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1.
JBMR Plus ; 8(4): ziae013, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38523663

ABSTRACT

Hip areal BMD (aBMD) is widely used to identify individuals with increased fracture risk. Low aBMD indicates low strength, but this association differs by sex with men showing greater strength for a given aBMD than women. To better understand the structural basis giving rise to this sex-specific discrepancy, cadaveric proximal femurs from White female and male donors were imaged using nano-CT and loaded in a sideways fall configuration to assess strength. FN pseudoDXA images were generated to identify associations among structure, aBMD, and strength that differ by sex. Strength correlated significantly with pseudoDXA aBMD for females (R2 = 0.468, P < .001) and males (R2 = 0.393, P < .001), but the elevations (y-intercepts) of the linear regressions differed between sexes (P < .001). Male proximal femurs were 1045 N stronger than females for a given pseudoDXA aBMD. However, strength correlated with pseudoDXA BMC for females (R2 = 0.433, P < .001) and males (R2 = 0.443, P < .001) but without significant slope (P = .431) or elevation (P = .058) differences. Dividing pseudoDXA BMC by FN-width, total cross-sectional area, or FN-volume led to significantly different associations between strength and the size-adjusted BMC measures for women and men. Three structural differences were identified that differentially affected aBMD and strength for women and men: First, men had more bone mass per unit volume than women; second, different cross-sectional shapes resulted in larger proportions of bone mass orthogonal to the DXA image for men than women; and third, men and women had different proportions of cortical and trabecular bone relative to BMC. Thus, the proximal femurs of women were not smaller versions of men but were constructed in fundamentally different manners. Dividing BMC by a bone size measure was responsible for the sex-specific associations between hip aBMD and strength. Thus, a new approach for adjusting measures of bone mass for bone size and stature is warranted.

2.
JBMR Plus ; 7(3): e10715, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36936363

ABSTRACT

Bone mineral density (BMD) is heavily relied upon to reflect structural changes affecting hip strength and fracture risk. Strong correlations between BMD and strength are needed to provide confidence that structural changes are reflected in BMD and, in turn, strength. This study investigated how variation in bone structure gives rise to variation in BMD and strength and tested whether these associations differ with external bone size. Cadaveric proximal femurs (n = 30, White women, 36-89+ years) were imaged using nanocomputed tomography (nano-CT) and loaded in a sideways fall configuration to assess bone strength and brittleness. Bone voxels within the nano-CT images were projected onto a plane to create pseudo dual-energy X-ray absorptiometry (pseudo-DXA) images consistent with a clinical DXA scan. A validation study using 19 samples confirmed pseudo-DXA measures correlated significantly with those measured from a commercially available DXA system, including bone mineral content (BMC) (R 2  = 0.95), area (R 2  = 0.58), and BMD (R 2  = 0.92). BMD-strength associations were conducted using multivariate linear regression analyses with the samples divided into narrow and wide groups by pseudo-DXA area. Nearly 80% of the variation in strength was explained by age, body weight, and pseudo-DXA BMD for the narrow subgroup. Including additional structural or density distribution information in regression models only modestly improved the correlations. In contrast, age, body weight, and pseudo-DXA BMD explained only half of the variation in strength for the wide subgroup. Including bone density distribution or structural details did not improve the correlations, but including post-yield deflection (PYD), a measure of bone material brittleness, did increase the coefficient of determination to more than 70% for the wide subgroup. This outcome suggested material level effects play an important role in the strength of wide femoral necks. Thus, the associations among structure, BMD, and strength differed with external bone size, providing evidence that structure-function relationships may be improved by judiciously sorting study cohorts into subgroups. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

3.
JBMR Plus ; 6(8): e10653, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35991534

ABSTRACT

Morphological parameters measured for the second metacarpal from hand radiographs are used clinically for assessing bone health during growth and aging. Understanding how these morphological parameters relate to metacarpal strength and strength at other anatomical sites is critical for providing informed decision-making regarding treatment strategies and effectiveness. The goals of this study were to evaluate the extent to which 11 morphological parameters, nine of which were measured from hand radiographs, relate to experimentally measured whole-bone strength assessed at multiple anatomical sites and to test whether these associations differed between men and women. Bone morphology and strength were assessed for the second and third metacarpals, radial diaphysis, femoral diaphysis, and proximal femur for 28 white male donors (18-89 years old) and 35 white female donors (36-89+ years old). The only morphological parameter to show a significant correlation with strength without a sex-specific effect was cortical area. Dimensionless morphological parameters derived from hand radiographs correlated significantly with strength for females, but few did for males. Males and females showed a significant association between the circularity of the metacarpal cross-section and the outer width measured in the mediolateral direction. This cross-sectional shape variation contributed to systematic bias in estimating strength using cortical area and assuming a circular cross-section. This was confirmed by the observation that use of elliptical formulas reduced the systematic bias associated with using circular approximations for morphology. Thus, cortical area was the best predictor of strength without a sex-specific difference in the correlation but was not without limitations owing to out-of-plane shape variations. The dependence of cross-sectional shape on the outer bone width measured from a hand radiograph may provide a way to further improve bone health assessments and informed decision making for optimizing strength-building and fracture-prevention treatment strategies. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

4.
Bone ; 163: 116481, 2022 10.
Article in English | MEDLINE | ID: mdl-35817317

ABSTRACT

Bone strength is generally thought to decline with aging and prior work has compared traits between younger and older cohorts to identify the structural and compositional changes that contribute to fracture risk with age. However, for men, the majority of individuals do not fracture a bone in their lifetime. While fracture occurrence is multifactorial, the absence of fracture in the majority of males suggests that some individuals maintain bone strength or do not lose enough strength to fracture, whereas others do lose strength with aging. Consequently, not all structural and material changes observed with age may lead to strength-decline. We propose that consideration of different subgroups of older individuals will provide a more precise understanding of which structural and material changes directly contribute to strength-decline. We identified subgroups using latent profile analysis (LPA), which is a clustering-based algorithm that takes multiple continuous variables into account. Human cadaveric male femoral diaphyses (n = 33, 26-89 years) were subjected to whole bone and tissue-level mechanical tests. Morphological traits, porosity, and cortical tissue mineral density (Ct.TMD) were obtained, as were measures of enzymatic cross-links and the advanced glycation end product, pentosidine (PEN). A univariate analysis first identified a younger cohort (YNG, n = 11) and older cohort (n = 22). LPA was then conducted using three mechanical traits (whole bone strength, tissue-level strength, and tissue-level post-yield strain), resulting in a further stratification of the older group into two similarly aged groups (p = 0.558), but one with higher (OHM, n = 16) and another with lower mechanical properties (OLM, n = 6). The OLM group exhibited lower whole bone strength (p = 0.016), tissue-level strength (p < 0.001), and tissue-level post-yield strain (p < 0.001) compared to the YNG group. Meanwhile, the OHM only exhibited significantly lower tissue-level post-yield strain (p < 0.001), compared to the YNG group. Between the two older groups, the OHM group exhibited higher whole bone strength (p = 0.037), tissue-level strength (p = 0.006), and tissue-level post-yield strain (p = 0.012) than the OLM group. Probing the morphological and compositional relationships among the three groups, both OHM and OLM exhibited increased PEN content (p < 0.001, p = 0.008 respectively) and increased Log(cortical pore score) relative to YNG (p = 0.003, p < 0.001 respectively). Compared to the OHM group, the OLM also exhibited increased marrow area (p = 0.049), water content (p = 0.048), and decreased Ct.TMD (p = 0.005). The key traits that were unique to the OLM group compared to YNG were decreased Ct.TMD (p < 0.001) and increased Log(porosity) (p = 0.002). There were many properties that differed between the younger and older groups, but not all were associated with reduced mechanical properties, highlighting the relative importance of certain age-related traits such as porosity, Ct.TMD, water content, and marrow area that were unique to the OLM group. Overall, this work supports the hypothesis that there are subgroups of men showing different strength-decline trajectories with aging and establishes a basis for refining our understanding of which age-related changes are directly contributing to decreased strength.


Subject(s)
Bone Density , Fractures, Bone , Aged , Biomechanical Phenomena , Bone and Bones , Femur , Humans , Male , Water
5.
J Biomech ; 139: 111144, 2022 06.
Article in English | MEDLINE | ID: mdl-35623287

ABSTRACT

Region-specific differences in age-related bone remodeling are known to exist. We therefore hypothesized that the decline in tissue-level strength and post-yield strain (PYS) with age is not uniform within the femur, but is driven by region-specific differences in porosity and composition. Four-point bending was conducted on anterior, posterior, medial, and lateral beams from male cadaveric femora (n = 33, 18-89 yrs of age). Mid-cortical porosity, composition, and mineralization were assessed using nano-computed tomography (nanoCT), Raman spectroscopy, and ashing assays. Traits between bones from young and elderly groups were compared, while multivariate analyses were used to identify traits that predicted strength and PYS at the regional level. We show that age-related decline in porosity and mechanical properties varied regionally, with highest positive slope of age vs. Log(porosity) found in posterior and anterior bone, and steepest negative slopes of age vs. strength and age vs. PYS found in anterior bone. Multivariate analyses show that Log(porosity) and/or Raman 1246/1269 ratio explained 46-51% of the variance in strength in anterior and posterior bone. Three out of five traits related to Log(porosity), mineral crystallinity, 1246/1269, mineral/matrix ratio, and/or hydroxyproline/proline (Hyp/Pro) ratio, explained 35-50% of the variance in PYS in anterior, posterior and lateral bones. Log(porosity) and Hyp/Pro ratio alone explained 13% and 19% of the variance in strength and PYS in medial bone, respectively. The predictive performance of multivariate analyses was negatively impacted by pooling data across all bone regions, underscoring the complexity of the femur and that the use of pooled analyses may obscure underlying region-specific differences.


Subject(s)
Bone and Bones , Femur , Aged , Bone Density , Bone Remodeling , Femur/diagnostic imaging , Humans , Male , Minerals , Porosity
6.
J Struct Biol ; 212(3): 107650, 2020 12 01.
Article in English | MEDLINE | ID: mdl-33096230

ABSTRACT

Understanding skeletal aging and predicting fracture risk is increasingly important with a growing elderly population. We hypothesized that when categorized by external bone size, the male femoral diaphysis would show different strength-age trajectories which can be explained by changes in morphology, composition and collagen cross-linking. Cadaveric male femora were sorted into narrow (n = 15, 26-89 years) and wide (n = 15, 29-82 years) groups based upon total cross-sectional area of the mid-shaft normalized to bone length (Tt.Ar/Le) and tested for whole bone strength, tissue-level strength, and tissue-level post-yield strain. Morphology, cortical TMD (Ct.TMD), porosity, direct measurements of enzymatic collagen cross-links, and pentosidine were obtained. The wide group alone showed significant negative correlations with age for tissue-level strength (R2 = 0.50, p = 0.002), tissue-level post-yield strain (R2 = 0.75, p < 0.001) and borderline significance for whole bone strength (R2 = 0.14, p = 0.108). Ct.TMD correlated with whole bone and tissue-level strength for both groups, but pentosidine normalized to enzymatic cross-links correlated negatively with all mechanical properties for the wide group only. The multivariate analysis showed that just three traits for each mechanical property explained the majority of the variance for whole bone strength (Ct.Area, Ct.TMD, Log(PEN/Mature; R2 = 0.75), tissue-level strength (Age, Ct.TMD, Log(DHLNL/HLNL); R2 = 0.56), and post-yield strain (Age, Log(Pyrrole), Ct.Area; R2 = 0.51). Overall, this highlights how inter-individual differences in bone structure, composition, and strength change with aging and that a one-size fits all understanding of skeletal aging is insufficient.


Subject(s)
Bone Density/physiology , Femur/physiology , Adult , Aged , Aged, 80 and over , Aging/metabolism , Aging/physiology , Collagen/metabolism , Femur/metabolism , Humans , Male , Middle Aged
7.
Bone ; 137: 115402, 2020 08.
Article in English | MEDLINE | ID: mdl-32360900

ABSTRACT

Bone morphogenetic protein (BMP) signaling in osteoblasts plays critical roles in skeletal development and bone homeostasis. Our previous studies showed loss of function of BMPR1A, one of the type 1 receptors for BMPs, in osteoblasts results in increased trabecular bone mass in long bones due to an imbalance between bone formation and bone resorption. Decreased bone resorption was associated with an increased mature-to-immature collagen cross-link ratio and mineral-matrix ratios in the trabecular compartments, and increased tissue-level biomechanical properties. Here, we investigated the bone mass, bone composition and biomechanical properties of ribs and spines in the same genetically altered mouse line to compare outcomes by loss of BMPR1A functions in bones from different anatomic sites and developmental origins. Bone mass was significantly increased in both cortical and trabecular compartments of ribs with minimal to modest changes in compositions. While tissue-levels of biomechanical properties were not changed between control and mutant animals, whole bone levels of biomechanical properties were significantly increased in association with increased bone mass in the mutant ribs. For spines, mutant bones showed increased bone mass in both cortical and trabecular compartments with an increase of mineral content. These results emphasize the differential role of BMP signaling in osteoblasts in bones depending on their anatomical locations, functional loading requirements and developmental origin.


Subject(s)
Bone Morphogenetic Protein Receptors, Type I , Bone and Bones , Osteoblasts , Signal Transduction , Animals , Bone Morphogenetic Protein Receptors, Type I/genetics , Bone Morphogenetic Proteins , Mice , Phenotype
8.
J Bone Miner Res ; 34(5): 825-837, 2019 05.
Article in English | MEDLINE | ID: mdl-30715752

ABSTRACT

Given prior work showing associations between remodeling and external bone size, we tested the hypothesis that wide bones would show a greater negative correlation between whole-bone strength and age compared with narrow bones. Cadaveric male radii (n = 37 pairs, 18 to 89 years old) were evaluated biomechanically, and samples were sorted into narrow and wide subgroups using height-adjusted robustness (total area/bone length). Strength was 54% greater (p < 0.0001) in wide compared with narrow radii for young adults (<40 years old). However, the greater strength of young-adult wide radii was not observed for older wide radii, as the wide (R2 = 0.565, p = 0.001), but not narrow (R2 = 0.0004, p = 0.944) subgroup showed a significant negative correlation between strength and age. Significant positive correlations between age and robustness (R2 = 0.269, p = 0.048), cortical area (Ct.Ar; R2 = 0.356, p = 0.019), and the mineral/matrix ratio (MMR; R2 = 0.293, p = 0.037) were observed for narrow, but not wide radii (robustness: R2 = 0.015, p = 0.217; Ct.Ar: R2 = 0.095, p = 0.245; MMR: R2 = 0.086, p = 0.271). Porosity increased with age for the narrow (R2 = 0.556, p = 0.001) and wide (R2 = 0.321, p = 0.022) subgroups. The wide subgroup (p < 0.0001) showed a significantly greater elevation of a new measure called the Cortical Pore Score, which quantifies the cumulative effect of pore size and location, indicating that porosity had a more deleterious effect on strength for wide compared with narrow radii. Thus, the divergent strength-age regressions implied that narrow radii maintained a low strength with aging by increasing external size and mineral content to mechanically offset increases in porosity. In contrast, the significant negative strength-age correlation for wide radii implied that the deleterious effect of greater porosity further from the centroid was not offset by changes in outer bone size or mineral content. Thus, the low strength of elderly male radii arose through different biomechanical mechanisms. Consideration of different strength-age regressions (trajectories) may inform clinical decisions on how best to treat individuals to reduce fracture risk. © 2019 American Society for Bone and Mineral Research.


Subject(s)
Aging , Bone Density , Radius , Adolescent , Adult , Aged , Aged, 80 and over , Aging/metabolism , Aging/pathology , Humans , Male , Middle Aged , Organ Size , Radius/metabolism , Radius/pathology
9.
J Biomech ; 83: 125-133, 2019 01 23.
Article in English | MEDLINE | ID: mdl-30527634

ABSTRACT

Accurately estimating whole bone strength is critical for identifying individuals that may benefit from prophylactic treatments aimed at reducing fracture risk. Strength is often estimated from stiffness, but it is not known whether the relationship between stiffness and strength varies with age and sex. Cadaveric proximal femurs (44 Male: 18-78 years; 40 Female: 24-95 years) and radial (36 Male: 18-89 years; 19 Female: 24-95 years) and femoral diaphyses (34 Male: 18-89 years; 19 Female: 24-95 years) were loaded to failure to evaluate how the stiffness-strength relationship varies with age and sex. Strength correlated significantly with stiffness at all sites and for both sexes, as expected. However, females exhibited significantly less strength for the proximal femur (58% difference, p < 0.001). Multivariate regressions revealed that stiffness, age and PYD were significant negative independent predictors of strength for the proximal femur (Age: M: p = 0.005, F: p < 0.001, PYD: M: p = 0.022, F: p = 0.025), radial diaphysis (Age: M = 0.055, PYD: F = 0.024), and femoral diaphysis (Age: M: p = 0.014, F: p = 0.097, PYD: M: p = 0.003, F: p = 0.091). These results indicated that older bones tended to be significantly weaker for a given stiffness than younger bones. These results suggested that human bones exhibit diminishing strength relative to stiffness with aging and with decreasing PYD. Incorporating these age- and sex-specific factors may help to improve the accuracy of strength estimates.


Subject(s)
Aging/physiology , Femur/physiology , Mechanical Phenomena , Radius/physiology , Sex Characteristics , Adolescent , Adult , Aged , Aged, 80 and over , Biomechanical Phenomena , Bone Density , Female , Humans , Male , Middle Aged , Young Adult
10.
JBMR Plus ; 2(3): 143-153, 2018 May.
Article in English | MEDLINE | ID: mdl-30283899

ABSTRACT

The phenotypic response of bones differing in morphological, compositional, and mechanical traits to an increase in loading during growth is not well understood. We tested whether bones of two inbred mouse strains that assemble differing sets of traits to achieve mechanical homeostasis at adulthood would show divergent responses to voluntary cage-wheel running. Female A/J and C57BL6/J (B6) 4-week-old mice were provided unrestricted access to a standard cage-wheel for 4 weeks. A/J mice have narrow and highly mineralized femora and B6 mice have wide and less mineralized femora. Both strains averaged 2 to 9.5 km of running per day, with the average-distance run between strains not significantly different (p = 0.133). Exercised A/J femora showed an anabolic response to exercise with the diaphyses showing a 2.8% greater total area (Tt.Ar, p = 0.06) and 4.7% greater cortical area (Ct.Ar, p = 0.012) compared to controls. In contrast, exercised B6 femora showed a 6.2% (p < 0.001) decrease in Tt.Ar (p < 0.001) and a 6.7% decrease in Ct.Ar (p = 0.133) compared to controls, with the femora showing significant marrow infilling (p = 0.002). These divergent morphological responses to exercise, which did not depend on the daily distance run, translated to a 7.9% (p = 0.001) higher maximum load (ML) for exercised A/J femora but no change in ML for exercised B6 femora compared to controls. A consistent response was observed for the humeri but not the vertebral bodies. This differential outcome to exercise has not been previously observed in isolated loading or forced treadmill running regimes. Our findings suggest there are critical factors involved in the metabolic response to exercise during growth that require further consideration to understand how genotype, exercise, bone morphology, and whole-bone strength interact during growth. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

11.
Orthop J Sports Med ; 5(10): 2325967117733433, 2017 Oct.
Article in English | MEDLINE | ID: mdl-29085847

ABSTRACT

BACKGROUND: Capsulectomy is performed during hip arthroscopic surgery in young adult patients with hip pain to improve intraoperative visualization. The stability of the hip joint after anterior capsulectomy is relatively unknown. PURPOSE: To evaluate anterior hip stability in capsular sectioned states with a labral injury to test whether the load required for anterior translation would decrease with greater capsular injuries. STUDY DESIGN: Controlled laboratory study. METHODS: Sixteen hips from 8 of 10 human cadaveric pelvises (mean age, 54.25 years) were prepared/mounted onto a custom-built fixture and tested in 5 states: intact capsule, intact labrum (all intact); sutured capsule, intact labrum (sutured intact); sutured capsule, 1-cm partial labrectomy (sutured labrectomy); partial capsulectomy, 1-cm partial labrectomy (partial capsulectomy); and total capsulectomy, 1-cm partial labrectomy (total capsulectomy). Each hip was tested in a neutral position with a 20-N compressive force. The load at 12 mm of anterior translation was recorded for each state after 2 preconditioning trials. RESULTS: A repeated-measures analysis of variance with Bonferroni adjustment showed no difference between the all-intact versus sutured-intact states and demonstrated no significant difference between the sutured-intact and sutured-labrectomy states. There were significant differences between the sutured-labrectomy and partial capsulectomy (P = .01), sutured-labrectomy and total capsulectomy (P < .001), and partial capsulectomy and total capsulectomy (P = .04) states. CONCLUSION: The findings demonstrate that the capsule/labrum plays an important role in anterior hip stability and that the iliofemoral ligament is crucial for preventing anterior translation in labral-injured states. In addition, the ischiofemoral and pubofemoral ligaments provide resistance to anterior translation in iliofemoral- and labral-deficient states. Intraoperative capsulectomy should be avoided in patients with large, irreparable labral tears to prevent postoperative anterior hip instability. CLINICAL RELEVANCE: This study quantifies the roles of the capsulolabral structures in anterior hip stability and demonstrates the importance of maintaining/repairing them during hip arthroscopic surgery.

12.
J Bone Miner Res ; 32(5): 1002-1013, 2017 May.
Article in English | MEDLINE | ID: mdl-28177139

ABSTRACT

Previously, we showed that cortical mineralization is coordinately adjusted to mechanically offset external bone size differences between A/J (narrow) and C57BL/6J (wide) mouse femora to achieve whole bone strength equivalence at adulthood. The identity of the genes and their interactions that are responsible for establishing this homeostatic state (ie, canalization) remain unknown. We hypothesize that these inbred strains, whose interindividual differences in bone structure and material properties mimic that observed among humans, achieve functional homeostasis by differentially adjusting key molecular pathways regulating external bone size and mineralization throughout growth. The cortices of A/J and C57BL/6J male mouse femora were phenotyped and gene expression levels were assessed across growth (ie, ages 2, 4, 6, 8, 12, 16 weeks). A difference in total cross-sectional area (p < 0.01) and cortical tissue mineral density were apparent between mouse strains by age 2 weeks and maintained at adulthood (p < 0.01). These phenotypic dissimilarities corresponded to gene expression level differences among key regulatory pathways throughout growth. A/J mice had a 1.55- to 7.65-fold greater expression among genes inhibitory to Wnt pathway induction, whereas genes involved in cortical mineralization were largely upregulated 1.50- to 3.77-fold to compensate for their narrow diaphysis. Additionally, both mouse strains showed an upregulation among Wnt pathway antagonists corresponding to the onset of adult ambulation (ie, increased physiological loads). This contrasts with other studies showing an increase in Wnt pathway activation after functionally isolated, experimental in vivo loading regimens. A/J and C57BL/6J long bones provide a model to develop a systems-based approach to identify individual genes and the gene-gene interactions that contribute to trait differences between the strains while being involved in the process by which these traits are coordinately adjusted to establish similar levels of mechanical function, thus providing insight into the process of canalization. © 2017 American Society for Bone and Mineral Research.


Subject(s)
Bone Density/physiology , Epistasis, Genetic/physiology , Gene Expression Regulation/physiology , Stress, Mechanical , Wnt Signaling Pathway/physiology , Animals , Femur , Humans , Mice , Species Specificity
13.
J Bone Miner Res ; 32(6): 1218-1228, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28084657

ABSTRACT

The impact of adult bone traits on changes in bone structure and mass during aging is not well understood. Having shown that intracortical remodeling correlates with external size of adult long bones led us to hypothesize that age-related changes in bone traits also depend on external bone size. We analyzed hip dual-energy X-ray absorptiometry images acquired longitudinally over 14 years for 198 midlife women transitioning through menopause. The 14-year change in bone mineral content (BMC, R2 = 0.03, p = 0.015) and bone area (R2 = 0.13, p = 0.001), but not areal bone mineral density (aBMD, R2 = 0.00, p = 0.931) correlated negatively with baseline femoral neck external size, adjusted for body size using the residuals from a linear regression between baseline bone area and height. The dependence of the 14-year changes in BMC and bone area on baseline bone area remained significant after adjusting for race/ethnicity, postmenopausal hormone use, the 14-year change in weight, and baseline aBMD, weight, height, and age. Women were sorted into tertiles using the baseline bone area-height residuals. The 14-year change in BMC (p = 0.009) and bone area (p = 0.001) but not aBMD (p = 0.788) differed across the tertiles. This suggested that women showed similar changes in aBMD for different structural and biological reasons: women with narrow femoral necks showed smaller changes in BMC but greater increases in bone area compared to women with wide femoral necks who showed greater losses in BMC but without large compensatory increases in bone area. This finding is opposite to expectations that periosteal expansion acts to mechanically offset bone loss. Thus, changes in femoral neck structure and mass during menopause vary widely among women and are predicted by baseline external bone size but not aBMD. How these different structural and mass changes affect individual strength-decline trajectories remains to be determined. © 2017 American Society for Bone and Mineral Research.


Subject(s)
Bone Density/physiology , Femur Neck/anatomy & histology , Femur Neck/physiology , Menopause/physiology , Absorptiometry, Photon , Adult , Female , Femur Neck/diagnostic imaging , Humans , Linear Models , Middle Aged , Multivariate Analysis , Organ Size , Tomography, X-Ray Computed
14.
Article in English | MEDLINE | ID: mdl-27672442

ABSTRACT

A major unmet challenge in developing preventative treatment programs for osteoporosis is that the optimal timing of treatment remains unknown. In this commentary we make the argument that the menopausal transition (MT) is a critical period in a woman's life for bone health, and that efforts aimed at reducing fracture risk later in life may benefit greatly from strategies that treat women earlier with the intent of keeping bones strong as long as possible. Bone strength is an important parameter to monitor during the MT because engineering principles can be applied to differentiate those women that maintain bone strength from those women that lose bone strength and are in need of early treatment. It is critical to understand the underlying mechanistic causes for reduced strength to inform treatment strategies. Combining measures of strength with data on how bone structure changes during the MT may help differentiate whether a woman is losing strength because of excessive bone resorption, insufficient compensatory bone formation, trabeculae loss, or some combination of these factors. Each of these biomechanical mechanisms may require a different treatment strategy to keep bones strong. The technologies that enable physicians to differentially diagnose and treat women in a preventive manner, however, have lagged behind the development of prophylactic treatments for osteoporosis. To take advantage of these treatment options, advances in preventive treatment strategies for osteoporosis may require developing new technologies with imaging resolutions that match the pace by which bone changes during the MT and supplementing a woman's bone mineral density (BMD)-status with information from engineering-based analyses that reveal the structural and material changes responsible for the decline in bone strength during the menopausal transition.

15.
Clin Orthop Relat Res ; 473(8): 2540-7, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25739343

ABSTRACT

BACKGROUND: The risk of fragility fractures in the United States is approximately 2.5 times greater among black and white women compared with their male counterparts. On average, men of both ethnicities have wider bones of greater cortical mass compared with the narrower bones of lower cortical mass among women. However, it remains uncertain whether the low cortical area observed in the long bones of women is consistent with their narrower bone diameter or if their cortical area is reduced beyond that which is expected for the sex differences in body size and external bone size. QUESTIONS/PURPOSES: We asked (1) do black and white women consistently have narrower bones of less strength across long bones compared with black and white men; and (2) do all long bones of black and white women have reduced cortical area compared with black and white men? METHODS: Peripheral quantitative CT was used to quantify bone strength and cross-sectional morphology from the major long bones of 125 white and 115 black adult men and women (20-35 years of age). Regression analyses were used to test for differences in bone strength and cortical area after for adjusting for either body size, bone size, or both. RESULTS: After adjusting bone strength for body size, regression analyses showed that black women had lower bone strength compared with black men (women: mean=298.7-25,522 mg HA mm4, 95% confidence interval [CI], 270-27,692 mg HA mm4; men: mean = 381.6-30,945 mg HA mm4, 95% CI, 358.2-32,853 mg HA mm4; percent difference=12%-38%, p=0.06-0.0001). Similarly, white women also had lower bone strength compared with white men (women: mean=229.5-22,892 mg HA mm4, 95% CI, 209.3-24,539 mg HA mm4; men: mean=314.3-29,986 mg HA mm4, 95% CI, 297.3-31,331 mg HA mm4; percent difference=27%-49%, p=0.0001). All long bones of women for both ethnicities showed lower cortical area compared with men. After accounting for both body size and external bone size, black women (women: mean=43.25-357.70 mm2, 95% CI, 41.45-367.52 mm2; men: mean=48.06-400.10 mm2, 95% CI, 46.67-408.72; percent difference=6%-25%, p=0.02-0.0001) and white women (women: mean=38.53-350.10 mm2, 95% CI, 36.99-359.80 mm2; men: mean=42.06-394.30 mm2, 95% CI, 40.95-402.10 mm2; percent difference=6%-22%, p=0.02-0.0001) were shown to have lower cortical area than their male counterparts. Therefore, the long bones of women are not only more slender than those of men, but also show a reduced cortical area that is 6% to 25% greater than expected for their external size, depending on the bone being considered. CONCLUSIONS: The long bones of females are not just a more slender version of male long bones. Women have less cortical area than expected for their body size and bone size, which in part explains their reduced bone strength when compared with the more robust bones of men. CLINICAL RELEVANCE: The outcome of this assessment may be clinically important for the development of diagnostics and treatment regimens used to combat fractures. Future work should look at how the relationship among parameters reported here translates to the more fracture-prone metaphyseal regions.


Subject(s)
Black or African American , Bone Development , Bone and Bones/physiology , Health Status Disparities , White People , Adult , Biomechanical Phenomena , Body Size/ethnology , Bone Density , Bone and Bones/diagnostic imaging , Female , Fractures, Bone/ethnology , Humans , Male , Risk Factors , Sex Factors , Tomography, X-Ray Computed , Young Adult
16.
Connect Tissue Res ; 56(2): 106-19, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25646568

ABSTRACT

Advances in computed tomography (CT) imaging are opening new avenues toward more precise characterization and quantification of connective tissue microarchitecture. In the last two decades, micro-computed tomography (microCT) has significantly augmented destructive methods for the 3D micro-analysis of tissue structure, primarily in the bone research field. Recently, microCT has been employed in combination with contrast agents to generate contrast-enhanced images of soft tissues that are otherwise difficult to visualize due to their native radiodensity. More recent advances in CT technology have enabled ultra-high resolution imaging by utilizing a more powerful nano-focused X-ray source, such as that found in nano-computed tomography (nanoCT) systems. NanoCT imaging has facilitated the expansion of musculoskeletal research by reducing acquisition time and significantly expanding the range of samples that can be imaged in terms of size, age and tissue-type (bone, muscle, tendon, cartilage, vessels and adipose tissue). We present the application and early results of nanoCT imaging in various tissue types and how this ultra-high resolution imaging modality is capable of characterizing microstructures at levels of details previously not possible. Contrast-enhanced imaging techniques to enable soft-tissue visualization and characterization are also outlined.


Subject(s)
Bone and Bones/cytology , Image Processing, Computer-Assisted , X-Ray Microtomography , Animals , Cartilage , Connective Tissue , Humans , Imaging, Three-Dimensional/methods
17.
Clin Orthop Relat Res ; 473(8): 2530-9, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25690167

ABSTRACT

BACKGROUND: The twofold greater lifetime risk of fracturing a bone for white women compared with white men and black women has been attributed in part to differences in how the skeletal system accumulates bone mass during growth. On average, women build more slender long bones with less cortical area compared with men. Although slender bones are known to have a naturally lower cortical area compared with wider bones, it remains unclear whether the relatively lower cortical area of women is consistent with their increased slenderness or is reduced beyond that expected for the sex-specific differences in bone size and body size. Whether this sexual dimorphism is consistent with ethnic background and is recapitulated in the widely used mouse model also remains unclear. QUESTIONS/PURPOSES: We asked (1) do black women build bones with reduced cortical area compared with black men; (2) do white women build bones with reduced cortical area compared with white men; and (3) do female mice build bones with reduced cortical area compared with male mice? METHODS: Bone strength and cross-sectional morphology of adult human and mouse bone were calculated from quantitative CT images of the femoral midshaft. The data were tested for normality and regression analyses were used to test for differences in cortical area between men and women after adjusting for body size and bone size by general linear model (GLM). RESULTS: Linear regression analysis showed that the femurs of black women had 11% lower cortical area compared with those of black men after adjusting for body size and bone size (women: mean=357.7 mm2; 95% confidence interval [CI], 347.9-367.5 mm2; men: mean=400.1 mm2; 95% CI, 391.5-408.7 mm2; effect size=1.2; p<0.001, GLM). Likewise, the femurs of white women had 12% less cortical area compared with those of white men after adjusting for body size and bone size (women: mean=350.1 mm2; 95% CI, 340.4-359.8 mm2; men: mean=394.3 mm2; 95% CI, 386.5-402.1 mm2; effect size=1.3; p<0.001, GLM). In contrast, female and male femora from recombinant inbred mouse strains showed the opposite trend; femurs from female mice had a 4% larger cortical area compared with those of male mice after adjusting for body size and bone size (female: mean=0.73 mm2; 95% CI, 0.71-0.74 mm2; male: mean=0.70 mm2; 95% CI, 0.68-0.71 mm2; effect size=0.74; p=0.04, GLM). CONCLUSIONS: Female femurs are not simply a more slender version of male femurs. Women acquire substantially less mass (cortical area) for their body size and bone size compared with men. Our analysis questions whether mouse long bone is a suitable model to study human sexual dimorphism. CLINICAL RELEVANCE: Identifying differences in the way bones are constructed may be clinically important for developing sex-specific diagnostics and treatment strategies to reduce fragility fractures.


Subject(s)
Body Size , Femur/growth & development , Health Status Disparities , Osteogenesis , Adult , Black or African American , Animals , Biomechanical Phenomena , Body Size/ethnology , Female , Femur/diagnostic imaging , Humans , Linear Models , Male , Mice , Mice, Inbred Strains , Models, Animal , Sex Characteristics , Sex Factors , Species Specificity , Tomography, X-Ray Computed , White People , Young Adult
18.
Bone ; 67: 15-22, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24999223

ABSTRACT

Traits of the skeletal system are coordinately adjusted to establish mechanical homeostasis in response to genetic and environmental factors. Prior work demonstrated that this 'complex adaptive' process is not perfect, revealing a two-fold difference in whole bone stiffness of the tibia across a population. Robustness (specifically, total cross-sectional area relative to length) varies widely across skeletal sites and between sexes. However, it is unknown whether the natural variation in whole bone stiffness and strength also varies across skeletal sites and between men and women. We tested the hypotheses that: 1) all major long bones of the appendicular skeleton demonstrate inherent, systemic constraints in the degree to which morphological and compositional traits can be adjusted for a given robustness; and 2) these traits covary in a predictable manner independent of body size and robustness. We assessed the functional relationships among robustness, cortical area (Ct.Ar), cortical tissue mineral density (Ct.TMD), and bone strength index (BSI) across the long bones of the upper and lower limbs of 115 adult men and women. All bones showed a significant (p<0.001) positive regression between BSI and robustness after adjusting for body size, with slender bones being 1.7-2.3 times less stiff and strong in men and 1.3-2.8 times less stiff and strong in women compared to robust bones. Our findings are the first to document the natural inter-individual variation in whole bone stiffness and strength that exist within populations and that is predictable based on skeletal robustness for all major long bones. Documenting and further understanding this natural variation in strength may be critical for differentially diagnosing and treating skeletal fragility.


Subject(s)
Bone and Bones/metabolism , Bone and Bones/physiology , Adult , Bone Density/physiology , Female , Humans , Male , Musculoskeletal System/metabolism , Sex Factors , Young Adult
19.
Bone ; 67: 130-8, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25003813

ABSTRACT

Functional adaptation may complicate the choice of phenotype used in genetic studies that seek to identify genes contributing to fracture susceptibility. Often, genetic variants affecting one trait are compensated by coordinated changes in other traits. Bone fracture is a prototypic example because mechanical function of long bones (stiffness and strength) depends on how the system coordinately adjusts the amount (cortical area) and quality (tissue-mineral density, TMD) of bone tissue to mechanically offset the natural variation in bone robustness (total area/length). We propose that efforts aimed at identifying genes regulating fracture resistance will benefit from better understanding how functional adaptation contributes to the genotype-phenotype relationship. We analyzed the femurs of C57BL/6J-Chr(A/J)/NaJ Chromosome Substitution Strains (CSSs) to systemically interrogate the mouse genome for chromosomes harboring genes that regulate mechanical function. These CSSs (CSS-i, i=the substituted chromosome) showed changes in mechanical function on the order of -26.6 to +11.5% relative to the B6 reference strain after adjusting for body size. Seven substitutions showed altered robustness, cortical area, or TMD, but no effect on mechanical function (CSS-4, 5, 8, 9, 17, 18, 19); six substitutions showed altered robustness, cortical area, or TMD, and reduced mechanical function (CSS-1, 2, 6, 10, 12, 15); and one substitution also showed reduced mechanical function but exhibited no significant changes in the three physical traits analyzed in this study (CSS-3). A key feature that distinguished CSSs that maintained function from those with reduced function was whether the system adjusted cortical area and TMD to the levels needed to compensate for the natural variation in bone robustness. These results provide a novel biomechanical mechanism linking genotype with phenotype, indicating that genes control function not only by regulating individual traits, but also by regulating how the system coordinately adjusts multiple traits to establish function.


Subject(s)
Bone and Bones/physiology , Animals , Bone Density/genetics , Bone Density/physiology , Bone and Bones/metabolism , Chromosomes/genetics , Genetic Association Studies , Genetic Heterogeneity , Male , Mice , Mice, Inbred C57BL
20.
J Appl Biomech ; 29(5): 639-44, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23182887

ABSTRACT

To determine whether peak vertical and horizontal impact accelerations were different while running on a track or on a treadmill, 12 healthy subjects (average age 32.8 ± 9.8 y), were fitted with a novel, wireless accelerometer capable of recording triaxial acceleration over time. The accelerometer was attached to a custom-made acrylic plate and secured at the level of the L5 vertebra via a tight fitting triathlon belt. Each subject ran 4 miles on a synthetic, indoor track at a self-selected pace and accelerations were recorded on three perpendicular axes. Seven days later, the subjects ran 4 miles on a treadmill set at the individual runner's average pace on the track and the peak vertical and horizontal impact magnitudes between the track and treadmill were compared. There was no difference (P = .52) in the average peak vertical impact accelerations between the track and treadmill over the 4 mile run. However, peak horizontal impact accelerations were greater (P = .0012) on the track when compared with the treadmill. This study demonstrated the feasibility for long-term impact accelerations monitoring using a novel wireless accelerometer.


Subject(s)
Acceleration , Exercise Test/instrumentation , Foot/physiology , Micro-Electrical-Mechanical Systems/instrumentation , Monitoring, Ambulatory/instrumentation , Running/physiology , Wireless Technology/instrumentation , Actigraphy/instrumentation , Adult , Equipment Design , Equipment Failure Analysis , Feasibility Studies , Female , Humans , Male
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