Search

Distal forearm fractures during growth are more common in males than females. Because metaphyseal cortical bone is formed by coalescence of trabeculae emerging from the periphery of the growth plate, we hypothesized that the later onset of puberty in males produces a longer delay in trabecular bone formation and coalescence, which leaves a transient phase of high cortical porosity, low matrix mineral density, and high trabecular density relative to females. We quantified the nondominant distal radial microstructure using high-resolution peripheral quantitative computed tomography in 214 healthy Chinese boys and 219 Chinese girls aged between 7 and 17 years living in Hong Kong. Measurements of 110 slices (9.02 mm) were acquired 5 mm proximal to the growth plate of the nondominant distal radius. Porosity was measured using StrAx1.0 (Straxcorp, Melbourne, VIC, Australia) and trabecular plate and rod structure were measured using individual trabecula segmentation (ITS). Mechanical properties were estimated using finite element analysis (FEA). Results were adjusted for age, total bone cross-sectional area (CSA), dietary calcium intake, and physical activity. In boys, total bone CSA was 17.2% to 22.9% larger throughout puberty, cortical/total bone CSA was 5.1% smaller in Tanner stage 2 only, cortical porosity was 9.4% to 17.5% higher, and matrix mineral density was 1.0% to 2.5% lower in Tanner stage 2 to 5, than girls. Boys had higher trabecular rod BV/TV in Tanner stage 3 and 4, but higher trabecular plate BV/TV and plate to rod ratio in Tanner stage 5, than girls. Boys had 17.0% lower apparent modulus than girls in Tanner stage 2. A transient phase of higher porosity due to dissociation between bone mineral accrual and linear growth may contribute to higher distal radial bone fragility in Chinese boys compared to girls. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Radiation therapy (RTx) is associated with increased risk for late-onset fragility fractures in bone tissue underlying the radiation field. Bone tissue outside the RTx field is often selected as a "normal" comparator tissue in clinical assessment of fragility fracture risk, but the robustness of this comparison is limited by an incomplete understanding of the systemic effects of local radiotherapy. In this study, a mouse model of limited field irradiation was used to quantify longitudinal changes in local (irradiated) and systemic (non-irradiated) femurs with respect to bone density, morphology, and strength. BALB/cJ mice aged 12 weeks underwent unilateral hindlimb irradiation (4 × 5 Gy) or a sham procedure. Femurs were collected at endpoints of 4 days before treatment and at 0, 1, 2, 4, 8, 12, and 26 weeks post-treatment. Irradiated (RTx), Contralateral (non-RTx), and Sham (non-RTx) femurs were imaged by micro-computed tomography and mechanically tested in three-point bending. In both the RTx and Contralateral non-RTx groups, the longer-term (12- to 26-week) outcomes included trabecular resorption, loss of diaphyseal cortical bone, and decreased bending strength. Contralateral femurs generally followed an intermediate response compared with RTx femurs. Change also varied by anatomic compartment; post-RTx loss of trabecular bone was more profound in the metaphyseal than the epiphyseal compartment, and cortical bone thickness decreased at the mid-diaphysis but increased at the metaphysis. These data demonstrate that changes in bone quantity, density, and architecture occur both locally and systemically after limited field irradiation and vary by anatomic compartment. Furthermore, the severity and persistence of systemic bone damage after limited field irradiation suggest selection of control tissues for assessment of fracture risk or changes in bone density after radiotherapy may be challenging. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Gα S is a heterotrimeric G protein that transduces signals from activated G protein-coupled receptors on the cell surface to stimulate adenylyl cyclase/cyclic adenosine monophosphate (AMP) signaling. Gα S plays a central role in mediating numerous growth and maintenance processes including osteogenesis and bone turnover. Decreased Gα S expression or activating mutations in Gα S both affect bone, suggesting that modulating Gα S protein levels may be important for bone health and development. To examine the effects of increased osteoblastic Gα S expression on bone development in vivo, we generated transgenic mice with Gα S overexpression in osteoblasts (HOM-Gs mice) driven by the 3.6-kilobase (kb) Col1A1 promoter. Both male and female HOM-Gs mice exhibit increased bone turnover with overactive osteoblasts and osteoclasts, resulting in a high bone mass phenotype with significantly reduced bone quality. At 9 weeks of age, HOM-Gs mice have increased trabecular number, volumetric BMD (vBMD), and bone volume; however, the bone was woven and disorganized. There was also increased cortical bone volume despite an overall reduction in size in HOM-Gs mice along with increased cortical porosity and brittleness. The skeletal phenotype of HOM-Gs mice progressed into maturity at 26 weeks of age with further accrual of trabecular bone, whereas WT mice lost trabecular bone at this age. Although cortical bone volume and geometry were similar between mature HOM-Gs and WT mice, increased porosity persisted and the bone was weaker. At the cellular level, these alterations were mediated by an increase in bone resorption by osteoclasts and an overwhelmingly higher increase in bone formation by osteoblasts. In summary, our findings demonstrate that high osteoblastic Gα S expression results in aberrant skeletal development in which bone production is favored at the cost of bone quality. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Risk for premature osteoporosis is a major health concern in astronauts and cosmonauts; the reversibility of the bone lost at the weight-bearing bone sites is not established, although it is suspected to take longer than the mission length. The bone three-dimensional structure and strength that could be uniquely affected by weightlessness is currently unknown. Our objective is to evaluate bone mass, microarchitecture, and strength of weight-bearing and non-weight-bearing bone in 13 cosmonauts before and for 12 months after a 4-month to 6-month sojourn in the International Space Station (ISS). Standard and advanced evaluations of trabecular and cortical parameters were performed using high-resolution peripheral quantitative computed tomography. In particular, cortical analyses involved determination of the largest common volume of each successive individual scan to improve the precision of cortical porosity and density measurements. Bone resorption and formation serum markers, and markers reflecting osteocyte activity or periosteal metabolism (sclerostin, periostin) were evaluated. At the tibia, in addition to decreased bone mineral densities at cortical and trabecular compartments, a 4% decrease in cortical thickness and a 15% increase in cortical porosity were observed at landing. Cortical size and density subsequently recovered and serum periostin changes were associated with cortical recovery during the year after landing. However, tibial cortical porosity or trabecular bone failed to recover, resulting in compromised strength. The radius, preserved at landing, unexpectedly developed postflight fragility, from 3 months post-landing onward, particularly in its cortical structure. Remodeling markers, uncoupled in favor of bone resorption at landing, returned to preflight values within 6 months, then declined farther to lower than preflight values. Our findings highlight the need for specific protective measures not only during, but also after spaceflight, because of continuing uncertainties regarding skeletal recovery long after landing. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Physical activity is believed to have the greatest effect on the skeleton if exerted early in life, but whether or not possible benefits of physical activity on bone microstructure or geometry remain at old age has not been investigated in women. The aim of this study was to investigate if physical activity during skeletal growth and young adulthood or at old age was associated with cortical geometry and trabecular microarchitecture in weight-bearing and non-weight-bearing bone, and areal bone mineral density (aBMD) in elderly women. In this population-based cross-sectional study 1013 women, 78.2 ± 1.6 (mean ± SD) years old, were included. Using high-resolution 3D pQCT (XtremeCT), cortical cross-sectional area (Ct.CSA), cortical thickness (Ct.Th), cortical periosteal perimeter (Ct.Pm), volumetric cortical bone density (D.Ct), trabecular bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), and trabecular separation (Tb.Sp) were measured at the distal (14% level) and ultra-distal tibia and radius, respectively. aBMD was assessed using DXA (Hologic Discovery A) of the spine and hip. A standardized questionnaire was used to collect information about previous exercise and the Physical Activity Scale for the Elderly (PASE) was used for current physical activity. A linear regression model (including levels of exercise during skeletal growth and young adulthood [10 to 30 years of age], PASE score, and covariates) revealed that level of current physical activity was independently associated with Ct.CSA (β = 0.18, p < 0.001) and Ct.Th (β = 0.15, p < 0.001) at the distal tibia, Tb.Th (β = 0.11, p < 0.001) and BV/TV (β = 0.10, p = 0.001) at the ultra-distal tibia, and total hip aBMD (β = 0.10, p < 0.001). Current physical activity was independently associated with cortical bone size, in terms of thicker cortex but not larger periosteal circumference, and higher bone strength at the distal tibia on elderly women, indicating that physical activity at old age may decrease cortical bone loss in weight-bearing bone in elderly women. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Although projections from cross-sectional studies have shown that bone loss leading to osteoporosis begins around menopause in women and later in life in men, this has not been examined longitudinally in population-based studies using high-resolution technology capable of distinguishing cortical (Ct) and trabecular (Tb) bone microarchitecture. The aim of this 3-year prospective study was to investigate age- and sex-related changes in bone compartment-specific geometry, volumetric bone mineral density (vBMD), microarchitecture, and estimated strength. The distal radius and tibia were imaged at baseline and after 3 years (median 3.0; range, 2.7 to 3.9 years) using high-resolution peripheral computed tomography (HRpCT) in an age- and sex-stratified, population-based, random sample of white men and women (n = 260) aged 21 to 82 years. In general, at the radius and tibia there was a moderate annual increase in cortical thickness (Ct.Th) that seemed to offset the increase in cortical porosity (Ct.Po), resulting in net annual increase in cortical vBMD (Ct.vBMD) in premenopausal women and young men. With advancing age, postmenopausal women displayed significant bone loss with decreased trabecular vBMD (Tb.vBMD) (due to loss of entire trabeculae) and Ct.vBMD (manifested as increase in Ct.Po and decrease in Ct.Th) at the radius, and a decline in Ct.vBMD (with increasing Ct.Po) at the tibia, resulting in loss of estimated bone strength. In contrast, men had a lower rate of bone loss with advancing age with smaller increases in Ct.Po at both the skeletal sites. In summary, the pattern of bone loss in men and women was discrepant, with women losing more bone than men with aging, although with a dominance of cortical over trabecular bone loss at the peripheral sites in both sexes. This conforms to epidemiological evidence that most fractures occurring in old age are predominantly at cortical peripheral sites, with women having a higher incidence of fractures than men at any given age. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Although the role of ERα in regulating bone metabolism has been extensively studied, ERβ has been largely dismissed as a relevant modulator of bone mass. Previous studies examining ERβ utilized a germline knockout mouse expressing transcript variants of ERβ and displaying systemic hormonal changes that confounded interpretation of the skeletal phenotype. Thus, we used a conditional ERβ mouse model to achieve deletion of ERβ specifically in early osteoprogenitor cells using the Prx1-Cre driver. We observed marked increases in the trabecular bone volume fraction (of 58% [p < 0.003] and 93% [p < 0.0003] in 6- and 12-week-old female ERβ(Prx1-CKO) mice, respectively) but no changes in cortical bone. Serum estradiol and IGF-I levels were unaltered in ERβ(Prx1-CKO) mice. Bone formation and resorption indices by histomorphometry and serum assays were unchanged in these mice, suggesting that alterations in bone turnover may have occurred early in development. However, the ratio of colony-forming unit-osteoblasts (CFU-OBs) to CFU-fibroblasts (CFU-Fs) was increased in bone marrow cultures from ERβ(Prx1-CKO) compared with control mice, indicating increased differentiation of osteoblast precursor cells into osteoblasts in ERβ(Prx1-CKO) mice. Detailed quantitative polymerase chain reaction analyses of 128 genes in 16 prespecified pathways revealed significant downregulation of 11 pathways in ERβ(Prx1-CKO) mice. Thus, deletion of ERβ specifically in osteoblast lineage cells, in the absence of all splice variants, increases trabecular bone mass and modulates multiple pathways related to bone metabolism. These findings suggest that pharmacological inhibition of ERβ in bone may provide a novel approach to treat osteoporosis., (© 2015 American Society for Bone and Mineral Research.)