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1.  Effect of type 2 diabetes-related non-enzymatic glycation on bone biomechanical properties 
Bone  2015;82:21-27.
There is clear evidence that patients with type 2 diabetes mellitus (T2D) have increased fracture risk, despite having high bone mineral density (BMD) and body mass index (BMI). Thus, poor bone quality has been implicated as a mechanism contributing to diabetic skeletal fragility. Poor bone quality in T2D may result from the accumulation of advanced glycation end-products (AGEs), which are post-translational modifications of collagen resulting from a spontaneous reaction between extracellular sugars and amino acid residues on collagen fibers. This review discusses what is known and what is not known regarding AGE accumulation and diabetic skeletal fragility, examining evidence from in vitro experiments to simulate a diabetic state, ex vivo studies in normal and diabetic human bone, and diabetic animal models. Key findings in the literature are that AGEs increase with age, affect bone cell behavior, and are altered with changes in bone turnover. Further, they affect bone mechanical properties and microdamage accumulation, and can be inhibited in vitro by various inhibitors and breakers (e.g. aminoguanidine, N-Phenacylthiazolium Bromide, vitamin B6). While a few studies report higher AGEs in diabetic animal models, there is little evidence of AGE accumulation in bone from diabetic patients. There are several limitations and inconsistencies in the literature that should be noted and studied in greater depth including understanding the discrepancies between glycation levels across reported studies, clarifying differences in AGEs in cortical versus cancellous bone, and improving the very limited data available regarding glycation content in diabetic animal and human bone, and its corresponding effect on bone material properties in T2D.
PMCID: PMC4679472  PMID: 26211993
diabetes; bone strength; bone mechanics; bone quality; advanced glycation end-products
2.  Altered trabecular bone morphology in adolescent and young adult athletes with menstrual dysfunction☆,☆☆,★ 
Bone  2015;81:24-30.
Young amenorrheic athletes (AA) have lower bonemineral density (BMD) and an increased prevalence of fracture compared with eumenorrheic athletes (EA) and non-athletes. Trabecular morphology is a determinant of skeletal strength and may contribute to fracture risk.
To determine the variation in trabecular morphology among AA, EA, and non-athletes and to determine the association of trabecular morphology with fracture among AA.
Design and setting
A cross-sectional study performed at an academic clinical research center.
161 girls and young women aged 14–26 years (97 AA, 32 EA, and 32 non-athletes).
Main outcome measure
We measured volumetric BMD (vBMD) and skeletal microarchitecture using high-resolution peripheral quantitative computed tomography. We evaluated trabecular morphology (plate-like vs. rod-like), orientation, and connectivity by individual trabecula segmentation.
At the non-weight-bearing distal radius, the groups did not differ for trabecular vBMD. However, plate-like trabecular bone volume fraction (pBV/TV) was lower in AA vs. EA (p = 0.03), as were plate number (p = 0.03) and connectivity (p = 0.03). At the weight-bearing distal tibia, trabecular vBMD was higher in athletes vs. non-athletes (p=0.05 for AA and p=0.009 for EA vs. non-athletes, respectively). pBV/TV was higher in athletes vs. non-athletes (p=0.04 AA and p=0.005 EA vs. non-athletes), as were axially-aligned trabeculae, plate number, and connectivity. Among AA, those with a history of recurrent stress fracture had lower pBV/TV, axially-aligned trabeculae, plate number, plate thickness, and connectivity at the distal radius.
Trabecular morphology and alignment differ among AA, EA, and non-athletes. These differences may be associated with increased fracture risk.
PMCID: PMC4745258  PMID: 26123592
Bone density; Microarchitecture; Amenorrhea; Athlete
3.  SIKs control osteocyte responses to parathyroid hormone 
Nature Communications  2016;7:13176.
Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. SIK inhibition mimics many of the effects of PTH in osteocytes as assessed by RNA-seq in cultured osteocytes and following in vivo administration. Once daily treatment with the small molecule SIK inhibitor YKL-05-099 increases bone formation and bone mass. Therefore, a major arm of PTH signalling in osteocytes involves SIK inhibition, and small molecule SIK inhibitors may be applied therapeutically to mimic skeletal effects of PTH.
Parathyroid hormone (PTH) is an endogenous hormone and osteoporosis therapeutic that suppresses sclerostin activity. Here the authors develop SIK inhibitors as potential therapeutic tools and use them to show that PTH-cAMP signalling in osteocytes inhibits SIK2 from driving Hdac4/5 nuclear shuttling to suppress sclerostin.
PMCID: PMC5075806  PMID: 27759007
4.  Serum FGF-21 levels are associated with worsened radial trabecular bone microarchitecture and decreased radial bone strength in women with anorexia nervosa 
Bone  2015;77:6-11.
Anorexia nervosa (AN) is a psychiatric disorder characterized by self-induced starvation and low body weight. Women with AN have impaired bone formation, low bone mass and an increased risk of fracture. FGF-21 is a hormone secreted by the liver in starvation and FGF-21 transgenic mice have significant bone loss due to an uncoupling of bone resorption and bone formation. We hypothesized that FGF-21 may contribute to the low bone mass state of AN.
We studied 46 women: 20 with AN (median age [interquartile range]: 27.5 [25, 30.75] years) and 26 normal-weight controls (NWC) of similar age (25 [24, 28.5] years). We investigated associations between serum FGF-21 and 1) aBMD measured by dual energy X-ray absorptiometry, 2) parameters of bone microarchitecture in the distal radius and tibia measured by high-resolution peripheral quantitative CT and 3) bone strength, estimated by microfinite element analysis.
FGF-21 levels were similar in AN and NWC (AN: 33.1 [18.1, 117.0] pg/ml vs NWC: 57.4 [23.8, 107.1] pg/ml; p=0.54). There was a significant inverse association between log FGF-21 and trabecular number in the radius in both AN (R= -0.57, p<0.01) and NWC (R= -0.53, p<0.01) and a significant positive association between log FGF-21 and trabecular separation in the radius in AN (R=0.50, p<0.03) and NWC (R=0.52, p<0.01). Estimates of radial bone strength were inversely associated with log FGF-21 in AN (R= -0.50, p<0.03 for both stiffness and failure load). There were no associations between FGF-21 and aBMD, cortical parameters or tibial parameters in the AN or NWC groups.
FGF-21 may be an important determinant of trabecular skeletal homeostasis in AN.
PMCID: PMC4447546  PMID: 25868802
FGF-21; anorexia nervosa; bone microarchitecture; bone strength
5.  Low Magnitude Mechanical Stimulation to Improve Bone Density in Persons of Advanced Age: A Randomized, Placebo-Controlled Trial 
Non-pharmacologic approaches to preserve or increase bone mineral density (BMD) include whole body vibration (WBV), but its efficacy in elderly persons is not clear. Therefore, we conducted the Vibration to Improve Bone in Elderly Subjects (“VIBES”) trial, a randomized, placebo-controlled trial of 10 minutes of daily WBV (0.3g at 37 Hz) in seniors recruited from 16 independent living communities. The primary outcomes were volumetric BMD of the hip and spine measured by quantitative computed tomography (QCT), and biochemical markers of bone turnover. We randomized 174 men and women (89 active, 85 placebo) with T-scores −1 to −2.5 who were not taking bone active drugs and had no diseases affecting the skeleton (mean age 82 ± 7 yrs, range 65–102). Participants received daily calcium (1,000 mg) and vitamin D (800 IU). Study platforms were activated using radio frequency ID cards providing electronic adherence monitoring; placebo platforms resembled the active platforms. In total, 61% of participants in the active arm and 73% in the placebo arm completed 24 months. The primary outcomes, median percent changes (inter-quartile range; IQR) in total volumetric femoral trabecular BMD (active group (2.2% [−0.8%, 5.2%]) vs. placebo 0.4% [−4.8%, 5.0%]), and in median mid-vertebral trabecular BMD of L1 and L2 (active group (5.3% [−6.9%, 13.3%]) vs. placebo (2.4% [−4.4%, 11.1%]), did not differ between groups (all p-values > 0.1). Changes in biochemical markers of bone turnover (P1NP and sCTX) also were not different between groups (p=0.19 and p=0.97, respectively). In conclusion, this placebo-controlled randomized trial of daily WBV in older adults did not demonstrate evidence of significant beneficial effects on volumetric BMD or bone biomarkers; however, the high variability in vBMD changes limited our power to detect small treatment effects. The beneficial effects of WBV observed in previous studies of younger women may not occur to the same extent in elderly individuals.
PMCID: PMC4834704  PMID: 25581217
7.  Spaceflight Activates Lipotoxic Pathways in Mouse Liver 
PLoS ONE  2016;11(4):e0152877.
Spaceflight affects numerous organ systems in the body, leading to metabolic dysfunction that may have long-term consequences. Microgravity-induced alterations in liver metabolism, particularly with respect to lipids, remain largely unexplored. Here we utilize a novel systems biology approach, combining metabolomics and transcriptomics with advanced Raman microscopy, to investigate altered hepatic lipid metabolism in mice following short duration spaceflight. Mice flown aboard Space Transportation System -135, the last Shuttle mission, lose weight but redistribute lipids, particularly to the liver. Intriguingly, spaceflight mice lose retinol from lipid droplets. Both mRNA and metabolite changes suggest the retinol loss is linked to activation of PPARα-mediated pathways and potentially to hepatic stellate cell activation, both of which may be coincident with increased bile acids and early signs of liver injury. Although the 13-day flight duration is too short for frank fibrosis to develop, the retinol loss plus changes in markers of extracellular matrix remodeling raise the concern that longer duration exposure to the space environment may result in progressive liver damage, increasing the risk for nonalcoholic fatty liver disease.
PMCID: PMC4838331  PMID: 27097220
8.  Defects in cortical microarchitecture among African-American women with type 2 diabetes 
Fracture risk is increased in patients with type 2 diabetes mellitus (DM2) despite normal areal bone mineral density (aBMD). DM2 is more common in African-Americans than in Caucasians. It is not known whether African-American women with DM2 have deficits in bone microstructure.
We measured aBMD at the spine and hip by DXA, and volumetric BMD (vBMD) and microarchitecture at the distal radius and tibia by HR-pQCT in 22 DM2 and 78 non-diabetic African-American women participating in the Study of Women Across the Nation (SWAN). We also measured fasting glucose and HOMA-IR.
Age, weight, and aBMD at all sites were similar in both groups. At the radius, cortical porosity was 26% greater, while cortical vBMD and tissue mineral density were lower in women with DM2 than in controls. There were no differences in radius total vBMD or trabecular vBMD between groups. Despite inferior cortical bone properties at the radius, FEA-estimated failure load was similar between groups. Tibia vBMD and microarchitecture were also similar between groups. There were no significant associations between cortical parameters and duration of DM2 or HOMA-IR. However, among women with DM2, higher fasting glucose levels were associated with lower cortical vBMD (r=−0.54, p=0.018).
DM2 and higher fasting glucose are associated with unfavorable cortical bone microarchitecture at the distal radius in African-American women. These structural deficits may contribute to the increased fracture risk among women with DM2. Further our results suggest that hyperglycemia may be involved in mechanisms of skeletal fragility associated with DM2.
PMCID: PMC4400116  PMID: 25398431
diabetes mellitus type 2; African-American; HR-pQCT; bone microarchitecture; microfinite element analysis
9.  Stk11 (Lkb1) deletion in the osteoblast lineage leads to high bone turnover, increased trabecular bone density and cortical porosity 
Bone  2014;69:98-108.
The mTOR pathway couples energy homeostasis to growth, division and survival of the cell. Stk11/Lkb1 is a critical serine-threonine protein kinase in the inhibition of mTOR pathway action. In the mammalian skeleton, Stk11 regulates the transition between immature and hypertrophic chondrocytes. Here, we have focused on the action of Stk11in the osteoblast lineage through osteoblast specific-removal of Stk11 activity. In the mouse model system, specification and primary organization of the neonatal boney skeleton is independent of Stk11. However, histological, molecular and micro-CT analysis revealed a marked perturbation of normal bone development evident in the immediate post-natal period. Cortical bone was unusually porous displaying a high rate of turnover with new trabeculae forming in the endosteal space. Trabecular bone also showed enhanced turnover and marked increase in the density of trabeculae and number of osteoclasts. Though mutants showed an expansion of bone volume and trabecular number their bone matrix comprised large amounts of osteoid and irregularly deposited woven bone highlighted by diffuse fluorochrome labeling. Additionally, we observed an increase in fibroblast-like cells associated with trabecular bone in Stk11 mutants. Stk11 down-regulates mTORC1 activity through control of upstream modulators of the AMP kinase family: an increase in the levels of the phosphorylated ribosomal protein S6, a target of mTORC1-mediated kinase activity, on osteoblast removal of Stk11 suggests deregulated mTORC1 activity contributes to the osteoblast phenotype. These data demonstrate Stk11 activity within osteoblasts is critical for the development of normally structured bone regulating directly the number and coordinated actions of osteoblasts, and indirectly osteoclast number.
PMCID: PMC4373701  PMID: 25240456
Serine/threonine kinase 11(Stk11/Lkb1); osteoblast differentiation; histomorphometry; peritrabecular marrow fibrosis; woven bone; mTOR signaling
10.  Sclerostin Antibody Inhibits Skeletal Deterioration Due to Reduced Mechanical Loading 
Sclerostin, a product of the SOST gene produced mainly by osteocytes, is a potent negative regulator of bone formation that appears to be responsive to mechanical loading, with SOST expression increasing following mechanical unloading. We tested the ability of a murine sclerostin antibody (SclAbII) to prevent bone loss in adult mice subjected to hindlimb unloading (HLU) via tail suspension for 21 days. Mice (n = 11–17/group) were assigned to control (CON, normal weight bearing) or HLU and injected with either SclAbII (subcutaneously, 25 mg/kg) or vehicle (VEH) twice weekly. SclAbII completely inhibited the bone deterioration due to disuse, and induced bone formation such that bone properties in HLU-SclAbII were at or above values of CON-VEH mice. For example, hindlimb bone mineral density (BMD) decreased –9.2%±1.0% in HLU-VEH, whereas it increased 4.2%±0.7%, 13.1%±1.0%, and 30.6%±3.0% in CON-VEH, HLU-SclAbII, and CON-SclAbII, respectively (p < 0.0001). Trabecular bone volume, assessed by micro–computed tomography (μCT) imaging of the distal femur, was lower in HLU-VEH versus CON-VEH (p < 0.05), and was 2- to 3-fold higher in SclAbII groups versus VEH (p < 0.001). Midshaft femoral strength, assessed by three-point bending, and distal femoral strength, assessed by micro–finite element analysis (μFEA), were significantly higher in SclAbII versus VEH-groups in both loading conditions. Serum sclerostin was higher in HLU-VEH (134±5 pg/mL) compared to CON-VEH (116±6 pg/mL, p < 0.05). Serum osteocalcin was decreased by hindlimb suspension and increased by SclAbII treatment. Interestingly, the anabolic effects of sclerostin inhibition on some bone outcomes appeared to be enhanced by normal mechanical loading. Altogether, these results confirm the ability of SclAbII to abrogate disuse-induced bone loss and demonstrate that sclerostin antibody treatment increases bone mass by increasing bone formation in both normally loaded and underloaded environments.
PMCID: PMC4076162  PMID: 23109229
11.  CT-Based Muscle Attenuation and Electrical Impedance Myography as Indicators of Trunk Muscle Strength Independent of Muscle Size in Older Adults 
To examine the associations of computed tomography (CT) -based x-ray attenuation and paraspinal electrical impedance myography (EIM) measures of trunk muscles with absolute and relative (normalized by body weight) trunk extension strength, independent of muscle cross-sectional area (CSA).
A cross-sectional study of mobility-limited community dwelling older adults (34 women, 15 men, mean age 78.2±7.2 years) recruited from within an existing prospective research cohort. Trunk extension strength, CT-based trunk muscle CSA and attenuation at L4 level, and paraspinal EIM measures were collected.
Attenuation was positively correlated with absolute and relative strength for multiple muscle groups (r = 0.32 to 0.61, p < 0.05). Paraspinal EIM phase was positively correlated with paraspinal attenuation (r = 0.30, p = 0.039) and with relative strength (r = 0.30, p = 0.042). In multivariable linear regressions adjusting for sex and CSA, attenuations of the anterior abdominal muscles (semipartial r2 = 0.11, p = 0.013) and combined muscles (semipartial r2 = 0.07, p = 0.046) were associated with relative strength.
While attenuation was associated with relative strength, small effect sizes indicate limited usefulness as clinical measures of muscle strength independent of muscle size. However, there remains a need for additional studies in larger and more diverse groups of subjects.
PMCID: PMC4105177  PMID: 24508931
Muscle Strength; Multidetector Computed Tomography; Myography; Aged
12.  Combined effects of botulinum toxin injection and hindlimb unloading on bone and muscle 
Calcified tissue international  2013;94(3):327-337.
Bone receives mechanical stimulation from two primary sources, muscle contractions and external gravitational loading, but the relative contribution of each source to skeletal health is not fully understood. Understanding the most effective loading for maintaining bone health has important clinical implications for prescribing physical activity for the treatment or prevention of osteoporosis. Therefore, we investigated the relative effects of muscle paralysis and reduced gravitational loading on changes in muscle mass, bone mineral density and microarchitecture. Adult female C57Bl/6J mice (n=10/group) underwent one of the following: unilateral botulinum toxin (BTX) injection of the hindlimb, hindlimb unloading (HLU), both unilateral BTX injection and HLU, or no intervention. BTX and HLU each led to significant muscle and bone loss. The effect of BTX was diminished when combined with HLU, though generally the leg that received the combined intervention (HLU + BTX) had the most detrimental changes in bone and muscle. We found an indirect effect of BTX affecting the uninjected (contralateral) leg that led to significant decreases in bone mineral density and deficits in muscle mass and bone architecture relative to the untreated controls; the magnitude of this indirect BTX effect was comparable to the direct effect of BTX treatment and HLU. Thus, while it was difficult to definitively conclude whether muscle forces or external gravitational loading contribute more to bone maintenance, it appears that BTX-induced muscle paralysis is more detrimental to muscle and bone than hindlimb unloading.
PMCID: PMC3921683  PMID: 24240478
disuse; botulinum toxin; mechanical loading; tail suspension; muscle-bone; interaction; hindlimb unloading; paralysis
14.  Differences in Skeletal Microarchitecture and Strength in African-American and Caucasian Women 
African-American women have a lower risk of fracture than Caucasian women, and this difference is only partially explained by differences in DXA areal bone mineral density (aBMD). Little is known about racial differences in skeletal microarchitecture and the consequences for bone strength. To evaluate potential factors underlying this racial difference in fracture rates, we used high-resolution peripheral quantitative computed tomography (HR-pQCT) to assess cortical and trabecular bone microarchitecture and estimate bone strength using micro-finite element analysis in African-American (n=100) and Caucasian (n=173) women participating in the Study of Women's Health Across the Nation (SWAN). African-American women had larger and denser bones than Caucasians, with greater total area, aBMD, and total volumetric BMD (vBMD) at the radius and tibia metaphysis (p<0.05 for all). African-Americans had greater trabecular vBMD at the radius, but higher cortical vBMD at the tibia. Cortical microarchitecture tended to show the most pronounced racial differences, with higher cortical area, thickness, and volumes in African-Americans at both skeletal sites (p<0.05 for all), and lower cortical porosity in African-Americans at the tibia (p<0.05). African-American women also had greater estimated bone stiffness and failure load at both the radius and tibia. Differences in skeletal microarchitecture and estimated stiffness and failure load persisted even after adjustment for DXA aBMD. The densitometric and microarchitectural predictors of failure load at the radius and tibia were the same in African-American and Caucasian women. In conclusion, differences in bone microarchitecture and density contribute to greater estimated bone strength in African-Americans and probably explain, at least in part, the lower fracture risk of African-American women.
PMCID: PMC3779478  PMID: 23572415
HR-pQCT; bone microarchitecture; microfinite element analysis; African-American; Caucasian
15.  Mechanical Contributions of the Cortical and Trabecular Compartments Contribute to Differences in Age-Related Changes in Vertebral Body Strength in Men and Women Assessed by QCT-Based Finite Element Analysis 
The biomechanical mechanisms underlying sex-specific differences in age-related vertebral fracture rates are ill defined. To gain insight into this issue, we used finite element analysis of clinical computed tomography (CT) scans of the vertebral bodies of L3 and T10 of young and old men and women to assess age- and sex-related differences in the strength of the whole vertebra, the trabecular compartment, and the peripheral compartment (the outer 2 mm of vertebral bone, including the thin cortical shell). We sought to determine whether structural and geometric changes with age differ in men and women, making women more susceptible to vertebral fractures. As expected, we found that vertebral strength decreased with age 2-fold more in women than in men. The strength of the trabecular compartment declined significantly with age for both sexes, whereas the strength of the peripheral compartment decreased with age in women but was largely maintained in men. The proportion of mechanical strength attributable to the peripheral compartment increased with age in both sexes and at both vertebral levels. Taken together, these results indicate that men and women lose vertebral bone differently with age, particularly in the peripheral (cortical) compartment. This differential bone loss explains, in part, a greater decline in bone strength in women and may contribute to the higher incidence of vertebral fractures among women than men. © 2011 American Society for Bone and Mineral Research.
PMCID: PMC3179306  PMID: 21542000
16.  Altered thermogenesis and impaired bone remodeling in Misty mice 
Fat mass may be modulated by the number of brown-like adipocytes in white adipose tissue (WAT) in humans and rodents. Bone remodeling is dependent on systemic energy metabolism and, with age, bone remodeling becomes uncoupled and brown adipose tissue (BAT) function declines. To test the interaction between BAT and bone, we employed Misty (m/m) mice, which were reported be deficient in BAT. We found that Misty mice have accelerated age-related trabecular bone loss and impaired brown fat function (including reduced temperature, lower expression of Pgc1a and less sympathetic innervation compared to wildtype (+/+)). Despite reduced BAT function, Misty mice had normal core body temperature, suggesting heat is produced from other sources. Indeed, upon acute cold exposure (4°C for 6 hr), inguinal WAT from Misty mice compensated for BAT dysfunction by increasing expression of Acadl, Pgc1a, Dio2 and other thermogenic genes. Interestingly, acute cold exposure also decreased Runx2 and increased Rankl expression in Misty bone, but only Runx2 was decreased in wildtype. Browning of WAT is under the control of the sympathetic nervous system (SNS) and, if present at room temperature, could impact bone metabolism. To test whether SNS activity could be responsible for accelerated trabecular bone loss, we treated wildtype and Misty mice with the β-blocker, propranolol. As predicted, propranolol slowed trabecular BV/TV loss in the distal femur of Misty mice without affecting wildtype. Finally, the Misty mutation (a truncation of DOCK7) also has a significant cell-autonomous role. We found DOCK7 expression in whole bone and osteoblasts. Primary osteoblast differentiation from Misty calvaria was impaired, demonstrating a novel role for DOCK7 in bone remodeling. Despite the multifaceted effects of the Misty mutation, we have shown that impaired brown fat function leads to altered SNS activity and bone loss, and for the first time that cold exposure negatively affects bone remodeling.
PMCID: PMC3743939  PMID: 23553822
bone; brown adipose tissue; DOCK7; Misty; thermogenesis
17.  Vertebral Size, Bone Density, and Strength in Men and Women Matched for Age and Areal Spine BMD 
To explore the possible mechanisms underlying sex-specific differences in skeletal fragility that may be obscured by two-dimensional areal bone mineral density (aBMD) measures, we compared quantitative computed tomography (QCT)-based vertebral bone measures among pairs of men and women from the Framingham Heart Study Multidetector Computed Tomography Study who were matched for age and spine aBMD. Measurements included vertebral body cross-sectional area (CSA, cm2), trabecular volumetric BMD (Tb.vBMD, g/cm3), integral volumetric BMD (Int.vBMD, g/cm3), estimated vertebral compressive loading and strength (Newtons) at L3, the factor-of-risk (load-to-strength ratio), and vertebral fracture prevalence. We identified 981 male-female pairs (1:1 matching) matched on age (± 1 year) and QCT-derived aBMD of L3 (± 1%), with an average age of 51 years (range 34 to 81 years). Matched for aBMD and age, men had 20% larger vertebral CSA, lower Int.vBMD (−8%) and Tb.vBMD (−9%), 10% greater vertebral compressive strength, 24% greater vertebral compressive loading, and 12% greater factor-of-risk than women (p < 0.0001 for all), as well as higher prevalence of vertebral fracture. After adjusting for height and weight, the differences in CSA and volumetric bone mineral density (vBMD) between men and women were attenuated but remained significant, whereas compressive strength was no longer different. In conclusion, vertebral size, morphology, and density differ significantly between men and women matched for age and spine aBMD, suggesting that men and women attain the same aBMD by different mechanisms. These results provide novel information regarding sex-specific differences in mechanisms that underlie vertebral fragility.
PMCID: PMC4149904  PMID: 23955966
18.  The Effects of GATA-1 and NF-E2 Deficiency on Bone Biomechanical, Biochemical, and Mineral Properties 
Journal of cellular physiology  2013;228(7):1594-1600.
Mice deficient in GATA-1 or NF-E2, transcription factors required for normal megakaryocyte (MK) development, have increased numbers of MKs, reduced numbers of platelets, and a striking high bone mass phenotype. Here, we show the bone geometry, microarchitecture, biomechanical, biochemical, and mineral properties from these mutant mice. We found that the outer geometry of the mutant bones was similar to controls, but that both mutants had a striking increase in total bone area (up to a 35% increase) and trabecular bone area (up to a 19% increase). Interestingly, only the NF-E2 deficient mice had a significant increase in cortical bone area (21%) and cortical thickness (27%), which is consistent with the increase in bone mineral density (BMD) seen only in the NF-E2 deficient femurs. Both mutant femurs exhibited significant increases in several biomechanical properties including peak load (up to a 32% increase) and stiffness (up to a 13% increase). Importantly, the data also demonstrate differences between the two mutant mice. GATA-1 deficient femurs break in a ductile manner, whereas NF-E2 deficient femurs are brittle in nature. To better understand these differences, we examined the mineral properties of these bones. Although none of the parameters measured were different between the NF-E2 deficient and control mice, an increase in calcium (21%) and an increase in the mineral/matrix ratio (32%) was observed in GATA-1 deficient mice. These findings appear to contradict biomechanical findings, suggesting the need for further research into the mechanisms by which GATA-1 and NF-E2 deficiency alter the material properties of bone.
PMCID: PMC4128339  PMID: 23359245
19.  Partial Reductions in Mechanical Loading Yield Proportional Changes in Bone Density, Bone Architecture, and Muscle Mass 
Although the musculoskeletal system is known to be sensitive to changes in its mechanical environment, the relationship between functional adaptation and below-normal mechanical stimuli is not well defined. We investigated bone and muscle adaptation to a range of reduced loading using the partial weight suspension (PWS) system, in which a two-point harness is used to offload a tunable amount of body weight while maintaining quadrupedal locomotion. Skeletally mature female C57Bl/6 mice were exposed to partial weight bearing at 20%, 40%, 70%, or 100% of body weight for 21 days. A hindlimb unloaded (HLU) group was included for comparison in addition to age-matched controls in normal housing. Gait kinematics was measured across the full range of weight bearing, and some minor alterations in gait from PWS were identified. With PWS, bone and muscle changes were generally proportional to the degree of unloading. Specifically, total body and hindlimb bone mineral density, calf muscle mass, trabecular bone volume of the distal femur, and cortical area of the femur midshaft were all linearly related to the degree of unloading. Even a load reduction to 70% of normal weight bearing was associated with significant bone deterioration and muscle atrophy. Weight bearing at 20% did not lead to better bone outcomes than HLU despite less muscle atrophy and presumably greater mechanical stimulus, requiring further investigation. These data confirm that the PWS model is highly effective in applying controllable, reduced, long-term loading that produces predictable, discrete adaptive changes in muscle and bone of the hindlimb.
PMCID: PMC4118556  PMID: 23165526
20.  A Biomechanical Model for Estimating Loads on Thoracic and Lumbar Vertebrae 
Biomechanical models are commonly used to estimate loads on the spine. Current models have focused on understanding the etiology of low back pain and have not included thoracic vertebral levels. Using experimental data on the stiffness of the thoracic spine, ribcage, and sternum, we developed a new quasi-static stiffness-based biomechanical model to calculate loads on the thoracic and lumbar spine during bending or lifting tasks.
To assess the sensitivity of the model to our key assumptions, we determined the effect of varying ribcage and sternal stiffness, maximum muscle stress, and objective function on predicted spinal loads. We compared estimates of spinal loading obtained with our model to previously reported in vivo intradiscal pressures and muscle activation patterns.
Inclusion of the ribs and sternum caused an average decrease in vertebral compressive force of 33% for forward flexion and 18% in a lateral moment task. The impact of maximum muscle stress on vertebral force was limited to a narrow range of values. Compressive forces predicted by our model were strongly correlated to in vivo intradiscal pressure measurements in the thoracic (r=0.95) and lumbar (r=1) spine. Predicted trunk muscle activity was also strongly correlated (r=0.95) with previously published EMG data from the lumbar spine.
The consistency and accuracy of the model predictions appear to be sufficient to justify the use of this model for investigating the relationships between applied loads and injury to the thoracic spine during quasi-static loading activities.
PMCID: PMC2949493  PMID: 20655634
Spine; biomechanical model; back injury; muscle activation
21.  Irisin Levels Are Lower in Young Amenorrheic Athletes Compared with Eumenorrheic Athletes and Non-Athletes and Are Associated with Bone Density and Strength Estimates 
PLoS ONE  2014;9(6):e100218.
Irisin and FGF21 are novel hormones implicated in the “browning” of white fat, thermogenesis, and energy homeostasis. However, there are no data regarding these hormones in amenorrheic athletes (AA) (a chronic energy deficit state) compared with eumenorrheic athletes (EA) and non-athletes. We hypothesized that irisin and FGF21 would be low in AA, an adaptive response to low energy stores. Furthermore, because (i) brown fat has positive effects on bone, and (ii) irisin and FGF21 may directly impact bone, we hypothesized that bone density, structure and strength would be positively associated with these hormones in athletes and non-athletes. To test our hypotheses, we studied 85 females, 14–21 years [38 AA, 24 EA and 23 non-athletes (NA)]. Fasting serum irisin and FGF21 were measured. Body composition and bone density were assessed using dual energy X-ray absorptiometry, bone microarchitecture using high resolution peripheral quantitative CT, strength estimates using finite element analysis, resting energy expenditure (REE) using indirect calorimetry and time spent exercising/week by history. Subjects did not differ for pubertal stage. Fat mass was lowest in AA. AA had lower irisin and FGF21 than EA and NA, even after controlling for fat and lean mass. Across subjects, irisin was positively associated with REE and bone density Z-scores, volumetric bone mineral density (total and trabecular), stiffness and failure load. FGF21 was negatively associated with hours/week of exercise and cortical porosity, and positively with fat mass and cortical volumetric bone density. Associations of irisin (but not FGF21) with bone parameters persisted after controlling for potential confounders. In conclusion, irisin and FGF21 are low in AA, and irisin (but not FGF21) is independently associated with bone density and strength in athletes.
PMCID: PMC4057451  PMID: 24926783
High-resolution peripheral quantitative computed tomography (HR-pQCT) has recently been introduced as a clinical research tool for in vivo assessment of bone quality. The utility of this technique to address important skeletal health questions requires translation to standardized multi-center data pools. Our goal was to evaluate the feasibility of pooling data in multi-center HR-pQCT imaging trials.
Reproducibility imaging experiments were performed using structure and composition-realistic phantoms constructed from cadaveric radii. Single-center precision was determined by repeat scanning over short (<72hrs), intermediate (3–5mo), and long-term intervals (28mo). Multi-center precision was determined by imaging the phantoms at nine different HR-pQCT centers. Least significant change (LSC) and root mean squared coefficient of variation (RMSCV) for each interval and across centers was calculated for bone density, geometry, microstructure, and biomechanical parameters.
Single-center short-term RMSCVs were <1% for all parameters except Ct.Th (1.1%), Ct.Th.SD (2.6%), Tb.Sp.SD (1.8%), and porosity measures (6–8%). Intermediate-term RMSCVs were generally not statistically different from short-term values. Long-term variability was significantly greater for all density measures (0.7–2.0%; p < 0.05 vs. short-term) and several structure measures: Ct.Th (3.4%; p < 0.01 vs. short-term), Ct.Po (15.4%; p < 0.01 vs. short-term), and Tb.Th (2.2%; p < 0.01 vs. short-term). Multi-center RMSCVs were also significantly higher than short-term values: 2–4% for density and µFE measures (p < 0.0001), 2.6–5.3% for morphometric measures (p < 0.001), while Ct.Po was 16.2% (p < 0.001).
In the absence of subject motion, multi-center precision errors for HR-pQCT parameters were generally less than 5%. Phantom-based multi-center precision was comparable to previously reported in vivo single-center precision errors, although this was approximately 2–5 times worse than ex vivo short-term precision. The data generated from this study will contribute to the future design and validation of standardized procedures that are broadly translatable to multi-center study designs.
PMCID: PMC3577969  PMID: 23074145
HR-pQCT; osteoporosis; precision; bone; microstructure; bone strength; multi-center studies
23.  Variations of CT-Based Trunk Muscle Attenuation by Age, Sex, and Specific Muscle 
Fat accumulation in muscle may contribute to age-related declines in muscle function and is indicated by reduced attenuation of x-rays by muscle tissue in computed tomography scans. Reduced trunk muscle attenuation is associated with poor physical function, low back pain, and increased hyperkyphosis in older adults. However, variations in trunk muscle attenuation with age, sex and between specific muscles have not been investigated.
A cross-sectional examination of trunk muscle attenuation in computed tomography scans was performed in 60 younger (35–50 years) and 60 older (75–87 years) adults randomly selected from participants in the Framingham Heart Study Offspring and Third Generation Multidetector Computed Tomography Study. Computed tomography attenuation of 11 trunk muscles was measured at vertebral levels T8 and L3, and the effects of age, sex, and specific muscle on computed tomography attenuation of trunk muscles were determined.
Muscle attenuation varied by specific muscle (p < .001), was lower in older adults (p < .001), and was generally lower in women than in men (p < .001), although not in all muscles. Age-related differences in muscle attenuation varied with specific muscle (p < .001), with the largest age differences occurring in the paraspinal and abdominal muscles.
Trunk muscle attenuation is lower in older adults than in younger adults in both women and men, but such age-related differences vary widely between muscle groups. The reasons that some muscles exhibit larger age-related differences in fat content than others should be further explored to better understand age-related changes in functional capacity and postural stability.
PMCID: PMC3605905  PMID: 22904095
24.  Microarchitecture Influences Microdamage Accumulation in Human Vertebral Trabecular Bone 
Journal of Bone and Mineral Research  2008;23(10):1613-1618.
It has been suggested that accumulation of microdamage with age contributes to skeletal fragility. However, data on the age-related increase in microdamage and the association between microdamage and trabecular microarchitecture in human vertebral cancellous bone are limited. We quantified microdamage in cancellous bone from human lumbar (L2) vertebral bodies obtained from 23 donors 54–93 yr of age (8 men and 15 women). Damage was measured using histologic techniques of sequential labeling with chelating agents and was related to 3D microarchitecture, as assessed by high-resolution μCT. There were no significant differences between sexes, although women tended to have a higher microcrack density (Cr.Dn) than men. Cr.Dn increased exponentially with age (r = 0.65, p < 0.001) and was correlated with bone volume fraction (BV/TV; r = −0.55; p < 0.01), trabecular number (Tb.N; r = −0.56 p = 0.008), structure model index (SMI; r = 0.59; p = 0.005), and trabecular separation (Tb.Sp; r = 0.59; p < 0.009). All architecture parameters were strongly correlated with each other and with BV/TV. Stepwise regression showed that SMI was the best predictor of microdamage, explaining 35% of the variance in Cr.Dn and 20% of the variance in diffuse damage accumulation. In addition, microcrack length was significantly greater in the highest versus lowest tertiles of SMI. In conclusion, in human vertebral cancellous bone, microdamage increases with age and is associated with low BV/TV and a rod-like trabecular architecture.
PMCID: PMC3276353  PMID: 18518771
microdamage; microcrack; human; vertebral; trabecular bone; microarchitecture; osteoporosis
25.  The effect of thoracic kyphosis and sagittal plane alignment on vertebral compressive loading 
To better understand the biomechanical mechanisms underlying the association between hyperkyphosis of the thoracic spine and risk of vertebral fracture and other degenerative spinal pathology, we used a previously validated musculoskeletal model of the spine to determine how thoracic kyphosis angle and spinal posture affect vertebral compressive loading. We simulated an age-related increase in thoracic kyphosis (T1-T12 Cobb angle 50° to 75°) during two different activities (relaxed standing and standing with 5 kg weights in the hands) and three different posture conditions: 1) an increase in thoracic kyphosis with no postural adjustment (uncompensated posture), 2) an increase in thoracic kyphosis with a concomitant increase in pelvic tilt that maintains a stable center of mass and horizontal eye gaze (compensated posture), and 3) an increase in thoracic kyphosis with a concomitant increase in lumbar lordosis that also maintains a stable center of mass and horizontal eye gaze (congruent posture). For all posture conditions, compressive loading increased with increasing thoracic kyphosis, with loading increasing more in the thoracolumbar and lumbar regions than in the mid-thoracic region. Loading increased the most for the uncompensated posture, followed by the compensated posture, with the congruent posture almost completely mitigating any increases in loading with increased thoracic kyphosis. These findings indicate that thoracic kyphosis and spinal posture both influence vertebral loading during daily activities, implying that thoracic kyphosis measurements alone are not sufficient to characterize the impact of spinal curvature on vertebral loading.
PMCID: PMC3431452  PMID: 22589006
Kyphosis; Spinal Loading; Posture; Biomechanical Model; Vertebral Fracture

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