Restrictive Eating and Prior Low-Energy Fractures Are Associated With History of Multiple Bone Stress Injuries.

Bone stress injuries (BSIs) are common among athletes and have high rates of recurrence. However, risk factors for multiple or recurrent BSIs remain understudied. Thus, we aimed to explore whether energy availability, menstrual function, measures of bone health, and a modified Female Athlete Triad Cumulative Risk Assessment (CRA) tool are associated with a history of multiple BSIs. We enrolled 51 female runners (ages 18-36 years) with history of ≤1 BSI (controls; n = 31) or ≥3 BSIs (multiBSI; n = 20) in this cross-sectional study. We measured lumbar spine, total hip, and femoral neck areal bone mineral density by dual-energy X-ray absorptiometry, bone material strength index using impact microindentation, and volumetric bone mineral density, microarchitecture, and estimated strength by high-resolution peripheral quantitative computed tomography. Participants completed questionnaires regarding medical history, low-energy fracture history, and disordered eating attitudes. Compared with controls, multiBSI had greater incidence of prior low-energy fractures (55% vs. 16%, p = .005) and higher modified Triad CRA scores (2.90 ± 2.05 vs. 1.84 ± 1.59, p = .04). Those with multiBSI had higher Eating Disorder Examination Questionnaire (0.92 ± 1.03 vs. 0.46 ± 0.49, p = .04) scores and a greater percentage difference between lowest and highest body mass at their current height (15.5% ± 6.5% vs. 11.5% ± 4.9% p = .02). These preliminary findings indicate that women with a history of multiple BSIs suffered more prior low-energy fractures and have greater historical and current estimates of energy deficit compared with controls. Our results provide strong rationale for future studies to examine whether subclinical indicators of energy deficit contribute to risk for multiple BSIs in female runners.

SOX10 Loss Sensitizes Melanoma Cells to Cytokine-Mediated Inflammatory Cell Death.

The transcription factor, SOX10, plays an important role in the differentiation of neural crest precursors to the melanocytic lineage. Malignant transformation of melanocytes leads to the development of melanoma, and SOX10 promotes melanoma cell proliferation and tumor formation. SOX10 expression in melanomas is heterogeneous, and loss of SOX10 causes a phenotypic switch toward an invasive, mesenchymal-like cell state and therapy resistance; hence, strategies to target SOX10-deficient cells are an active area of investigation. The impact of cell state and SOX10 expression on antitumor immunity is not well understood but will likely have important implications for immunotherapeutic interventions. To this end, we tested whether SOX10 status affects the response to CD8+ T cell-mediated killing and T cell-secreted cytokines, TNFα and IFNγ, which are critical effectors in the cytotoxic killing of cancer cells. We observed that genetic ablation of SOX10 rendered melanoma cells more sensitive to CD8+ T cell-mediated killing and cell death induction by either TNFα or IFNγ. Cytokine-mediated cell death in SOX10-deficient cells was associated with features of caspase-dependent pyroptosis, an inflammatory form of cell death that has the potential to increase immune responses. IMPLICATIONS: These data support a role for SOX10 expression altering the response to T cell-mediated cell death and contribute to a broader understanding of the interaction between immune cells and melanoma cells.

Gene signature reveals decreased SOX10-dependent transcripts in malignant cells from immune checkpoint inhibitor-resistant cutaneous melanomas.

Evidence is mounting for cross-resistance between immune checkpoint and targeted kinase inhibitor therapies in cutaneous melanoma patients. Since the loss of the transcription factor, SOX10, causes tolerance to MAPK pathway inhibitors, we used bioinformatic techniques to determine if reduced SOX10 expression/activity is associated with immune checkpoint inhibitor resistance. We integrated SOX10 ChIP-seq, knockout RNA-seq, and knockdown ATAC-seq data from melanoma cell models to develop a robust SOX10 gene signature. We used computational methods to validate this signature as a measure of SOX10-dependent activity in independent single-cell and bulk RNA-seq SOX10 knockdown, cell line panel, and MAPK inhibitor drug-resistant datasets. Evaluation of patient single-cell RNA-seq data revealed lower levels of SOX10-dependent transcripts in immune checkpoint inhibitor-resistant tumors. Our results suggest that SOX10-deficient melanoma cells are associated with cross-resistance between targeted and immune checkpoint inhibitors and highlight the need to identify therapeutic strategies that target this subpopulation.

Total Calcium Intake Is Associated With Trabecular Bone Density in Adolescent Girls With Type 1 Diabetes.

Type 1 diabetes (T1D) confers an increased risk of fracture and is associated with lower bone mineral density (BMD) and altered microarchitecture compared with controls. Adequate calcium (Ca) intake promotes bone mineralization, thereby increasing BMD. The objective of this analysis was to evaluate the associations of total daily Ca intake with bone outcomes among youth with T1D. This was a cross-sectional analysis of girls ages 10-16 years with (n = 62) and without (n = 60) T1D. We measured Ca intake with a validated food-frequency questionnaire and BMD, microarchitecture, and strength estimates with dual-energy X-ray absorptiometry and high-resolution peripheral quantitative computed tomography. Total daily Ca intake did not differ between groups (950 ± 488 in T1D versus 862 ± 461 mg/d in controls, p = 0.306). Serum 25OHD was lower in T1D (26.3 ± 7.6 versus 32.6 ± 9.0 ng/mL, p = <0.001), and parathyroid hormone (PTH) was higher in T1D (38.9 ± 11 versus 33.4 ± 9.7 pg/mL, p = 0.004). Trabecular volumetric BMD and thickness at the tibia were lower in T1D (p = 0.013, p = 0.030). Ca intake correlated with trabecular BMD at the radius and tibia among T1D participants (ß = 0.27, p = 0.047, and ß = 0.28, p = 0.027, ß = 0.28, respectively) but not among controls (pinteraction = 0.009 at the radius, pinteraction = 0.010 at the tibia). Similarly, Ca intake was associated with estimated failure load at the tibia in T1D but not control participants (p = 0.038, ß = 0.18; pinteraction = 0.051). We observed the expected negative association of Ca intake with parathyroid hormone in controls (p = 0.022, ß = -0.29) but not in T1D participants (pinteraction = 0.022). Average glycemia as measured by hemoglobin A1c did not influence the relationship of Ca and PTH among participants with T1D (pinteraction = 0.138). These data suggest that youth with T1D may be particularly vulnerable to dietary Ca insufficiency. Increasing Ca intake may be an effective strategy to optimize bone health in this population. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Targeting Upregulated cIAP2 in SOX10-Deficient Drug Tolerant Melanoma.

Drug tolerance and minimal residual disease (MRD) are likely to prelude acquired resistance to targeted therapy. Mechanisms that allow persister cells to survive in the presence of targeted therapy are being characterized but selective vulnerabilities for these subpopulations remain uncertain. We identified cellular inhibitor of apoptosis protein 2 (cIAP2) as being highly expressed in SOX10-deficient drug tolerant persister (DTP) melanoma cells. Here, we show that cIAP2 is sufficient to induce tolerance to MEK inhibitors, likely by decreasing the levels of cell death. Mechanistically, cIAP2 is upregulated at the transcript level in SOX10-deficient cells and the AP-1 complex protein, JUND, is required for its expression. Using a patient-derived xenograft model, we demonstrate that treatment with the cIAP1/2 inhibitor, birinapant, during the MRD phase delays the onset of resistance to BRAF inhibitor and MEK inhibitor combination therapy. Together, our data suggest that cIAP2 upregulation in SOX10-deficient subpopulations of melanoma cells induces drug tolerance to MAPK targeting agents and provides a rationale to test a novel therapeutical approach to target MRD.

The future of targeted kinase inhibitors in melanoma.

Melanoma is a cancer of the pigment-producing cells of the body and its incidence is rising. Targeted inhibitors that act against kinases in the MAPK pathway are approved for BRAF-mutant metastatic cutaneous melanoma and increase patients' survival. Response to these therapies is limited by drug resistance and is less durable than with immune checkpoint inhibition. Conversely, rare melanoma subtypes have few therapeutic options for advanced disease and MAPK pathway targeting agents show minimal anti-tumor effects. Nevertheless, there is a future for targeted kinase inhibitors in melanoma: in new applications such as adjuvant or neoadjuvant therapy and in novel combinations with immunotherapies or other targeted therapies. Pre-clinical studies continue to identify tumor dependencies and their corresponding actionable drug targets, paving the way for rational targeted kinase inhibitor combinations as a personalized medicine approach for melanoma.

A ß-Catenin-TCF-Sensitive Locus Control Region Mediates GUCY2C Ligand Loss in Colorectal Cancer.

BACKGROUND & AIMS: Sporadic colorectal cancers arise from initiating mutations in APC, producing oncogenic ß-catenin/TCF-dependent transcriptional reprogramming. Similarly, the tumor suppressor axis regulated by the intestinal epithelial receptor GUCY2C is among the earliest pathways silenced in tumorigenesis. Retention of the receptor, but loss of its paracrine ligands, guanylin and uroguanylin, is an evolutionarily conserved feature of colorectal tumors, arising in the earliest dysplastic lesions. Here, we examined a mechanism of GUCY2C ligand transcriptional silencing by ß-catenin/TCF signaling. METHODS: We performed RNA sequencing analysis of 4 unique conditional human colon cancer cell models of ß-catenin/TCF signaling to map the core Wnt-transcriptional program. We then performed a comparative analysis of orthogonal approaches, including luciferase reporters, chromatin immunoprecipitation sequencing, CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats) knockout, and CRISPR epigenome editing, which were cross-validated with human tissue chromatin immunoprecipitation sequencing datasets, to identify functional gene enhancers mediating GUCY2C ligand loss. RESULTS: RNA sequencing analyses reveal the GUCY2C hormones as 2 of the most sensitive targets of ß-catenin/TCF signaling, reflecting transcriptional repression. The GUCY2C hormones share an insulated genomic locus containing a novel locus control region upstream of the guanylin promoter that mediates the coordinated silencing of both genes. Targeting this region with CRISPR epigenome editing reconstituted GUCY2C ligand expression, overcoming gene inactivation by mutant ß-catenin/TCF signaling. CONCLUSIONS: These studies reveal DNA elements regulating corepression of GUCY2C ligand transcription by ß-catenin/TCF signaling, reflecting a novel pathophysiological step in tumorigenesis. They offer unique genomic strategies that could reestablish hormone expression in the context of canonical oncogenic mutations to reconstitute the GUCY2C axis and oppose transformation.

Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma.

Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies. Mechanisms underlying tumor cell plasticity remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads to invasive properties, including the expression of mesenchymal genes and extracellular matrix, and promotes tolerance to BRAF and/or MEK inhibitors. We identify the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as inducing cell death selectively in SOX10-deficient cells. Targeted therapy selects for SOX10 knockout cells underscoring their drug tolerant properties. Combining cIAP1/2 inhibitor with BRAF/MEK inhibitors delays the onset of acquired resistance in melanomas in vivo. These data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a therapeutic strategy to selectively eliminate SOX10-deficient cells.

SOX10 requirement for melanoma tumor growth is due, in part, to immune-mediated effects.

Developmental factors may regulate the expression of immune modulatory proteins in cancer, linking embryonic development and cancer cell immune evasion. This is particularly relevant in melanoma because immune checkpoint inhibitors are commonly used in the clinic. SRY-box transcription factor 10 (SOX10) mediates neural crest development and is required for melanoma cell growth. In this study, we investigate immune-related targets of SOX10 and observe positive regulation of herpesvirus entry mediator (HVEM) and carcinoembryonic-antigen cell-adhesion molecule 1 (CEACAM1). Sox10 knockout reduces tumor growth in vivo, and this effect is exacerbated in immune-competent models. Modulation of CEACAM1 expression but not HVEM elicits modest effects on tumor growth. Importantly, Sox10 knockout effects on tumor growth are dependent, in part, on CD8+ T cells. Extending this analysis to samples from patients with cutaneous melanoma, we observe a negative correlation with SOX10 and immune-related pathways. These data demonstrate a role for SOX10 in regulating immune checkpoint protein expression and anti-tumor immunity in melanoma.

Physical Activity, Menstrual History, and Bone Microarchitecture in Female Athletes with Multiple Bone Stress Injuries.

PURPOSE: To determine differences in health and physical activity history, bone density, microarchitecture, and strength among female athletes with a history of multiple BSI, athletes with ≤1 BSI, and nonathletes. METHODS: We enrolled 101 women (age, 18-32 yr) for this cross-sectional study: nonathlete controls (n = 17) and athletes with a history of ≥3 BSIs (n = 21) or ≤1 BSI (n = 63). We collected subjects' health and training history and measured bone microarchitecture of the distal tibia via high-resolution peripheral quantitative computed tomography (HR-pQCT) and areal bone mineral density of the hip and spine by dual-energy X-ray absorptiometry. RESULTS: Groups did not differ according to age, body mass index, age at menarche, areal bone mineral density, or tibial bone microarchitecture. Women with multiple BSI had a higher prevalence of primary and secondary amenorrhea (P < 0.01) compared with other groups. Total hours of physical activity in middle school were similar across groups; however, women with multiple BSI performed more total hours of physical activity in high school (P = 0.05), more hours of uniaxial loading in both middle school and high school (P = 0.004, P = 0.02), and a smaller proportion of multiaxial loading activity compared with other groups. CONCLUSIONS: These observations suggest that participation in sports with multiaxial loading and maintaining normal menstrual status during adolescence and young adulthood may reduce the risk of multiple bone stress injuries.

Hip Structural Analysis Reveals Impaired Hip Geometry in Girls With Type 1 Diabetes.

CONTEXT: Among patients with type 1 diabetes (T1D), the risk of hip fracture is up to 6-fold greater than that of the general population. However, the cause of this skeletal fragility remains poorly understood. OBJECTIVE: To assess differences in hip geometry and imaging-based estimates of bone strength between youth with and without T1D using dual-energy x-ray absorptiometry (DXA)-based hip structural analysis. DESIGN: Cross-sectional comparison. PARTICIPANTS: Girls ages 10 to 16 years, including n = 62 with T1D and n = 61 controls. RESULTS: The groups had similar age, bone age, pubertal stage, height, lean mass, and physical activity. Bone mineral density at the femoral neck and total hip did not differ in univariate comparisons but was lower at the femoral neck in T1D after adjusting for bone age, height, and lean mass. Subjects with T1D had significantly lower cross-sectional area, cross-sectional moment of inertia, section modulus, and cortical thickness at the narrow neck, with deficits of 5.7% to 10.3%. Cross-sectional area was also lower at the intertrochanteric region in girls with T1D. Among those T1D subjects with HbA1c greater than the cohort median of 8.5%, deficits in hip geometry and strength estimates were more pronounced. CONCLUSIONS: DXA-based hip structural analysis revealed that girls with T1D have unfavorable geometry and lower estimates of bone strength at the hip, which may contribute to skeletal fragility and excess hip fracture risk in adulthood. Higher average glycemia may exacerbate effects of T1D on hip geometry.

Elevated HbA1c Is Associated with Altered Cortical and Trabecular Microarchitecture in Girls with Type 1 Diabetes.

CONTEXT: Skeletal fragility is a significant complication of type 1 diabetes (T1D), with an increased risk of fracture observed starting in childhood. Altered bone accrual and microarchitectural development during the critical peripubertal years may contribute to this fragility. OBJECTIVE: To evaluate differences in skeletal microarchitecture between girls with T1D and controls and to assess factors associated with these differences. DESIGN: Cross-sectional comparison. PARTICIPANTS: Girls ages 10-16 years, 62 with T1D and 61 controls. RESULTS: Areal bone mineral density (BMD) measured by dual-energy x-ray absorptiometry did not differ between girls with and without T1D. At the distal tibia, trabecular BMD was 7.3 ± 2.9% lower in T1D (P = 0.013), with fewer plate-like and axially-aligned trabeculae. Cortical porosity was 21.5 ± 10.5% higher, while the estimated failure load was 4.7 ± 2.2% lower in T1D (P = 0.043 and P = 0.037, respectively). At the distal radius, BMD and microarchitecture showed similar differences between the groups but did not reach statistical significance. After stratifying by HbA1c, only those girls with T1D and HbA1c > 8.5% differed significantly from controls. P1NP, a marker of bone formation, was lower in T1D while CTX and TRAcP5b, markers of bone resorption and osteoclast number, respectively, did not differ. The insulin-like growth factor 1 (IGF-1) Z-score was lower in T1D, and after adjustment for the IGF-1 Z-score, associations between T1D status and trabecular microarchitecture were largely attenuated. CONCLUSIONS: Skeletal microarchitecture is altered in T1D early in the course of disease and among those with higher average glycemia. Suppressed bone formation and lower circulating IGF-1 likely contribute to this phenotype.

Cortical Bone Material Strength Index and Bone Microarchitecture in Postmenopausal Women With Atypical Femoral Fractures.

Atypical femoral fractures are rare fractures that occur in the subtrochanteric or diaphyseal region of the femur with minimal or no trauma. Though the association of atypical femoral fractures (AFFs) and bisphosphonate (BP) use is a growing concern in the management of osteoporosis, currently there is little knowledge about which patients may be at risk for an atypical femoral fracture. Given that these fractures initiate in the femoral cortex, we aimed to determine whether cortical bone tissue properties (bone material strength index; BMSi), as measured by in vivo impact microindentation, are altered in atypical fracture patients. We also aimed to identify factors associated with the BMSi measurements. We enrolled postmenopausal women with recent AFFs (n = 15) or hip fractures (Hip Fxs; n = 20), long-term (>5 years) BP users (n = 30), and treatment naïve controls (n = 88). We measured total hip and femoral neck BMD by DXA, cortical bone microstructure at the distal tibia by HR-pQCT, and BMSi at the midtibia by impact microindentation. BMSi values were similar in all groups, with no effects of long-term BP use or lower values in patients with AFFs or Hip Fxs, even after multivariable adjustment. BMSi measurements were independent of age, femoral BMD, duration of BP treatment, vitamin D level, and cortical bone microstructure, including cortical porosity and cortical tissue mineral density. In conclusion, impact microindentation values are not negatively affected by long-term BP use and do not appear to discriminate individuals who suffer AFFs. Thus, our results do not support clinical use of impact microindentation to identify those at risk for AFFs. This remains to be verified in larger studies. © 2018 American Society for Bone and Mineral Research.

Influence of soft tissue on bone density and microarchitecture measurements by high-resolution peripheral quantitative computed tomography.

High-resolution peripheral quantitative computed tomography (HR-pQCT) is a non-invasive method of measuring volumetric bone mineral density (vBMD) and microarchitecture at the distal radius and tibia. With increasing use of this technology, it is crucial to understand the potential impact of overlying soft tissue on the accuracy of HR-pQCT measures. Thus, we examined the effects of a simulated increase in adiposity (via 6- and 12-mm thick layers of overlying circumferential fat) on HR-pQCT measures of a hydroxyapatite (HA) phantom and in women (n = 20, aged 18-75 years). In the phantom, increasing the amount of overlying fat tissue led to a corresponding decrease in the mean measured density for each HA rod. In women, fat-layering led to a decrease in total vBMD (-2.9 to -3.7%, p < 0.001), cortical vBMD (-1.4% to -5.5%, p < 0.001), and estimated failure load (-1.4 to -5.7%, p = 0.002) at the radius, with similar changes in the tibia. Trabecular microarchitectural measurements were also impacted by simulated adiposity, with fat-layering leading to decreased trabecular thickness and separation and increased trabecular number at the radius (Δ's = 5 to 12%) with more pronounced differences at the tibia (Δ's = 14 to 40%). At the tibia, fat-layering also led to decreased cortical thickness and increased cortical porosity. Altogether, these results demonstrate that overlying adipose tissue can lead to artifacts in bone measurements by HR-pQCT, resulting in an underestimation of vBMD and generally, an overestimation of bone microarchitecture impairment. Therefore, soft tissue artifact should be considered when interpreting HR-pQCT results, particularly in those with high BMI and/or marked changes in adiposity.

Trabecular Bone Morphology Correlates With Skeletal Maturity and Body Composition in Healthy Adolescent Girls.

Context: Growth in healthy children is associated with changes in bone density and microarchitecture. Trabecular morphology is an additional important determinant of bone strength, but little is currently known about trabecular morphology in healthy young people. Objective: To investigate associations of trabecular morphology with increasing maturity and with body composition in healthy girls. Design: Cross-sectional study. Setting: Academic research center. Participants: Eighty-six healthy girls aged 9 to 18 years. Main Outcome Measures: High-resolution peripheral quantitative computed tomography and individual trabecula segmentation were used to assess volumetric bone density, microarchitecture, and trabecular morphology (plate-like vs rod-like) at the distal radius and tibia. Results: Plate-like bone volume divided by total volume (pBV/TV) increased statistically significantly at the tibia (R = 0.41, P < 0.001), whereas rod-like BV/TV (rBV/TV) decreased statistically significantly at both the radius and tibia (R = -0.34, P = 0.003 and R = -0.28, P = 0.008, respectively) with increasing bone age. In multivariable models, lean mass positively correlated with pBV/TV and plate number at the radius and with plate thickness at both sites. In contrast, fat mass negatively correlated with plate thickness at the tibia and plate surface at both sites. In addition, fat mass positively correlated with rBV/TV and number at the tibia. pBV/TV at both the distal radius and tibia was positively correlated with spine bone mineral density. Conclusions: Increasing maturity across late childhood and adolescence is associated with changes in trabecular morphology anticipated to contribute to bone strength. Body composition correlates with trabecular morphology, suggesting that muscle mass and adiposity in youth may contribute to long-term skeletal health.

Bone Material Strength Index as Measured by Impact Microindentation in Postmenopausal Women With Distal Radius and Hip Fractures.

We tested whether cortical bone tissue properties assessed by in vivo impact microindentation would distinguish postmenopausal women with recent distal radius (DRF) or hip fracture (HF) from nonfracture controls (CONT). We enrolled postmenopausal women with recent DRF (n = 57), HF (n = 41), or CONT (n = 93), and used impact microindentation to assess bone material strength index (BMSi) at the anterior surface of the mid-tibia diaphysis. Areal bone mineral density (aBMD) (g/cm2 ) of the femoral neck (FN), total hip (TH), and lumbar spine (LS) were measured by dual-energy X-ray absorptiometry (DXA). HF and DRF subjects had significantly lower BMD than CONT at all sites (-5.6% to -8.2%, p < 0.001 for all). BMSi was 4% lower in DRF compared to CONT (74.36 ± 8.77 versus 77.41 ± 8.79, p = 0.04). BMSi was similarly lower in HF versus CONT, but the difference did not reach statistical significance (74.62 ± 8.47 versus 77.41 ± 8.79, p = 0.09). Lower BMSi was associated with increased risk of DRF (unadjusted OR, 1.43; 95% CI, 1.02 to 2.00, per SD decrease, p = 0.04), and remained statistically significant after adjustment for age, age and BMI, and age, BMI, and FN BMD (OR = 1.48 to 1.55). Lower BMSi tended to be associated with HF, but only reached borderline significance (unadjusted OR = 1.39; 95% CI, 0.96 to 2.01, p = 0.08). These results provide strong rationale for future investigations aimed at assessing whether BMSi can predict fracture in prospective studies and improve identification of women at risk for fragility fractures. © 2017 American Society for Bone and Mineral Research.

Regional variation of bone density, microarchitectural parameters, and elastic moduli in the ultradistal tibia of young black and white men and women.

Whole-bone analyses can obscure regional heterogeneities in bone characteristics. Quantifying these heterogeneities might improve our understanding of the etiology of injuries, such as lower-extremity stress fractures. Here, we performed regional analyses of high-resolution peripheral quantitative computed tomography images of the ultradistal tibia in young, healthy subjects (age range, 18 to 30 years). We quantified bone characteristics across four regional sectors of the tibia for the following datasets: white women (n = 50), black women (n = 51), white men (n = 50), black men (n = 34), and all subjects (n = 185). After controlling for potentially confounding variables, we observed statistically significant variations in most of the characteristics across sectors (p < 0.05). Most of the bone characteristics followed a similar trend for all datasets but with different magnitudes. Regardless of race or sex, the anterior sector had the lowest trabecular and total volumetric bone mineral density and highest trabecular separation (p < 0.001), while cortical thickness was lowest in the medial sector (p < 0.05). Accordingly, the anterior sector also had the lowest elastic modulus in the anterior-posterior and superior-inferior directions (p < 0.001). In all sectors, the mean anisotropy was ~3, suggesting cross-sector similarity in the ratios of loading in these directions. In addition, the bone characteristics from regional and whole-bone analyses differed in all datasets (p < 0.05). Our findings on the heterogeneous nature of bone microarchitecture in the ultradistal tibia may reflect an adaptation of the bone to habitual loading conditions.

Bone mass, microarchitecture and strength are influenced by race/ethnicity in young adult men and women.

Lower rates of fracture in both Blacks compared to Whites, and men compared to women are not completely explained by differences in bone mineral density (BMD). Prior evidence suggests that more favorable cortical bone microarchitecture may contribute to reduced fracture rates in older Black compared to White women, however it is not known whether these differences are established in young adulthood or develop during aging. Moreover, prior studies using high-resolution pQCT (HR-pQCT) have reported outcomes from a fixed-scan location, which may confound sex- and race/ethnicity-related differences in bone structure. PURPOSE: We determined differences in bone mass, microarchitecture and strength between young adult Black and White men and women. METHODS: We enrolled 185 young adult (24.2±3.4yrs) women (n=51 Black, n=50 White) and men (n=34 Black, n=50 White) in this cross-sectional study. We used dual-energy X-ray absorptiometry (DXA) to determine areal BMD (aBMD) at the femoral neck (FN), total hip (TH) and lumbar spine (LS), as well as HR-pQCT to assess bone microarchitecture and failure load by micro-finite element analysis (µFEA) at the distal tibia (4% of tibial length). We used two-way ANOVA to compare bone outcomes, adjusted for age, height, weight and physical activity. RESULTS: The effect of race/ethnicity on bone outcomes did not differ by sex, and the effect of sex on bone outcomes did not differ by race/ethnicty. After adjusting for covariates, Blacks had significantly greater FN, TH and LS aBMD compared to Whites (p<0.05 for all). Blacks also had greater cortical area, vBMD, and thickness, and lower cortical porosity, with greater trabecular thickness and total vBMD compared to Whites. µFEA-estimated FL was significantly higher among Blacks compared to Whites. Men had significantly greater total vBMD, trabecular thickness and cortical area and thickness, but greater cortical porosity than women, the net effects being a higher failure load in men than women. CONCLUSION: These findings demonstrate that more favorable bone microarchitecture in Blacks compared to Whites and in men compared to women is established by young adulthood. Advantageous bone strength among Blacks and men likely contributes to their lower risk of fractures throughout life compared to their White and women counterparts.