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There is a clinical need to identify new molecular targets for the treatment of osteoporosis, particularly those that simultaneously inhibit bone resorption while stimulating bone formation. We have previously shown in overexpression studies that retinoic acid receptor-related orphan receptor β (Rorβ) suppresses in vitro osteoblast differentiation. In addition, the expression of Rorβ is markedly increased in bone marrow-derived mesenchymal stromal cells with aging in both mice and humans. Here we establish a critical role for Rorβ in regulating bone metabolism using a combination of in vitro and in vivo studies. We used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 gene editing to demonstrate that loss of Rorβ in osteoblasts enhances Wnt signaling, specifically through increased recruitment of β-catenin to T-cell factor/lymphoid enhancer factor (Tcf/Lef) DNA binding sites in the promoters of the Wnt target genes Tcf7 and Opg. This resulted in increased osteogenic gene expression and suppressed osteoclast formation through increased osteoprotegerin (OPG) secretion in Rorβ-deficient cells. Consistent with our in vitro data, genetic deletion of Rorβ in both female and male mice resulted in preserved bone mass and microarchitecture with advancing age due to increased bone formation with a concomitant decrease in resorption. The improved skeletal phenotype in the Rorβ -/- mice was also associated with increased bone protein levels of TCF7 and OPG. These data demonstrate that loss of Rorβ has beneficial skeletal effects by increasing bone formation and decreasing bone resorption, at least in part through β-catenin-dependent activation of the Wnt pathway. Thus, inhibition of Rorβ represents a novel approach to potentially prevent or reverse osteoporosis. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Although fractures in both the pediatric and, especially, the elderly populations have been extensively investigated, comparatively little attention has been given to the age group in between. Thus, we used the comprehensive (inpatient and outpatient) data resources of the Rochester Epidemiology Project to determine incidence rates for all fractures among young adult (age range, 18 to 49 years) residents of Olmsted County, Minnesota, in 2009 to 2011, and compared the distribution of fracture sites and causes in this young adult cohort with those for older residents aged 50 years or older. During the 3-year study period, 2482 Olmsted County residents aged 18 to 49 years experienced 1 or more fractures. There were 1730 fractures among 1447 men compared with 1164 among 1035 women, and the age-adjusted incidence of all fractures was 66% greater among the men (1882 [95% confidence interval 1793-1971] versus 1135 [95% CI 1069-1201] per 100,000 person-years; p < 0.001). Of all fractures, 80% resulted from severe trauma (eg, motor vehicle accidents) compared with 33% in Olmsted County residents age ≥50 years who sustained a fracture in 2009 to 2011. Younger residents (aged 18 to 49 years), when compared with older residents (aged ≥50 years), had a greater proportion of fractures of the hands and feet (40% versus 18%) with relatively few fractures observed at traditional osteoporotic fracture sites (14% versus 43%). Vertebral fractures were still more likely to be the result of moderate trauma than at other sites, especially in younger women. In conclusion, whereas pediatric and elderly populations often fracture from no more than moderate trauma, young adults, and more commonly men, suffer fractures primarily at non-osteoporotic sites due to more significant trauma. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities. Here we investigate a role for senescent cells in age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells) or pharmacological (i.e., 'senolytic' compounds) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi). In aged (20- to 22-month-old) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2-4 months resulted in higher bone mass and strength and better bone microarchitecture than in vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular) or higher (cortical) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent-cell conditioned medium impaired osteoblast mineralization and enhanced osteoclast-progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging, and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities.

A complex interplay of genetic, environmental, hormonal, and behavioral factors affect skeletal development, several of which are associated with childhood fractures. Given the rise in obesity worldwide, it is of particular concern that excess fat accumulation during childhood appears to be a risk factor for fractures. Plausible explanations for this higher fracture risk include a greater propensity for falls, greater force generation upon fall impact, unhealthy lifestyle habits, and excessive adipose tissue that may have direct or indirect detrimental effects on skeletal development. To date, there remains little resolution or agreement about the impact of obesity and adiposity on skeletal development as well as the mechanisms underpinning these changes. Limitations of imaging modalities, short duration of follow-up in longitudinal studies, and differences among cohorts examined may all contribute to conflicting results. Nonetheless, a linear relationship between increasing adiposity and skeletal development seems unlikely. Fat mass may confer advantages to the developing cortical and trabecular bone compartments, provided that gains in fat mass are not excessive. However, when fat mass accumulation reaches excessive levels, unfavorable metabolic changes may impede skeletal development. Mechanisms underpinning these changes may relate to changes in the hormonal milieu, with adipokines potentially playing a central role, but again findings have been confounding. Changes in the relationship between fat and bone also appear to be age and sex dependent. Clearly, more work is needed to better understand the controversial impact of fat and obesity on skeletal development and fracture risk during childhood.

Cellular senescence is a fundamental mechanism by which cells remain metabolically active yet cease dividing and undergo distinct phenotypic alterations, including upregulation of p16 Ink4a , profound secretome changes, telomere shortening, and decondensation of pericentromeric satellite DNA. Because senescent cells accumulate in multiple tissues with aging, these cells and the dysfunctional factors they secrete, termed the senescence-associated secretory phenotype (SASP), are increasingly recognized as promising therapeutic targets to prevent age-related degenerative pathologies, including osteoporosis. However, the cell type(s) within the bone microenvironment that undergoes senescence with aging in vivo has remained poorly understood, largely because previous studies have focused on senescence in cultured cells. Thus in young (age 6 months) and old (age 24 months) mice, we measured senescence and SASP markers in vivo in highly enriched cell populations, all rapidly isolated from bone/marrow without in vitro culture. In both females and males, p16 Ink4a expression by real-time quantitative polymerase chain reaction (rt-qPCR) was significantly higher with aging in B cells, T cells, myeloid cells, osteoblast progenitors, osteoblasts, and osteocytes. Further, in vivo quantification of senescence-associated distension of satellites (SADS), ie, large-scale unraveling of pericentromeric satellite DNA, revealed significantly more senescent osteocytes in old compared with young bone cortices (11% versus 2%, p < 0.001). In addition, primary osteocytes from old mice had sixfold more (p < 0.001) telomere dysfunction-induced foci (TIFs) than osteocytes from young mice. Corresponding with the age-associated accumulation of senescent osteocytes was significantly higher expression of multiple SASP markers in osteocytes from old versus young mice, several of which also showed dramatic age-associated upregulation in myeloid cells. These data show that with aging, a subset of cells of various lineages within the bone microenvironment become senescent, although senescent myeloid cells and senescent osteocytes predominantly develop the SASP. Given the critical roles of osteocytes in orchestrating bone remodeling, our findings suggest that senescent osteocytes and their SASP may contribute to age-related bone loss. © 2016 American Society for Bone and Mineral Research., Competing Interests: All authors state that they have no conflicts of interest., (© 2016 American Society for Bone and Mineral Research.)

Bone loss and increased marrow adiposity are hallmarks of aging skeletons. Conditional deletion of histone deacetylase 3 (Hdac3) in murine osteochondroprogenitor cells causes osteopenia and increases marrow adiposity, even in young animals, but the origins of the increased adiposity are unclear. To explore this, bone marrow stromal cells (BMSCs) from Hdac3-depleted and control mice were cultured in osteogenic medium. Hdac3-deficient cultures accumulated lipid droplets in greater abundance than control cultures and expressed high levels of genes related to lipid storage (Fsp27/Cidec, Plin1) and glucocorticoid metabolism (Hsd11b1) despite normal levels of Pparγ2. Approximately 5% of the lipid containing cells in the wild-type cultures expressed the master osteoblast transcription factor Runx2, but this population was threefold greater in the Hdac3-depleted cultures. Adenoviral expression of Hdac3 restored normal gene expression, indicating that Hdac3 controls glucocorticoid activation and lipid storage within osteoblast lineage cells. HDAC3 expression was reduced in bone cells from postmenopausal as compared to young women, and in osteoblasts from aged as compared to younger mice. Moreover, phosphorylation of S424 in Hdac3, a posttranslational mark necessary for deacetylase activity, was suppressed in osseous cells from old mice. Thus, concurrent declines in transcription and phosphorylation combine to suppress Hdac3 activity in aging bone, and reduced Hdac3 activity in osteochondroprogenitor cells contributes to increased marrow adiposity associated with aging. © 2015 American Society for Bone and Mineral Research., (© 2015 American Society for Bone and Mineral Research.)

There is growing evidence that the higher fracture rate observed in patients with type 2 diabetes mellitus (T2DM) is associated with normal, or even increased, areal bone mineral density (aBMD) by DXA. This has led to the hypothesis that patients with T2DM may have abnormalities in bone microarchitecture and/or material composition - i.e., key determinants of bone "quality." Consistent with this hypothesis, several studies using high-resolution peripheral quantitative computed tomography (HRpQCT) have demonstrated preserved indices of trabecular microarchitecture but increased cortical porosity in T2DM patients. In addition, a recent study using a novel in vivo microindentation device found an impairment in a measure of bone material properties (bone material strength index, BMSi) in postmenopausal women with longstanding T2DM; notably, the reduction in BMSi was associated with chronic glycemic control, suggesting that the skeleton should be included as another target organ subject to diabetic complications. The underlying pathogenesis of skeletal fragility in T2DM remains to be defined, although high levels of advanced glycation endproducts (AGEs) may play a role. In addition, T2DM is associated with reduced bone turnover, perhaps with an imbalance between bone resorption and bone formation. Although several studies have found increased serum sclerostin levels in patients with T2DM, the role of these increased levels in mediating the observed increases in cortical porosity or reduction in BMSi remains to be defined. Thus, although bone quality appears to be impaired in T2DM, the pathogenesis of these abnormalities and their relationship to the increased fracture risk observed in these patients needs further study., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: While teriparatide is the only skeletal anabolic agent approved in the United States, treatment failure is a major concern which complicates its clinical utility. We sought to identify factors that predict response failure in patients with low bone mass., Method: We performed a retrospective study of adults with osteopenia or osteoporosis (T-scores < - 1.0 and - 2.5 SD below normal, respectively, at the total hip or lumbar spine) treated with teriparatide at the Mayo Clinic (Rochester, Minnesota) between November 2002-December 2012. Trained study investigators blinded to patient outcomes collected electronic medical record data. Potential response failure predictors were identified using univariate analysis. Multivariable logistic regression modeling was used to identify independent predictors of treatment failure based on either osteoporotic fragility fracture or BMD response., Results: During the 10-year period, 494 patients received teriparatide treatment and met eligibility criteria. Thirty-five patients had osteoporotic fractures, while 172 did not achieve a ≥ 3% BMD increase. Among predictors as defined by BMD change, both prior bisphosphonate treatment [odds ratio (95% confidence interval), 1.50 (1.01-2.24)] and vitamin D therapy [1.50 (1.01-2.22)] were significantly (P < 0.05) associated with teriparatide treatment failure. By contrast, no predictors were associated with treatment failure when fracture was the endpoint., Conclusion: These data suggest that prior bisphosphonate or vitamin D exposure may predict response failure to teriparatide therapy. Although these findings may, in part, reflect increased severity or longer duration of disease, this knowledge should help guide clinicians and patients when therapy choices are made.

Unlabelled: Precise delineation of the specific genes and pathways altered with aging and estrogen (E) therapy may lead to new skeletal biomarkers and the development of novel bone therapeutics. Previous human bone studies, however, have been limited by only examining pre-specified genes and pathways. High-throughput RNA sequencing (RNAseq), on the other hand, offers an unbiased approach to examine the entire transcriptome. Here we present an RNAseq analysis of human bone samples, obtained from iliac crest needle biopsies, to yield the first in vivo interrogation of all genes and pathways that may be altered in bone with aging and E therapy in humans. 58 healthy women were studied, including 19 young women (mean age ± SD, 30.3 ± 5.4 years), 19 old women (73.1 ± 6.6 years), and 20 old women treated with 3 weeks of E therapy (70.5 ± 5.2 years). Using generally accepted criteria (false discovery rate [q] < 0.10), aging altered a total of 678 genes and 12 pathways, including a subset known to regulate bone metabolism (e.g., Notch). Interestingly, the LEF1 transcription factor, which is a classical downstream target of the Wnt/β-catenin signaling pathway, was significantly downregulated in the bones from the old versus young women; consistent with this, LEF1 binding sites were significantly enriched in the promoter regions of the differentially expressed genes in the old versus young women, suggesting that aging was associated with alterations in Wnt signaling in bone. Further, of the 21 unique genes altered in bone by E therapy, the expression of INHBB (encoding for the inhibin, beta B polypeptide), which decreased with aging (by 0.6-fold), was restored to young adult levels in response to E therapy. In conclusion, our data demonstrate that aging alters a substantial portion of the skeletal transcriptome, whereas E therapy appears to have significant, albeit less wide-ranging effects. These data provide a valuable resource for the potential identification of novel biomarkers associated with age-related bone loss and also highlight potential pathways that could be targeted to treat osteoporosis., Trial Registration: ClinicalTrials.gov NCT02349113.

Age-related fragility fractures are an enormous public health problem. Both acquisition of bone mass during growth and bone loss associated with ageing affect fracture risk late in life. The development of high-resolution peripheral quantitative CT (HRpQCT) has enabled in vivo assessment of changes in the microarchitecture of trabecular and cortical bone throughout life. Studies using HRpQCT have demonstrated that the transient increase in distal forearm fractures during adolescent growth is associated with alterations in cortical bone, which include cortical thinning and increased porosity. Children with distal forearm fractures in the setting of mild, but not moderate, trauma also have increased deficits in cortical bone at the distal radius and in bone mass systemically. Moreover, these children transition into young adulthood with reduced peak bone mass. Elderly men, but not elderly women, with a history of childhood forearm fractures have an increased risk of osteoporotic fractures. With ageing, men lose trabecular bone primarily by thinning of trabeculae, whereas the number of trabeculae is reduced in women, which is much more destabilizing from a biomechanical perspective. However, age-related losses of cortical bone and increases in cortical porosity seem to have a much larger role than previously recognized, and increased cortical porosity might characterize patients at increased risk of fragility fractures.

The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1(-/Δ) mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1(-/∆) mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan., (© 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Background: Myostatin is a protein synthesized and secreted by skeletal muscle that negatively regulates muscle mass. The extent to which circulating myostatin levels change in the context of aging is controversial, largely due to methodological barriers., Methods: We developed a specific and sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) assay to measure concentrations of myostatin and two of its key inhibitors, follistatin-related gene (FLRG) protein and growth and serum protein-1 (GASP-1) in 80 younger (<40 years), 80 older (>65 years), and 80 sarcopenic older women and men., Results: Older women had 34 % higher circulating concentrations of myostatin than younger women. Per unit of lean mass, both older and sarcopenic older women had >23 % higher myostatin levels than younger women. By contrast, younger men had higher myostatin concentrations than older men with and without sarcopenia. Younger men had approximately twofold higher concentrations of myostatin than younger women; however, older women and sarcopenic older women had significantly higher relative myostatin levels than the corresponding groups of men. In both sexes, sarcopenic older subjects had the highest concentrations of FLRG. Circulating concentrations of myostatin exhibited positive, but not robust, correlations with relative muscle mass in both sexes., Conclusions: Our data suggest that myostatin may contribute to the higher prevalence of sarcopenia in women but acts as a homeostatic regulator of muscle mass in men. Moreover, this new LC-MS/MS-based approach offers a means to determine the extent to which myostatin serves as a biomarker of muscle health in diverse conditions of muscle loss and deterioration.

Age-related bone loss in humans is associated with a decrease in bone formation relative to bone resorption, although the mechanisms for this impairment in bone formation with aging are not well understood. It is known that the precursors for the bone-forming osteoblasts reside in the mesenchymal cell population in bone marrow. Thus, in an effort to identify relevant genetic pathways that are altered with aging, we examined the gene expression and DNA methylation patterns from a highly enriched bone marrow mesenchymal cell population from young (mean age, 28.7 years) versus old (mean age, 73.3 years) women. Bone marrow mononuclear cells from these women were depleted of hematopoietic lineage (lin) and endothelial cells using a combination of magnetic- and fluorescence-activated cell sorting, yielding a previously characterized mesenchymal cell population (lin-/CD34-/CD31- cells) that is capable of osteoblast differentiation. Whole transcriptome RNA sequencing (RNAseq) of freshly isolated cells (without in vitro culture) identified 279 differentially expressed genes (p < 0.05, false discovery rate [q]< 0.10) between the young and old subjects. Pathway analysis revealed statistically significant (all p < 0.05) alterations in protein synthesis and degradation pathways, as well as mTOR, gap junction, calcium, melatonin and NFAT signaling pathways. Further, Reduced Representational Bisulphite sequencing (RRBS DNA methylation sequencing) revealed significant differences in methylation between the young and old subjects surrounding the promoters of 1528 target genes that also exhibited significant differences in gene expression by RNAseq. In summary, these studies provide novel insights into potential pathways affected by aging in a highly enriched human mesenchymal cell population analyzed without the confounding effects of in vitro culture. Specifically, our finding of alterations in several genes and pathways leading to impaired protein synthesis and turnover with aging in bone marrow mesenchymal cells points to the need for further studies examining how these changes, as well as the other alterations with aging that we identified, may contribute to the age-related impairment in osteoblast formation and/or function., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Context: Numerous studies have examined the association of body composition with bone development in children and adolescents, but none have used micro-finite element (μFE) analysis of high-resolution peripheral quantitative computed tomography images to assess bone strength., Objective: This study sought to examine the relations of appendicular lean mass (ALM) and total body fat mass (TBFM) to bone strength (failure load) at the distal radius and tibia., Design, Participants, and Setting: This was a cross-sectional study of 198 healthy 8- to <15-year-old boys (n = 109) and girls (n = 89) performed in a Clinical Research Unit., Results: After adjusting for bone age, height, fracture history, ALM, and TBFM, multiple linear regression analyses in boys and girls, separately, showed robust positive associations between ALM and failure loads at both the distal radius (boys: β = 0.92, P < .001; girls: β = 0.66, P = .001) and tibia (boys: β = 0.96, P < .001; girls: β = 0.66, P < .001). By contrast, in both boys and girls the relationship between TBFM and failure load at the distal radius was virtually nonexistent (boys: β = -0.07; P = .284; girls: β = -0.03; P = .729). At the distal tibia, positive, albeit weak, associations were observed between TBFM and failure load in both boys (β = 0.09, P = .075) and girls (β = 0.17, P = .033)., Conclusions: Our data highlight the importance of lean mass for optimizing bone strength during growth, and suggest that fat mass may have differential relations to bone strength at weight-bearing vs non-weight-bearing sites in children and adolescents. These observations suggest that the strength of the distal radius does not commensurately increase with excess gains in adiposity during growth, which may result in a mismatch between bone strength and the load experienced by the distal forearm during a fall. These findings may explain, in part, why obese children are over-represented among distal forearm fracture cases.

Although primarily considered a disorder of the elderly, emerging evidence suggests the antecedents of osteoporosis are established during childhood and adolescence. A complex interplay of genetic, environmental, hormonal and behavioral factors determines skeletal development, and a greater effort is needed to identify the most critical factors that establish peak bone strength. Indeed, knowledge of modifiable factors that determine skeletal development may permit optimization of skeletal health during growth and could potentially offset reductions in bone strength with aging. The peripubertal years represent a unique period when the skeleton is particularly responsive to loading exercises, and there is now overwhelming evidence that exercise can optimize skeletal development. While this is not controversial, the most effective exercise prescription and how much investment in this prescription is needed to significantly impact bone health continues to be debated. Despite considerable progress, these issues are not easy to address, and important questions remain unresolved. This review focuses on the key determinants of skeletal development, whether exercise during childhood and adolescence should be advocated as a safe and effective strategy for optimizing peak bone strength, and whether investment in exercise early in life protects against the development of osteoporosis and fractures later in life.

Children and adolescents who sustain a distal forearm fracture (DFF) owing to mild, but not moderate, trauma have reduced bone strength and cortical thinning at the distal radius and tibia. Whether these skeletal deficits track into adulthood is unknown. Therefore, we studied 75 women and 75 men (age range, 20 to 40 years) with a childhood (age < 18 years) DFF and 150 sex-matched controls with no history of fracture using high-resolution peripheral quantitative computed tomography (HRpQCT) to examine bone strength (ie, failure load) by micro-finite element (µFE) analysis, as well as cortical and trabecular bone parameters at the distal radius and tibia. Level of trauma (mild versus moderate) was assigned using a validated classification scheme, blind to imaging results. When compared to sex-matched, nonfracture controls, women and men with a mild trauma childhood DFF (eg, fall from standing height) had significant reductions in failure load (p < 0.05) of the distal radius, whereas women and men with a moderate trauma childhood DFF (eg, fall while riding a bicycle) had values similar to controls. Consistent findings were observed at the distal tibia. Furthermore, women and men with a mild trauma childhood DFF had significant deficits in distal radius cortical area (p < 0.05), and significantly lower dual-energy X-ray absorptiometry (DXA)-derived bone density at the radius, hip, and total body regions compared to controls (all p < 0.05). By contrast, women and men with a moderate trauma childhood DFF had bone density, structure, and strength that did not differ significantly from controls. These findings in young adults are consistent with our observations in children/adolescents with DFF, and they suggest that a mild trauma childhood DFF may presage suboptimal peak bone density, structure, and strength in young adulthood. Children and adolescents who suffer mild trauma DFFs may need to be targeted for lifestyle interventions to help achieve improved skeletal health., (© 2014 American Society for Bone and Mineral Research.)

Purpose of Review: Recent data suggest that inhibitors of sclerostin, an osteocyte-produced Wnt signaling pathway antagonist, can stimulate bone formation. This review provides rationale and summarizes recent evidence supporting this novel approach to skeletal anabolism., Recent Findings: Data from numerous preclinical models in rodents and monkeys consistently demonstrate that antisclerostin monoclonal antibody (Scl-Ab) treatment leads to improvements in bone mass and strength, as well as enhanced fracture repair. Delivery of Scl-Ab therapy either subcutaneously or intravenously in phase 1 and 2 human clinical trials demonstrates short-term anabolic responses in excess of those seen with teriparatide, the only currently available anabolic skeletal agent. Gains have been primarily at central (spine and hips) versus peripheral (wrist) sites. Strikingly, Scl-Ab treatment appears to both stimulate bone formation and inhibit bone resorption in humans. If proven, Scl-Ab would be the first pharmacologic agent with such dual properties. Data on fractures are not yet available., Summary: Scl-Ab therapy represents a novel pharmacologic approach to skeletal anabolism. Although many questions remain before Scl-Ab treatment can be introduced into clinical practice, phase 3 human clinical trials are currently underway and could provide the necessary data to bring this exciting class of skeletal anabolic agents to patient care.

Objective: We sought to determine whether muscle density, an index of skeletal muscle fat content, was predictive of 2-year changes in weight-bearing bone parameters in young girls., Methods: Two-year prospective data from 248 girls, aged 8-13 years at baseline. Peripheral quantitative computed tomography was used to measure changes in bone strength indices (bone strength index [BSI, mg(2)/mm(4)] and strength-strain index [SSIp, mm(3)]) and volumetric bone mineral density [vBMD, mg/cm(3)] at distal metaphyseal and diaphyseal regions of the femur and tibia, as well as calf and thigh muscle density (mg/cm(3)), and muscle cross-sectional area (MCSA, mm(2)), indices of skeletal muscle fat content and muscle force production, respectively., Results: After controlling for potential confounders, greater gains in femur BSI (44%, P<0.002), total femur vBMD (114%, P<0.04) and femur trabecular vBMD (306%, P<0.002) occurred in girls in the lowest versus the highest groups of baseline thigh muscle density. Greater gains in tibial BSI (25%, P<0.03) and trabecular vBMD (190%, P<0.002) were also observed in the lowest versus the highest baseline calf muscle density groups., Conclusion: Baseline muscle density is a significant predictor of changes in bone density and bone strength in young girls during a period of rapid skeletal development.

Although patients with type 2 diabetes (T2D) are at significant risk for well-recognized diabetic complications, including macrovascular disease, retinopathy, nephropathy, and neuropathy, it is also clear that T2D patients are at increased risk for fragility fractures. Furthermore, fragility fractures in patients with T2D occur at higher bone mineral density (BMD) values compared to nondiabetic controls, suggesting abnormalities in bone material strength (BMS) and/or bone microarchitecture (bone "quality"). Thus, we performed in vivo microindentation testing of the tibia to directly measure BMS in 60 postmenopausal women (age range, 50-80 years) including 30 patients diagnosed with T2D for >10 years and 30 age-matched, nondiabetic controls. Regional BMD was measured by dual-energy X-ray absorptiometry (DXA); cortical and trabecular bone microarchitecture was assessed from high-resolution peripheral quantitative computed tomography (HRpQCT) images of the distal radius and tibia. Compared to controls, T2D patients had significantly lower BMS: unadjusted (-11.7%; p<0.001); following adjustment for body mass index (BMI) (-10.5%; p<0.001); and following additional adjustment for age, hypertension, nephropathy, neuropathy, retinopathy, and vascular disease (-9.2%; p=0.022). By contrast, after adjustment for confounding by BMI, T2D patients had bone microarchitecture and BMD that were not significantly different than controls; however, radial cortical porosity tended to be higher in the T2D patients. In addition, patients with T2D had significantly reduced serum markers of bone turnover (all p<0.001) compared to controls. Of note, in patients with T2D, the average glycated hemoglobin level over the previous 10 years was negatively correlated with BMS (r=-0.41; p=0.026). In conclusion, these findings represent the first demonstration of compromised BMS in patients with T2D. Furthermore, our results confirm previous studies demonstrating low bone turnover in patients with T2D and highlight the potential detrimental effects of prolonged hyperglycemia on bone quality. Thus, the skeleton needs to be recognized as another important target tissue subject to diabetic complications. © 2014 American Society for Bone and Mineral Research., (© 2014 American Society for Bone and Mineral Research.)

Summary: We isolate and characterize osteoblasts from humans without in vitro culture. These techniques should be broadly applicable to studying the pathogenesis of osteoporosis and other bone disorders., Introduction: There is currently no data regarding the expression of specific genes or pathways in human osteoblasts that have not been subjected to extensive in vitro culture. Thus, we developed methods to rapidly isolate progressively enriched osteoblast populations from humans and characterized these cells., Methods: Needle bone biopsies of the posterior iliac crest were subjected to sequential collagenase digests. The cells from the second digest were stained with an alkaline phosphatase (AP) antibody, and the AP+ cells were isolated using magnetic cell sorting., Results: Relative to AP- cells, the AP+ cells contained virtually all of the mineralizing cells and were enriched for key osteoblast marker genes. The AP+ cells were further purified by depletion of cells expressing CD45, CD34, or CD31 (AP+/CD45/34/31- cells), which represented a highly enriched human osteoblast population devoid of hematopoietic/endothelial cells. These cells expressed osteoblast marker genes but very low to undetectable levels of SOST. We next used high-throughput RNA sequencing to compare the transcriptome of the AP+/CD45/34/31- cells to human fibroblasts and identified genes and pathways expressed only in human osteoblasts in vivo, but not in fibroblasts, including 448 genes unique to human osteoblasts., Conclusions: We provide a detailed characterization of highly enriched human osteoblast populations without in vitro culture. These techniques should be broadly applicable to studying the pathogenesis of osteoporosis and other bone disorders.

Although distal forearm fractures (DFFs) are common during childhood and adolescence, it is unclear whether they reflect underlying skeletal deficits or are simply a consequence of the usual physical activities, and associated trauma, during growth. Therefore, we examined whether a recent DFF, resulting from mild or moderate trauma, is related to deficits in bone strength and cortical and trabecular bone macro- and microstructure compared with nonfracture controls. High-resolution peripheral quantitative computed tomography was used to assess micro-finite element-derived bone strength (ie, failure load) and to measure cortical and trabecular bone parameters at the distal radius and tibia in 115 boys and girls with a recent (<1 year) DFF and 108 nonfracture controls aged 8 to 15 years. Trauma levels (mild versus moderate) were assigned based on a validated classification scheme. Compared with sex-matched controls, boys and girls with a mild-trauma DFF (eg, fall from standing height) showed significant deficits at the distal radius in failure load (-13% and -11%, respectively; p < 0.05) and had higher ("worse") fall load-to-strength ratios (both +10%; p < 0.05 for boys and p = 0.06 for girls). In addition, boys and girls with a mild-trauma DFF had significant reductions in cortical area (-26% and -23%, respectively; p < 0.01) and cortical thickness (-14% and -13%, respectively; p < 0.01) compared with controls. The skeletal deficits in the mild-trauma DFF patients were generalized, as similar changes were present at the distal tibia. By contrast, both boys and girls with a moderate-trauma DFF (eg, fall from a bicycle) had virtually identical values for all of the measured bone parameters compared with controls. In conclusion, DFFs during growth have two distinct etiologies: those owing to underlying skeletal deficits leading to fractures with mild trauma versus those owing to more significant trauma in the setting of normal bone strength., (© 2014 American Society for Bone and Mineral Research.)

Peripheral quantitative computed tomography (pQCT) is an essential tool for assessing bone parameters of the limbs, but subject movement and its impact on image quality remains a challenge to manage. The current approach to determine image viability is by visual inspection, but pQCT lacks a quantitative evaluation. Therefore, the aims of this study were to (1) examine the reliability of a qualitative visual inspection scale and (2) establish a quantitative motion assessment methodology. Scans were performed on 506 healthy girls (9-13 years) at diaphyseal regions of the femur and tibia. Scans were rated for movement independently by three technicians using a linear, nominal scale. Quantitatively, a ratio of movement to limb size (%Move) provided a measure of movement artifact. A repeat-scan subsample (n = 46) was examined to determine %Move's impact on bone parameters. Agreement between measurers was strong (intraclass correlation coefficient = 0.732 for tibia, 0.812 for femur), but greater variability was observed in scans rated 3 or 4, the delineation between repeat and no repeat. The quantitative approach found ≥95% of subjects had %Move <25 %. Comparison of initial and repeat scans by groups above and below 25% initial movement showed significant differences in the >25 % grouping. A pQCT visual inspection scale can be a reliable metric of image quality, but technicians may periodically mischaracterize subject motion. The presented quantitative methodology yields more consistent movement assessment and could unify procedure across laboratories. Data suggest a delineation of 25% movement for determining whether a diaphyseal scan is viable or requires repeat.

Patients with monoclonal gammopathy of undetermined significance (MGUS) are at increased fracture risk, and we have previously shown that MGUS patients have altered trabecular bone microarchitecture compared with controls. However, there are no data on whether the porosity of cortical bone, which may play a greater role in bone strength and the occurrence of fractures, is increased in MGUS. Thus, we studied cortical porosity and bone strength (apparent modulus) using high-resolution peripheral quantitative computed tomography imaging of the distal radius in 50 MGUS patients and 100 age-, gender-, and body mass index-matched controls. Compared with controls, MGUS patients had both significantly higher cortical porosity (+16.8%; P < .05) and lower apparent modulus (-8.9%; P < .05). Despite their larger radial bone size, MGUS patients have significantly increased cortical bone porosity and reduced bone strength relative to controls. This increased cortical porosity may explain the increased fracture risk seen in MGUS patients.

A novel, hand-held Reference Point Indentation (RPI) instrument, measures how well the bone of living patients and large animals resists indentation. The results presented here are reported in terms of Bone Material Strength, which is a normalized measure of how well the bone resists indentation, and is inversely related to the indentation distance into the bone. We present examples of the instrument's use in: (1) laboratory experiments on bone, including experiments through a layer of soft tissue, (2) three human clinical trials, two ongoing in Barcelona and at the Mayo Clinic, and one completed in Portland, OR, and (3) two ongoing horse clinical trials, one at Purdue University and another at Alamo Pintado Stables in California. The instrument is capable of measuring consistent values when testing through soft tissue such as skin and periosteum, and does so handheld, an improvement over previous Reference Point Indentation instruments. Measurements conducted on horses showed reproducible results when testing the horse through tissue or on bare bone. In the human clinical trials, reasonable and consistent values were obtained, suggesting the Osteoprobe ® is capable of measuring Bone Material Strength in vivo, but larger studies are needed to determine the efficacy of the instrument's use in medical diagnosis.

Introduction: Poor muscle quality and sedentary behavior are risk factors for metabolic dysfunction in children and adolescents. However, because longitudinal data are scarce, relatively little is known about how changes in muscle quality and physical activity influence bone development., Purpose: In a 2-yr longitudinal study, we examined the effects of physical activity and changes in muscle quality on bone parameters in young girls., Methods: The sample included 248 healthy girls age 9-12 yr at baseline. Peripheral quantitative computed tomography was used to measure calf and thigh muscle density, an indicator of skeletal muscle fat content or muscle quality, as well as bone parameters at diaphyseal and metaphyseal sites of the femur and tibia. Physical activity was assessed using a validated questionnaire specific for youth., Results: After controlling for covariates in multiple regression models, increased calf muscle density was independently associated with greater gains in cortical (β = 0.13, P < 0.01) and trabecular (β = 0.25, P < 0.001) volumetric bone mineral density and the bone strength index (β = 0.25, P < 0.001) of the tibia. Importantly, these relationships were generalized, as similar changes were present at the femur. Associations between physical activity and changes in bone parameters were weaker than those observed for muscle density. Nevertheless, physical activity was significantly (all P < 0.05) associated with greater gains in trabecular volumetric bone mineral density and the bone strength index of the distal femur., Conclusions: These findings suggest that poor muscle quality may put girls at risk for suboptimal bone development. Physical activity is associated with more optimal gains in weight-bearing bone density and strength in girls, but to a lesser extent than changes in muscle quality.

Context: In women, cortical bone mass decreases significantly at menopause. By contrast, loss of trabecular bone begins in the third decade and accelerates after menopause., Objective: The aim of the study was to investigate the effects of estrogen on cortical and trabecular bone., Design: The Kronos Early Estrogen Prevention Study is a double-blind, randomized, placebo-controlled trial of menopausal hormone treatment (MHT) in women, enrolled within 6-36 months of their final menstrual period., Setting: The study was conducted at the Mayo Clinic, Rochester, Minnesota., Intervention: Subjects were treated with placebo (n = 31), or .45 mg/d conjugated equine estrogens (n = 20), or transdermal 50 μg/d 17β-estradiol (n = 25) with pulsed micronized progesterone., Main Outcome Measures: Cortical and trabecular microarchitecture at the distal radius was assessed by high-resolution peripheral quantitative computed tomography., Results: At the distal radius, cortical volumetric bone mineral density (vBMD) decreased, and cortical porosity increased in the placebo group; MHT prevented these changes. By contrast, MHT did not prevent decreases in trabecular microarchitecture at the radius. However, MHT prevented decreases in trabecular vBMD at the thoracic spine (assessed in a subset of subjects; n = 51). These results indicate that MHT prevents deterioration in radial cortical vBMD and porosity in recently menopausal women., Conclusion: The maintenance of cortical bone in response to estrogen likely has important clinical implications because cortical bone morphology plays an important role in bone strength. However, effects of MHT on trabecular bone at the radius differ from those at the thoracic spine. Underlying mechanisms for these site-specific effects of MHT on cortical vs trabecular bone require further investigation.

Unlabelled: Longitudinal relationships between adiposity (total body and central) and bone development were assessed in young girls. Total body and android fat masses were positively associated with bone strength and density parameters of the femur and tibia. These results suggest adiposity may have site-specific stimulating effects on the developing bone., Introduction: Childhood obesity may impair bone development, but the relationships between adiposity and bone remain unclear. Failure to account for fat pattern may explain the conflicting results., Purpose: Longitudinal associations of total body fat mass (TBFM) and android fat mass (AFM) with 2-year changes in weight-bearing bone parameters were examined in 260 girls aged 8-13 years at baseline. Peripheral quantitative computed tomography was used to measure bone strength index (BSI, square milligrams per quartic millimeter), strength-strain index (SSI, cubic millimeters), and volumetric bone mineral density (vBMD, milligrams per cubic centimeter) at distal metaphyseal and diaphyseal regions of the femur and tibia. TBFM and AFM were assessed by dual-energy x-ray absorptiometry., Results: Baseline TBFM and AFM were positively associated with the change in femur BSI (r = 0.20, r = 0.17, respectively) and femur trabecular vBMD (r = 0.19, r = 0.19, respectively). Similarly, positive associations were found between TBFM and change in tibia BSI and SSI (r = 0.16, r = 0.15, respectively), and femur total and trabecular vBMD (r = 0.12, r = 0.14, respectively). Analysis of covariance showed that girls in the middle thirds of AFM had significantly lower femur trabecular vBMD and significantly higher tibia cortical vBMD than girls in the highest thirds of AFM. All results were significant at p < 0.05., Conclusions: Whereas baseline levels of TBFM and AFM are positive predictors of bone strength and density at the femur and tibia, higher levels of AFM above a certain level may impair cortical vBMD growth at weight-bearing sites. Future studies in obese children will be needed to test this possibility.

Objective: Assess the utility of peripheral quantitative computed tomography (pQCT) for estimating whole body fat in adolescent girls., Research Methods and Procedures: Our sample included 458 girls (aged 10.7 ± 1.1y, mean BMI = 18.5 ± 3.3 kg/m 2 ) who had DXA scans for whole body percent fat (DXA %Fat). Soft tissue analysis of pQCT scans provided thigh and calf subcutaneous percent fat and thigh and calf muscle density (muscle fat content surrogates). Anthropometric variables included weight, height and BMI. Indices of maturity included age and maturity offset. The total sample was split into validation (VS; n = 304) and cross-validation (CS; n = 154) samples. Linear regression was used to develop prediction equations for estimating DXA %Fat from anthropometric variables and pQCT-derived soft tissue components in VS and the best prediction equation was applied to CS., Results: Thigh and calf SFA %Fat were positively correlated with DXA %Fat (r = 0.84 to 0.85; p <0.001) and thigh and calf muscle densities were inversely related to DXA %Fat (r = -0.30 to -0.44; p < 0.001). The best equation for estimating %Fat included thigh and calf SFA %Fat and thigh and calf muscle density (adj. R 2 = 0.90; SEE = 2.7%). Bland-Altman analysis in CS showed accurate estimates of percent fat (adj. R 2 = 0.89; SEE = 2.7%) with no bias., Discussion: Peripheral QCT derived indices of adiposity can be used to accurately estimate whole body percent fat in adolescent girls.

The extent to which nutrient intake may influence bone structure and strength during maximal rates of skeletal growth remains uncertain. We examined the relationship of dietary intake of micronutrients and bone macroarchitectural structure in young girls. This cross-sectional analysis included baseline data from 363 fourth- and sixth-grade girls enrolled in the Jump-In study. Nutrient intake was assessed using the Harvard Youth/Adolescent Food Frequency Questionnaire. Volumetric BMD (vBMD), bone geometry, and strength were measured by peripheral quantitative computed tomography. Correlations and regression modeling assessed relations between usual nutrient intake and bone parameters. In fourth-grade girls, metaphyseal and diaphyseal area and circumferences as well as diaphyseal strength were associated with vitamin C intake (r = 0.15-0.19, p < 0.05). Zinc intake was correlated with diaphyseal vBMD (r = 0.15-0.16, p < 0.05). Using multiple linear regression to adjust for important covariates, we observed significant independent associations for vitamin C and zinc with bone parameters. For every milligram per day of vitamin C intake trabecular area increased by 11 %, cortical strength improved by 14 %, and periosteal and endosteal circumferences increased by 5 and 8.6 %, respectively. For every milligram per day of zinc intake, cortical vBMD increased by <1 %. No significant associations were observed in sixth-grade girls. Results of this study suggests that vitamin C and zinc intake are positively associated with objective measures of bone geometry, size, and strength in fourth-grade girls. This indicates that potential differences in micronutrient and bone associations at various age-associated stages of bone maturation may be indicative of competing hormonal influences.

Context: Studies in rodents have demonstrated that sympathetic activity reduces bone formation and bone mass; these effects are mediated by the noncollagenous matrix protein, osteopontin., Objective: The objective of the study was to relate sympathetic activity (measured using microneurography at the peroneal nerve) to bone microstructure (assessed by high resolution peripheral quantitative computed tomography), bone turnover, and plasma osteopontin levels., Design, Setting, and Patients: Twenty-three women aged 20-72 yr (10 premenopausal and 13 postmenopausal) were studied in the Clinical Research Unit., Results: Sympathetic activity (bursts per 100 heart beats) was 2.4-fold higher in postmenopausal as compared with premenopausal women (P < 0.001). In the two groups combined and after age adjustment, sympathetic activity was inversely correlated with trabecular bone volume fraction (r = -0.55, P < 0.01) and thickness (r = -0.59, P < 0.01) and positively correlated with trabecular separation (r = 0.45, P < 0.05). Sympathetic activity was negatively correlated with serum amino-terminal propeptide of type I collagen in postmenopausal women (r = -0.65, P = 0.015), with a similar trend in premenopausal women (r = -0.58, P = 0.082). Sympathetic activity was also negatively correlated with plasma osteopontin levels (r = -0.43, P = 0.045), driven mainly by the correlation in postmenopausal women (r = -0.76, P = 0.002)., Conclusion: These findings represent the first demonstration in humans of a relationship between sympathetic activity and bone microstructure and circulating levels of amino-terminal propeptide of type I collagen and osteopontin. Given the critical role of osteopontin in mediating the effects of β-adrenergic signaling on bone, the inverse association between sympathetic activity and plasma osteopontin levels may reflect a negative feedback loop to limit the deleterious effects of sympathetic activity on bone metabolism. Based on the higher sympathetic activity observed in postmenopausal women, additional human studies are needed to define the role of increased sympathetic activity in mediating postmenopausal bone loss.

Unlabelled: Fat contained within skeletal muscle is strongly associated with obesity, type 2 diabetes mellitus, and metabolic syndrome. Physical inactivity may be a risk factor for greater fat infiltration within skeletal muscle during growth., Purpose: We sought to examine the relationship between physical activity and skeletal muscle fat content of the calf and thigh in girls., Methods: Data from 464 girls, age 8-13 yr, were used to examine the relationship between physical activity and skeletal muscle fat content of the calf and thigh. Calf and thigh muscle density (mg·cm(-3)), an index of skeletal muscle fat content, was assessed at the 66% tibia and 20% femur sites relative to the respective distal growth plates of the nondominant limb using peripheral quantitative computed tomography. Physical activity level was classified by past-year physical activity questionnaire score., Results: Muscle densities of the calf and thigh were inversely correlated with percent total body fat (r = -0.37 and -0.48, P values < 0.001) and total body fat mass (r = -0.33 and -0.40, P values < 0.001). Multiple linear regression with physical activity, ethnicity, maturity offset, and muscle cross-sectional area as independent variables showed that physical activity was independently associated with muscle densities of the calf (β = 0.14, P = 0.002) and thigh (β = 0.15, P < 0.001). Thus, lower physical activity was associated with higher skeletal muscle fat content., Conclusions: Our results suggest that a lower level of physical activity may lead to excess skeletal muscle fat content of the calf and thigh in girls.

Childhood obesity is an established risk factor for metabolic disease. The influence of obesity on bone development, however, remains controversial and may depend on the pattern of regional fat deposition. Therefore, we examined the associations of regional fat compartments of the calf and thigh with weight-bearing bone parameters in girls. Data from 444 girls aged 9 to 12 years from the Jump-In: Building Better Bones study were analyzed. Peripheral quantitative computed tomography (pQCT) was used to assess bone parameters at metaphyseal and diaphyseal sites of the femur and tibia along with subcutaneous adipose tissue (SAT, mm(2) ) and muscle density (mg/cm(3) ), an index of skeletal muscle fat content. As expected, SAT was positively correlated with total-body fat mass (r = 0.87-0.89, p < .001), and muscle density was inversely correlated with total-body fat mass (r = -0.24 to -0.28, p < .001). Multiple linear regression analyses with SAT, muscle density, muscle cross-sectional area, bone length, maturity, and ethnicity as independent variables showed significant associations between muscle density and indices of bone strength at metaphyseal (β = 0.13-0.19, p < .001) and diaphyseal (β = 0.06-0.09, p < .01) regions of the femur and tibia. Associations between SAT and indices of bone strength were nonsignificant at all skeletal sites (β = 0.03-0.05, p > .05), except the distal tibia (β = 0.09, p = .03). In conclusion, skeletal muscle fat content of the calf and thigh is inversely associated with weight-bearing bone strength in young girls., (Copyright © 2011 American Society for Bone and Mineral Research.)

Summary: More efficacious physical activity (PA) prescriptions for optimal bone development are needed. This study showed that PA duration, frequency, and load were all independently associated with bone parameters in young girls. Increased PA duration, frequency, and load are all important osteogenic stimuli that should be incorporated into future PA interventions., Introduction: This study evaluated the associations of physical activity (PA) duration, frequency, load, and their interaction (total PA score = duration × frequency × load) with volumetric bone mineral density, geometry, and indices of bone strength in young girls., Methods: Four hundred sixty-five girls (aged 8-13 years) completed a past year physical activity questionnaire (PYPAQ) which inquires about the frequency (days per week) and duration (average minutes per session) of leisure-time PA and sports. Load (peak strain score) values were assigned to each activity based on ground reaction forces. Peripheral quantitative computed tomography was used to assess bone parameters at metaphyseal and diaphyseal sites of the femur and tibia of the non-dominant leg., Results: Correlations across all skeletal sites between PA duration, frequency, load and periosteal circumference (PC), bone strength index (BSI), and strength-strain index (SSI) were significant (p ≤ 0.05), although low (0.10-0.17). A 2.7-3.7% greater PC across all skeletal sites was associated with a high compared to a low PYPAQ score. Also, a high PYPAQ score was associated with greater BSI (6.5-8.7%) at metaphyseal sites and SSI (7.5-8.1%) at diaphyseal sites of the femur and tibia. The effect of a low PYPAQ score on bone geometric parameters and strength was greater than a high PYPAQ score., Conclusions: PA duration, frequency, and load were all associated with bone geometry and strength, although their independent influences were modest and site specific. Low levels of PA may compromise bone development whereas high levels have only a small benefit over more average levels.

Unlabelled: Physical activity (PA) is critical for maximizing bone development during growth. However, there is no consensus on how well existing PA measurement tools predict bone strength., Purpose: The purposes of this study were to compare four methods of quantifying PA (pedometer, 3-d PA recall (3DPAR), bone-specific PA questionnaire (BPAQ), and past year PA questionnaire (PYPAQ)), in young girls and to evaluate their ability to predict indices of bone strength., Methods: A total of 329 girls aged 8-13 yr completed a pedometer assessment, the 3DPAR, the BPAQ, and a modified PYPAQ. Peripheral quantitative computed tomography was used to assess bone strength index (BSI) at metaphyseal (4% distal femur and tibia) sites and strength-strain index (SSI) at diaphyseal (femur = 20%, tibia = 66%) sites of the nondominant leg. Correlations and hierarchical multiple regression were used to assess relationships among PA measures and indices of bone strength., Results: After adjusting for maturity, correlations between PA measures and indices of bone strength were positive, although low (r = 0.01-0.20). Regression models that included covariates (maturity, body mass, leg length, and ethnicity) and PA variables showed that PYPAQ score was significantly (P < 0.05) associated with BSI and SSI at all sites and explained more variance in BSI and SSI than any other PA measure. Pedometer steps were significantly (P < 0.05) associated with metaphyseal femur and tibia BSI, and 3DPAR score was significantly (P < 0.05) associated with metaphyseal femur BSI. BPAQ score was not significantly (P > 0.05) associated with BSI or SSI at any sites., Conclusions: A modified PYPAQ that accounts for the duration, frequency, and load of PA predicted indices of bone strength better than other PA measures.

Understanding the etiology of skeletal fragility during growth is critical for the development of treatments and prevention strategies aimed at reducing the burden of childhood fractures. Thus we evaluated the relationship between prior fracture and bone parameters in young girls. Data from 465 girls aged 8 to 13 years from the Jump-In: Building Better Bones study were analyzed. Bone parameters were assessed at metaphyseal and diaphyseal sites of the nondominant femur and tibia using peripheral quantitative computed tomography (pQCT). Dual-energy X-ray absorptiometry (DXA) was used to assess femur, tibia, lumbar spine, and total body less head bone mineral content. Binary logistic regression was used to evaluate the relationship between prior fracture and bone parameters, controlling for maturity, body mass, leg length, ethnicity, and physical activity. Associations between prior fracture and all DXA and pQCT bone parameters at diaphyseal sites were nonsignificant. In contrast, lower trabecular volumetric BMD (vBMD) at distal metaphyseal sites of the femur and tibia was significantly associated with prior fracture. After adjustment for covariates, every SD decrease in trabecular vBMD at metaphyseal sites of the distal femur and tibia was associated with 1.4 (1.1-1.9) and 1.3 (1.0-1.7) times higher fracture prevalence, respectively. Prior fracture was not associated with metaphyseal bone size (ie, periosteal circumference). In conclusion, fractures in girls are associated with lower trabecular vBMD, but not bone size, at metaphyseal sites of the femur and tibia. Lower trabecular vBMD at metaphyseal sites of long bones may be an early marker of skeletal fragility in girls., (Copyright © 2011 American Society for Bone and Mineral Research.)

Understanding the influence of total body fat mass (TBFM) on bone during the peri-pubertal years is critical for the development of future interventions aimed at improving bone strength and reducing fracture risk. Thus, we evaluated the relationship of TBFM to volumetric bone mineral density (vBMD), geometry, and strength at metaphyseal and diaphyseal sites of the femur and tibia of young girls. Data from 396 girls aged 8-13 years from the "Jump-In: Building Better Bones" study were analyzed. Bone parameters were assessed using peripheral quantitative computed tomography (pQCT) at the 4% and 20% distal femur and 4% and 66% distal tibia of the non-dominant leg. Bone parameters at the 4% sites included trabecular vBMD, periosteal circumference, and bone strength index (BSI), while at the 20% femur and 66% tibia, parameters included cortical vBMD, periosteal circumference, and strength-strain index (SSI). Multiple linear regression analyses were used to assess associations between bone parameters and TBFM, controlling for muscle cross-sectional area (MCSA). Regression analyses were then repeated with maturity, bone length, physical activity, and ethnicity as additional covariates. Analysis of covariance (ANCOVA) was used to compare bone parameters among tertiles of TBFM. In regression models with TBFM and MCSA, associations between TBFM and bone parameters at all sites were not significant. TBFM explained very little variance in all bone parameters (0.2-2.3%). In contrast, MCSA was strongly related (p<0.001) to all bone parameters, except cortical vBMD. The addition of maturity, bone length, physical activity, and ethnicity did not alter the relationship between TBFM and bone parameters. With bone parameters expressed relative to total body mass, ANCOVA showed that all outcomes were significantly (p<0.001) greater in the lowest compared to the middle and highest tertiles of TBFM. Although TBFM is correlated with femur and tibia vBMD, periosteal circumference, and strength in young girls, this relationship is significantly attenuated after adjustment for MCSA. Nevertheless, girls with higher TBFM relative to body mass have markedly diminished vBMD, geometry, and bone strength at metaphyseal and diaphyseal sites of the femur and tibia., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: Prescription of resistance training (RT) exercises is an essential aspect of management for knee osteoarthritis (OA). However, whether patients with knee OA who are randomly assigned to receive RT simply substitute RT for other modes of physical activity remains unclear., Objective: The aim of this study was to determine the effect of a structured RT intervention on overall levels of moderate- and vigorous-intensity physical activity (MVPA) in patients with early-onset knee OA. The study compared patients with early-onset OA who participated in an RT program, those who participated in a self-management (SM) program, and those who participated in both RT and SM. Because participants randomly assigned to receive the RT intervention may simply switch activity modes, resulting in little net effect, we assessed total MVPA in addition to tracking changes in strength (force-generating capacity)., Design and Intervention: This study was a randomized controlled trial comparing the effectiveness of SM alone, RT alone, and combined RT+SM on MVPA in patients with early OA of the knee., Setting: The study was conducted on a university campus, with patient recruitment from the local community., Participants: The participants in this study were 171 patients (74% women, 26% men) with knee OA. They had a mean age of 55.1 (SD=7.1) years, a mean body mass index of 27.6 (SD=4.2) kg/m(2), and radiographic status of grade II OA (and no higher) in at least one knee, as defined by the Kellgren and Lawrence classification. They wore an accelerometer while awake (X=14.2 [SD=2.2] hours) for 5 to 7 contiguous days (X=6.8 [SD=0.5] days) at baseline and at 3 and 9 months of intervention., Results: The participants engaged in MVPA a mean of 26.2 (SD=19.3) minutes per day at baseline. Both groups significantly increased their MVPA from baseline to 3 months (RT group by 18% [effect size (d)=0.26]; SM group by 22% [effect size (d)=0.25]), but only the RT group sustained those changes at 9 months (RT group maintained a 10% increase [effect size (d)=0.15]; SM group maintained a 2% increase [effect size (d)=0.03]). A significant group x time interaction for MVPA indicated that the RT group maintained higher MVPA levels than the SM group., Limitations: Lack of direct measures of energy expenditure and physical function was a limitation of the study., Conclusions: Patients with early-onset OA of the knee can engage in an RT program without sacrificing their overall MVPA levels. These results support the value of RT for management of knee OA.