Variation In Bone Mass Research Articles

Mechanism of action of gut microbiota and probiotic Lactobacillus rhamnosus GG on skeletal remodeling in mice.

Gut microbiota (GM) is the collection of small organisms such as bacteria, fungi, bacteriophages and protozoans living in the intestine in symbiotics relation within their host. GM regulates host metabolism by various mechanisms. This review aims to consolidate current information for physicians on the effect of GM on bone health. For this, an online search of the literature was conducted using the keywords gut microbiota, bone mass, osteoporosis, Lactobacillus and sex steroid. There is a considerable degree of variation in bone mineral density (BMD) within populations, and it is estimated that a significant component of BMD variability is due to genetics. However, the remaining causes of bone mass variance within populations remain largely unknown. A well-recognized cause of phenotypic variation in bone mass is the composition of the microbiome. Studies have shown that germ-free (GF) mice have higher bone mass compared to conventionally raised (CR) mice. Furthermore, GM dysbiosis, also called dysbacteriosis, is defined as any alteration in the composition of the microbial community that has been colonized in the host intestine and associated with the development of bone diseases. For instance, postmenopausal osteoporosis (PMO) and diabetes. GM can be modulated by several factors such as genetics, age, drugs, food habits and probiotics. Probiotics are defined as viable bacteria that confer health benefits by modulating GM when administered in adequate quantity. Lactobacillus rhamnosus GG (LGG) is a great example of such a probiotic. LGG has been shown to regulate bone mass in healthy mice as well as ovariectomized (OVX) mice via two different mechanisms. This review will focus on the literature regarding the mechanism by which GM and probiotic LGG regulate bone mass in healthy mice as well as in OVX mice, a model of PMO.

Genetic variation influences the skeletal response to hindlimb unloading in the eight founder strains of the diversity outbred mouse population.

During disuse, mechanical unloading causes extensive bone loss, decreasing bone volume and strength. Variations in bone mass and risk of osteoporosis are influenced by genetics; however, it remains unclear how genetic variation affects the skeletal response to unloading. We previously found that genetic variation affects the musculoskeletal response to 3 weeks of immobilization in the 8 Jackson Laboratory J:DO founder strains: C57Bl/6J, A/J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ. Hindlimb unloading (HLU) is the best model for simulating local and systemic contributors of disuse and therefore may have a greater impact on bones than immobilization. We hypothesized that genetic variation would affect the response to HLU across the eight founder strains. Mice of each founder strain were placed in HLU for 3 weeks, and the femurs and tibias were analyzed. There were significant HLU and mouse strain interactions on body weight, femur trabecular BV/TV, and femur ultimate force. This indicates that unloading only caused significant catabolic effects in some mouse strains. C57BL/6 J mice were most affected by unloading while other strains were more protected. There were significant HLU and mouse strain interactions on gene expression of genes encoding bone metabolism genes in the tibia. This indicates that unloading only caused significant effects on bone metabolism genes in some mouse strains. Different mouse strains respond to HLU differently, and this can be explained by genetic differences. These results suggest the outbred J:DO mice will be a powerful model for examining the effects of genetics on the skeletal response to HLU.

Identification of Bone Density Changes Applying Impedance Spectroscopy with a Piezo-Device Coupled to a Human Tooth

Bone tissue is a calcium deposit and supporting structure of the human body, it is exposed to several pathologies that modify its mineral content. To determine these changes, different diagnostic procedures are performed with techniques using invasive ionizing radiation, which are limited by the negative effects in the long term on human health. A methodology is explored that could be applicable in the diagnosis of pathologic variations in bone mineral density, using structural monitoring tools. The proposed technique estimates changes in bone conditions by applying impedance spectroscopy with a tooth-borne piezo-device. Bone-tooth samples were prepared to simulate a section of maxillary bone and subsequently treated with chemical agents, simulating pathologic decalcification. The piezo-device is inserted in the slot of an orthodontic bracket, previously bonded to the crown of the tooth, in order to transmit vibration to surrounding bone. The variations in bone micro-architecture were computed by image processing analyzed with samples prepared in transparent resin, allowing the measurement of morphometry before and after the induced changes in mineral content. Using vibrational bone response, impedance measurements allowed to observe the variations in bone mass as the samples were progressively decalcified. In the 5-50kHz spectrum, it was demonstrated the sensitivity of the electro-mechanical impedance during the bone alteration procedure since the electrical resistance signals of the piezo-device consistently changed in the frequency spectrum (5-50kHz). The piezo-device shows to be sensitive to the changes produced by the bone alterations, which were caused by the stiffness variations made in the sample during the decalcifying. These changes were statistically correlated to demonstrate that in a less invasive way, bone alterations could be monitored from the teeth. This result opens the door to search for a new way to diagnose bone density changes in real applications.

Bone Toolbox: Biomarkers, Imaging Tools, Biomechanics, and Histomorphometry.

Bone is a unique tissue with turnover, metabolic, and cellular activities that vary through development to aging and with a mineralized matrix in which the current state and the history of a bone coexist. Qualitative histopathology often lacks sensitivity to detect changes in bone formation, mineralization and resorption, which often requires chronic dosing to result in structural changes such as variation in bone mass and geometry. A large panel of modalities can be used to fully analyze the health of the skeleton, including biomarker evaluation in serum or urine, imaging techniques ranging from radiology to computed tomography, biomechanical testing, and undecalcified tissue processing with bone histomorphometry. The use of clinically relevant biomarkers provides an important noninvasive, sensitive, rapid, and real-time tool to monitor bone activity at the whole skeleton level when conducting safety assessments in a preclinical setting. Imaging modalities also allow in vivo longitudinal assessments with a powerful, noninvasive and clinically translatable tools to monitor drug effects. Different imaging modalities are used in the preclinical studies to evaluate the bone tissues: standard radiography, dual-energy X-ray absorptiometry, peripheral quantitative computed tomography (pQCT), micro-computed tomography, and high-resolution pQCT. Bone histomorphometry is an important tool that provides sensitive evaluation to detect effects of test articles on bone resorption, formation, mineralization, remodeling rates and growth to address a potential target- or class-related theoretical bone liability. Ultimately, the measurement of bone mechanical properties in pharmaceutical testing is critical to understand the potential effects of that pharmaceutical on bone health and fracture risk. Important considerations are required for including these different techniques in toxicology rodents and nonrodent studies, to actually integrate these into safety assessment.

Screening Gene Knockout Mice for Variation in Bone Mass: Analysis by μCT and Histomorphometry.

The international mouse phenotyping consortium (IMPC) is producing defined gene knockout mouse lines. Here, a phenotyping program is presented that is based on micro-computed tomography (μCT) assessment of distal femur and vertebra. Lines with significant variation undergo a computer-based bone histomorphometric analysis. Of the 220 lines examined to date, approximately 15% have a significant variation (high or low) by μCT, most of which are not identified by the IMPC screen. Significant dimorphism between the sexes and bone compartments adds to the complexity of the skeletal findings. The μCT information that is posted at www.bonebase.org can group KOMP lines with similar morphological features. The histological data is presented in a graphic form that associates the cellular features with a specific anatomic group. The web portal presents a bone-centric view appropriate for the skeletal biologist/clinician to organize and understand the large number of genes that can influence skeletal health. Cataloging the relative severity of each variant is the first step towards compiling the dataset necessary to appreciate the full polygenic basis of degenerative bone disease.

Sports Participation in High School and College Leads to High Bone Density and Greater Rates of Bone Loss in Young Men: Results from a Population-Based Study.

Estimated lifetime risk of an osteoporotic fracture in men over the age of 50years is substantial and lifestyle factors such as physical activity may explain variation in bone mass and bone loss associated with aging. Men (n = 253) aged 20-66years were followed for 7.5years and factors that influence changes in means and rates of change in bone mass, density, and size using dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) were investigated; in particular, seasons of sports participation during high school and college. Men with greater sports participation had higher total hip bone mineral content (BMC) (48.4 ± 0.9 and 48.6 ± 0.9g for 7-12 and 13+ seasons vs. 45.6 ± 0.8 and 45.4 ± 0.7g for 0 and 1-6 seasons, respectively p < 0.05) and areal bone mineral density (aBMD) (1.082 ± 0.015 and 1.087 ± 0.015g/cm2 for 7-12 and 13+ seasons vs. 1.011 ± 0.015 and 1.029 ± 0.013g/cm2 for 0 and 1-6 seasons, respectively p < 0.05) than men who participated in less sport-seasons. However, men with higher sports participation also had greater rates of bone loss in their mid-twenties at the hip (BMC - 0.8 and - 1.2% and aBMD - 0.8 and - 0.9% for 7-12 and 13+ seasons of sport participation, respectively) compared to those with 0 seasons of sport participation (BMC - 0.6% and aBMD - 0.6%) (all p < 0.05). Similar results were observed for femoral neck aBMD. Men with 7+ seasons of sport participation had higher cross-sectional area at the 20% distal radius site than those with no sports participation (all p < 0.05). These findings support significant effects of high school and/or college sports participation on bone mass and geometry in men throughout adulthood.

MECHANISMS IN ENDOCRINOLOGY: Genetics of human bone formation.

Throughout life, bone is continuously remodelled to be able to fulfil its multiple functions. The importance of strictly regulating the bone remodelling process, which is defined by the sequential actions of osteoclasts and osteoblasts, is shown by a variety of disorders with abnormalities in bone mass and strength. The best known and most common example of such a disorder is osteoporosis, which is marked by a decreased bone mass and strength that consequently results in an increased fracture risk. As osteoporosis is a serious health problem, a large number of studies focus on elucidating the aetiology of the disease as well as on the identification of novel therapeutic targets for the treatment of osteoporotic patients. These studies have demonstrated that a large amount of variation in bone mass and strength is often influenced by genetic variation in genes encoding important regulators of bone homeostasis. Throughout the years, studies into the genetic causes of osteoporosis as well as several rare monogenic disorders with abnormal high or low bone mass and strength have largely increased the knowledge on regulatory pathways important for bone resorption and formation. This review gives an overview of genes and pathways that are important for the regulation of bone formation and that are identified through their involvement in monogenic and complex disorders with abnormal bone mass. Furthermore, novel bone-forming strategies for the treatment of osteoporosis that resulted from these discoveries, such as antibodies against sclerostin, are discussed as well.

Bone Mineral Density and Biochemical Markers of Bone Metabolism in Women Engaging in Recreational Horseback Riding.

An increased occurrence of lifestyle-related diseases such as osteoporosis indicates the necessity for taking preventive action, including regularly engaging in physical activity. The aim of the study was to assess the areal bone mineral density (aBMD) and bone turnover markers levels in young adult women engaging in recreational horseback riding and to determine the relationship between training characteristics and bone metabolism indices. The study involved 43 women: 23 equestrians and 20 age- and body mass index-matched controls. The hip and spine aBMD and serum levels of the bone turnover markers: osteocalcin and collagen type I cross-linked C-telopeptide were measured. No significant differences were found in somatic features, concentrations of bone turnover markers, or bone mass variables. Correlation analysis of the equestrian participants showed significant relationship between body mass and BMDL1-L4 (P < .05) as well as between BMI and BMDL1-L4 (P ≤ .01) and z-score L1-L4 (P < .05). The study showed no differences in bone mass and levels of bone metabolic indices between groups of women practicing horseback riding at the recreational level and subjects who do not participate in frequent systematic physical activity. No relationship between training characteristics and bone turnover markers were found.

PS-042c Is Low-dose Combined Oral Contraceptives Use Associated To Lower Bone Mineral Content Variation In Adolescents Over A One-year Period?

Background Low dose combined oral contraceptives (COC) can interfere in bone mass acquisition during adolescence. To evaluate bone mineral density (BMD) and bone mineral content (BMC) in female adolescents taking a standard low-dose (EE 20 µg/Desogestrel 150 µg) combination oral contraceptive (COC) over a one-year period and compare with healthy adolescents from the same age group not taking COCs. Methods A non-randomised parallel control study with one-year follow-up. Sixty-seven adolescents from 12 to 20 years of age, divided into COC users (n = 41) taking 20 µg EE/150 µg Desogestrel and non-user controls (n = 26), were evaluated through bone densitometry examinations at baseline and 12 months later. Comparisons between groups at study start was done through the Mann-Whitney test with significance level fixed at 5% or corresponding p value; comparisons between groups at study start and 12 months later used variations in median percentages for bone mass variables. Results COC users presented low bone mass acquisition in the lumbar spine and BMD and BMC median variations between baseline and at 12 months of 2.07% and +1.57% respectively whereas the control group presented variations of +12.16% and +16.84% for BMD and BMC, respectively, over the same period. The total body BMD and BMC presented similar evolution during the study in both groups. Statistical significance (p Conclusion The use of a low COC dose (EE 20 µg/Desogestrel 150 µg) was associated to lower bone mass acquisition in adolescents during the study period. Trial registration: (Register Number):RBR-5 h9b3c.

A single nucleotide polymorphism in osteonectin 3' untranslated region regulates bone volume and is targeted by miR-433.

Osteonectin/SPARC is one of the most abundant noncollagenous extracellular matrix proteins in bone, regulating collagen fiber assembly and promoting osteoblast differentiation. Osteonectin-null and haploinsufficient mice have low-turnover osteopenia, indicating that osteonectin contributes to normal bone formation. In male idiopathic osteoporosis patients, osteonectin 3' untranslated region (UTR) single-nucleotide polymorphism (SNP) haplotypes that differed only at SNP1599 (rs1054204) were previously associated with bone mass. Haplotype A (containing SNP1599G) was more frequent in severely affected patients, whereas haplotype B (containing SNP1599C) was more frequent in less affected patients and healthy controls. We hypothesized that SNP1599 contributes to variability in bone mass by modulating osteonectin levels. Osteonectin 3' UTR reporter constructs demonstrated that haplotype A has a repressive effect on gene expression compared with B. We found that SNP1599G contributed to an miR-433 binding site, and miR-433 inhibitor relieved repression of the haplotype A, but not B, 3' UTR reporter construct. We tested our hypothesis in vivo, using a knock-in approach to replace the mouse osteonectin 3' UTR with human haplotype A or B 3' UTR. Compared with haplotype A mice, bone osteonectin levels were higher in haplotype B mice. B mice displayed higher bone formation rate and gained more trabecular bone with age. When parathyroid hormone was administered intermittently, haplotype B mice gained more cortical bone area than A mice. Cultured marrow stromal cells from B mice deposited more mineralized matrix and had higher osteocalcin mRNA compared with A mice, demonstrating a cell-autonomous effect on differentiation. Altogether, SNP1599 differentially regulates osteonectin expression and contributes to variability in bone mass, by a mechanism that may involve differential targeting by miR-433. This work validates the findings of the previous candidate gene study, and it assigns a physiological function to a common osteonectin allele, providing support for its role in the complex trait of skeletal phenotype. © 2014 American Society for Bone and Mineral Research.

Cortical bone thickness can adapt locally to muscular loading while changing with age

Mechanical loading of muscle action is concentrated at muscle attachment sites; thus there may be a potential for site-specific variation in cortical bone thickness. Humeri from an early 20th-century Finnish (Helsinki) and two medieval English (Newcastle, Blackgate and York, Barbican) populations were subjected to pQCT scanning to calculate site-specific cross-sectional cortical bone area (CA) for four locations and to measure cortical thickness at muscle attachment sites and non-attachment sites. We found that CA at 80% of humerus length was significantly reduced compared to more distal cross-sections, which can be due to reduced stresses at the proximal shaft. The principal direction of loading at 80% humerus length was towards mediolateral plane, likely due to fixing the humerus close to the torso. At 35% the main direction of loading was towards anteroposterior plane, reflecting elbow flexing forces. The principal direction of loading varied between populations, sides and sexes at 50% humerus length due to preference between elbow and shoulder joint; thus this location might be useful when trying to infer differences in activity. These changes are likely due to overall shaft adaptation to forces acting at the humerus. In addition, we found a potential for site-specific variation in cortical thickness; cortical bone at muscle attachment sites was significantly thicker compared to non-attachment sites. Lastly, CA at 35% of humerus length and cortical thickness at non-attachment sites decreased with age. These results underline the importance of muscle loading for bone mass preservation as well as indicate that a site-specific variation of bone mass is possible.

Exercise, bone and nutrition.

Predisposition to poor skeletal health resulting in osteoporotic fracture is a major public health problem, the future economical impact of which is likely to be phenomenal. Two mechanisms principally determine adult bone health: (1) maximum attainment of peak bone mass (PBM); (2) the rate of bone loss with advancing age. Both aspects are regulated by a combination of endogenous and exogenous factors, and although genetic influences are believed to account for up to 75% of the variation in bone mass, there is still room for modifiable factors to play a vital role. Weight-bearing physical activity is beneficial to the skeleton, but clarification of the exact type, intensity and duration required for optimum bone mass is needed. Excessive levels of exercise, which result in amenorrhoea, are detrimental to skeletal health. The importance of Ca to bone remains controversial. There is evidence that Ca is effective in reducing late post-menopausal bone loss, but more research is required on the long-term benefit of increased Ca intake on PBM attainment. Vitamin D 'insufficiency' appears to be widespread amongst population groups and is an area of considerable public health concern. The role of other micronutrients on bone metabolism remains to be fully quantified, but data from a combination of experimental, clinical and observational studies suggest a positive link between alkaline-forming foods and indices of bone health. The influence of nutrient-gene interactions on the skeleton requires further elucidation, but it may be useful in the future to target nutrition advice at those individuals who are genetically susceptible to osteoporosis.

Experimental study on effect of Salvia miltiorrhiza on alveolar bone metabolism and variation in bone mass in diabetic rats

To study the effect of Salvia miltiorrhiza on alveolar bone metabolism and variation in bone mass in diabetic rats, in order to detect whether it has an inhibitory effect on alveolar bone osteoporosis caused by diabetics. Intraperitoneal injection of alloxan induced diabetes in rats. After one week of observation and maintenance of stable blood sugar level, they were treated with S. miltiorrhiza. The rats were sacrificed at the eighth week after fasting for 12 h and blood samples were collected for analysis of blood glucose and rate of bone metabolism. Meanwhile, their alveolar bones were collected for determining bone mineral density (BMD) and histological sections were made for histomorphology observation. Diabetic rats showed varying degrees of abnormality in bone metabolism indicators and significant reduction in bone mineral density. After treatment with S. miltiorrhiza, their symptoms reduced to some extend and all indicators were improved especially bone density. S. miltiorrhiza has a certain inhibitory effect on alveolar bone osteoporosis in diabetic rats in early stage.

The role of Dkk1 in bone mass regulation: Correlating serum Dkk1 expression with bone mineral density

The Wnt/β-catenin pathway is a major signaling cascade in bone biology, playing a key role in regulating bone development and remodeling, with aberrations in signaling resulting in disturbances in bone mass. The objectives of our study were to correlate serum Dkk1 expression with bone mineral density (BMD) and assess the potential role of Dkk1 as a serological marker of bone mass. Serum was collected from a cohort of patients (n = 36), 18 patients with a reduced BMD and 18 control patients. Serum Dkk1 expression as quantified by ELISA was correlated with lumbar and femoral t- and z-scores. Serum Dkk1 concentration in the osteoporosis group was significantly higher than control group (941 ± 116 vs. 558 ± 47 pg/ml, p < 0.01). Serum Dkk1 expression was highly correlated with bone mass variables with inverse associations found between serum Dkk1 expression and lumbar t-score (r = -0.34, p = 0.00433), lumbar z-score (r = -0.22, p = 0.1907), femur t-score (r = -0.42, p = 0.0101), and femur z-score (r = -0.43, p = 0.0089). Our data further emphasizes the pivotal role played by Wnt/β-catenin signaling in bone mass regulation. Dkk1, a powerful antagonist of canonical Wnt signaling, may have a role to play as a serological marker for disorders of bone mass, warranting further evaluation.

Bone mass acquisition in female rhythmic gymnasts during puberty: no direct role for leptin

Although hypoleptinaemia has been reported in female peripubertal athletes, data are lacking on leptin and bone mass variations in puberty and the effects of leptin on bone mineralization during this period. This study therefore investigated the variations in leptin level and bone mineral density (BMD) in young elite female rhythmic gymnasts (FRG) according to pubertal stage. The effects of leptin, IGF-1 and sex hormones on bone mineral acquisition were also evaluated. Plasma leptin levels were analysed in 43 elite FRG (mean age: 13.3 +/- 1.8 years range: 10.6-17.2, body mass index: 17.52 +/- 1.85 kg/m(2), training status: 17.9-23.8 h/week) according to their pubertal stage (Tanner I, n = 7; II, n = 10; III, n = 9; IV, n = 8; V, n = 9). IGF-1, IGFBP-3 and sex hormones were also evaluated. BMD was measured by dual-energy X-ray absorptiometry at various bone sites. Plasma leptin increased throughout pubertal growth and the values measured in Tanner stages IV-V were significantly higher than in stages I-II. Gains in BMD were measured throughout puberty at all bone sites, particularly between Tanner stages II and IV. In simple correlation analysis, BMD at all bone sites was positively correlated with plasma leptin, age, bone age, BMI, oestrogen, testosterone, IGF-1 and IGFBP-3. However, multivariate analysis using a linear regression model by block (including bone age, anthropometric data and biological parameters) was then performed to determine the factors independently associated with each BMD site, and only bone age, fat-free soft tissue and BMI remained independent predictors. In FRG characterized by high training volume and low fat mass, plasma leptin levels increased throughout puberty and were partially related to body composition changes. Despite the simultaneous increases in plasma leptin and BMD during pubertal growth, it was not possible to differentiate the leptin impact on bone independently from anthropometric parameters.

Modeling Pathways for Low Bone Mass in Children With Malignancies

Children with malignancies have low bone mass. Pathways for metabolic bone disease were investigated in children with cancer by concomitantly assessing lifestyle, clinical, and biochemical predictors of bone mass. Forty-one children who were receiving cancer therapy for 61 weeks and 39 controls were studied. Data on lifestyle factors, biochemical and hormonal parameters, dual-energy X-ray absorptiometry bone mass measurements, body composition, and bone age were obtained. Compared with controls, patients had higher weight percentile and fat mass, a 6-month delay in bone age, and lower estradiol levels. They also had higher parathyroid hormone levels and lower bone remodeling markers and bone mass. Age, height, lean mass, fat mass, and bone maturation correlated positively with several bone mass variables, so did serum estradiol, testosterone, and markers of bone remodeling. Conversely, corticosteroids, methotrexate (MTX), and intrathecal therapy negatively correlated with bone mass at the spine and hip ( R = −0.33 to 0.40, p < 0.04). In the adjusted analyses, bone maturation, serum osteocalcin level, MTX, and intrathecal therapy were significant predictors of lumbar spine and total body Z-scores, bone maturation accounting for the largest proportion in Z-score variance. Chemotherapy-induced delay in bone maturation and suppression of bone modeling are major pathophysiologic pathways predicting bone mass in children with malignancies.

Variation in lumbar spine bone mineral content by age and gender in apparently healthy Indians

The aim of this study was to assess variation in bone mass from childhood through later age and to examine bone health status of Indian males and females. Lumbar spine (LS) bone mineral content (BMC) was measured by dual energy X-ray absorptiometry of lumbar vertebrae (L1-L4) in 683 males and 858 females (5-70 years) from Pune, India and apparent bone mineral density (BMAD) was calculated. A cubic regression model was fitted to describe the change in bone mineral content (BMC) with age in males and females separately. Regression analysis revealed that peak LS BMC was achieved around 26 years (63.6 +/- 11.0 g) for males and 30 years (54.1 +/- 11.6 g) for females. After 50 years of age, BMC showed an average annual decrease of 2.7% in males and 4.1% in females. Males had 11-15% higher mean BMAD than females after 50 years of age. T scores of 19% males and 28% females above 50 years, were less than -2.5 and T scores of 36% males and 43% females were between -1.0 and -2.5 when compared with the Lunar reference database. Low peak bone mass at a young age and higher bone loss in adults are alarming features of apparently healthy Indians.

How genomics has informed our understanding of the pathogenesis of osteoporosis

Osteoporosis is a skeletal disorder characterized by compromised bone strength that predisposes a person to an increased risk of fracture. Osteoporosis is a complex trait that involves multiple genes, environmental factors, and gene-gene and gene-environment interactions. Twin and family studies have indicated that between 25% and 85% of the variation in bone mass and other skeletal phenotypes is heritable, but our knowledge of the underlying genes is limited. Bone mineral density is the most common assessment for diagnosing osteoporosis and is the most often used quantitative value in the design of genetic studies. In recent years, our understanding of the pathophysiology of osteoporosis has been greatly facilitated by advances brought about by the Human Genome Project. Genetic approaches ranging from family studies of monogenic traits to association studies with candidate genes, to whole-genome scans in both humans and animals have identified a small number of genes that contribute to the heritability of bone mass. Studies with transgenic and knockout mouse models have revealed major new insights into the biology of many of these identified genes, but much more needs to be learned. Ultimately, we hope that by revealing the underlying genetics and biology driving the pathophysiology of osteoporosis, new and effective treatment can be developed to combat and possibly cure this devastating disease. Here we review the rapidly evolving field of the genomics of osteoporosis with a focus on important gene discoveries, new biological/physiological paradigms that are emerging, and many of the unanswered questions and hurdles yet to be overcome in the field.

Densitometric and finite-element analysis of bone remodeling further to implantation of an uncemented anatomical femoral stem

Introduction Implantation of a femoral stem changes the load transmission dynamics in the hip and gives rise to the so-called adaptive remodeling. The goal pursued by all stems, whether cemented or not, is to achieve a perfect load transmission mechanism in order to avoid the phenomenon of stress-shielding, which may cause proximal bone devitalization. Materials and methods In order to quantify bone mass variations in the 7 Gruen zones, a serial DEXA analysis was carried out in 80 patients, with preoperative measurements as well as postoperative measurements at 6 months and 1, 3, 5, 7 and 10 years post implantation. Results and conclusions Finite-element (FE) simulations make it possible to characterize the biomechanical changes that occur in the femur further to implantation of a prosthetic stem, as well as the stem's long-term performance. The purpose of our study is to determine whether the results of the simulation can explain the biomechanical changes that may lie behind the evolution of bone density observed through DEXA scanning after implantation of an uncemented anatomical stem. The results of the FE simulation show an excellent match between the bone loss observed on DEXA scans and the evolution of stress patterns observed in each of the Gruen zones, which confirms that even if the stem implanted was metaphyseal, stress shielding was manifest in the proximal femoral area, giving rise to the devitalization of bone in Gruen zones 1 and 7.

Steroid hormone receptor gene polymorphisms and osteoporosis: a pharmacogenomic review

Osteoporosis is a common skeletal disorder with a strong genetic component. In recent years, significant progress has been made in understanding the genetic basis of osteoporosis. Given the biological significance of signalling through steroid hormone receptors, bone biology and calcium homeostasis, alleles of steroid hormone receptor genes have been postulated to contribute to the well-documented genetic predisposition to osteoporosis; and in different studies, these alleles have been associated with variation in bone mass and fracture risk. Even though results are still conflicting and the molecular mechanisms by which these polymorphisms influence receptor activity remain, in part, to be investigated, an additional important issue is represented by potential pharmacogenomic (the investigation of variations of DNA or RNA characteristics as related to drug response) or pharmacogenetic (the influence of variations of DNA sequence on drug response) implications. In fact, steroid hormone receptors actually mediate the action of several compounds known to positively or negatively affect bone homeostasis, such as vitamin D, estrogen and glucocorticoids. This review analyses major pharmacogenetic studies of polymorphisms in steroid hormone receptor genes.