk in women with osteopenia and Osteoporos Int (2007) 18:569–573 DOI 10.1007/s00198-007-0350-z

Age-related change in the damage morphology of human cortical bone and its role in bone fragility

Application of cyclic loading results in the formation of distinct strain-dependent microdamage morphologies. It is still unknown; however, how the morphology of microdamage affects age-related increase in bone fragility. In this study, four-point bending fatigue tests were conducted on aging human bone (age 26 to 89) in conjunction with histological evaluation of the resultant tensile (diffuse damage) and compressive (linear microcracks) damage to identify the damage morphologies associated with an increase in age-related bone fragility. The results demonstrate that young donors (38 ± 9 years) had a longer fatigue life ( P < 0.05) and formed more diffuse damage than the older donors (82 ± 5 years) ( P < 0.05). In contrast, old donors had a shorter fatigue life and formed more linear microcracks than the younger donors ( P < 0.05). Linear microcracks were longer in older than in younger donors ( P < 0.05) and were associated with weak lamellar interfaces. Areas of diffuse damage were, however, larger in younger than in older donors ( P < 0.05), and these showed no relationship with the lamellar arrangement of bone. These findings show, for the first time, that the propensity of bone to form a particular damage morphology is subject to change with age and that the propensity of young donors to form diffuse damage over interlamellae linear microcracks plays a critical role in the ability of bone to dissipate energy and resist a catastrophic fracture. Age-related changes in damage morphology may therefore be an important contributor to the increased bone fragility in the elderly.

Age-dependent fatigue behaviour of human cortical bone

Despite a general understanding that bone quality contributes to skeletal fragility, very little information exits on the age-dependent fatigue behavior of human bone. In this study four-point bending fatigue tests were conducted on aging bone in conjunction with the analysis of stiffness loss and preliminary investigation of nanoindentation based measurements of local tissue stiffness and histological evaluation of resultant tensile and compressive damage to identify the damage mechanism responsible for the increase in age-related bone fragility. The results obtained show that there is an exponential decrease in fatigue life with age, and old bone exhibits different modulus degradation profiles than young bone. In addition, this study provides preliminary evidence indicating that during fatigue loading, younger bone formed diffuse damage, lost local tissue stiffness on the tensile side. Older bone, in contrast, formed linear microcracks lost local tissue stiffness on the compressive side. Thus, the propensity of aging human bone to form more linear microcracks than diffuse damage may be a significant contributor to bone quality, and age related fragility in bone.

Determinants of age-associated changes in os calcis ultrasonic indices in elderly women: potential involvement of geriatric hyposomatotropism in bone fragility.

ultrasound measures a clinically relevant property of bone strength in addition to and distinct from bone mass. The aim of the present study was to examine the effects of healthy ageing on ultrasound measurements of the calcaneus. cross-sectional study. a sample of 177 community-dwelling healthy women aged 70-87 years. Exclusion criteria were diseases or medications known to affect the musculoskeletal system or the somatotrophic axis. serum levels of 1,25-dihydroxyvitamin D3 and insulin-like growth factor-I (IGF-I) were measured by radioimmunoassay, serum 25-hydroxyvitamin D3 (25(OH)D3) was determined by competitive binding assay and serum parathyroid hormone was assessed immunochemically. Isometric and isokinetic quadriceps strength were evaluated using a Cybex II system. Calcaneal ultrasound indices--broadband ultrasound attenuation (BUA) and speed of sound (SOS)--were measured with an Achilles system. we found a significant decrease with ageing in BUA and SOS (-0.5 and -1.3% per year, respectively), suggesting a continuing loss of bone quality. Quadriceps strength, serum IGF-I and 25(OH)D3 constituted the best predictors of BUA, while IGF-I was the only parameter found to be independently associated with SOS. these findings suggest that, among other factors, the activity of the growth hormone-IGF-I axis is of importance for skeletal integrity. Age-related bone fragility may, in part, be related to geriatric hyposomatotropism.