Structural differences contributing to sex-specific associations between FN BMD and whole-bone strength for adult White women and men.

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.

Bone quality following peripubertal growth in a mouse model of transmasculine gender-affirming hormone therapy.

During peri-puberty, bone growth and the attainment peak bone mass is driven predominantly by sex steroids. This is important when treating transgender and gender diverse youth, who have become increasingly present at pediatric clinics. Analogues of gonadotropin-releasing hormone (GnRH) are commonly prescribed to transgender and gender diverse youth prior to starting gender-affirming hormone therapy (GAHT). However, the impact of GnRH agonists on long bones with the addition of GAHT is relatively unknown. To explore this, we developed a trans-masculine model by introducing either GnRHa or vehicle treatment to female-born mice at a pre-pubertal age. This treatment was followed by male GAHT (testosterone, T) or control treatment three weeks later. Six weeks after T therapy, bone quality was compared between four treatment groups: Control (vehicle only), GnRHa-only, GnRHa + T, and T-only. Bone length/size, bone shape, mechanical properties, and trabecular morphology were modulated by GAHT. Independent of GnRHa administration, mice treated with T had shorter femurs, larger trabecular volume and increased trabecular number, higher trabecular bone mineral density, and wider superstructures on the surface of bone (e.g., third trochanters) when compared to control or GnRHa-only mice. In conclusion, prolonged treatment of GnRHa with subsequent GAHT treatment directly affect the composition, parameters, and morphology of the developing long bone. These findings provide insight to help guide clinical approaches to care for transgender and gender diverse youth.

Optogenetic-induced muscle loading leads to mechanical adaptation of the Achilles tendon enthesis in mice.

Skeletal shape depends on the transmission of contractile muscle forces from tendon to bone across the enthesis. Loss of muscle loading impairs enthesis development, yet little is known if and how the postnatal enthesis adapts to increased loading. Here, we studied adaptations in enthesis structure and function in response to increased loading, using optogenetically induced muscle contraction in young (i.e., growth) and adult (i.e., mature) mice. Daily bouts of unilateral optogenetic loading in young mice led to radial calcaneal expansion and warping. This also led to a weaker enthesis with increased collagen damage in young tendon and enthisis, with little change in adult mice. We then used RNA sequencing to identify the pathways associated with increased mechanical loading during growth. In tendon, we found enrichment of glycolysis, focal adhesion, and cell-matrix interactions. In bone, we found enrichment of inflammation and cell cycle. Together, we demonstrate the utility of optogenetic-induced muscle contraction to elicit in vivo adaptation of the enthesis.

Associations Among Hip Structure, Bone Mineral Density, and Strength Vary With External Bone Size in White Women.

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.

Bone Morphology and Vascular Supply of Pedicled Distal Radius Bone Using Nano-Computed Tomography.

BACKGROUND: The goal of this study was to use nano-computed tomography to describe the intraosseous vascularity and structural characteristics of commonly used distal radius vascularized bone grafts for treatment of scaphoid nonunion. METHODS: We obtained 8 fresh frozen human cadaver forearm specimens for infusion of barium contrast. Specimens were scanned and segmented to quantify the vascular volume and trabecular density within 3 common graft regions, including 1, 2 intercompartmental supraretinacular artery (1,2 ICSRA), fourth extensor compartment artery (4 ECA), and volar carpal artery (VCA), as well as thirds of the scaphoid. Outcomes also included mean and maximum cortical thickness and number of cortical perforators. Single-specimen analyses were also performed comparing vascularity and trabecular density of each graft with scaphoid regions of a single specimen. Statistical analysis was performed using analysis of variance with post hoc Tukey testing when P value was less than .05. RESULTS: There was no significant difference between groups in the mean percent vascularity (P = .76). The ratio of trabecular bone in each graft to scaphoid thirds was less than 1. The mean cortical thickness (0.79 mm, 95% confidence interval [CI], 0.66-0.93 mm) and maximum cortical thickness (1.45 mm, 95% CI, 1.27-1.63 mm) of VCA grafts were both significantly greater than those of 4 ECA and 1,2 ICSRA (P < .001). CONCLUSIONS: There were no differences between vascular density of the 3 grafts and the scaphoid. Pedicled distal radius bone grafts have similar vascularity but morphometric differences such as cortical thickness and trabecular density which have unclear clinical implications.

Osteochondral Allografts for Large Oval Defects of the Medial Femoral Condyle: A Comparison of Single Lateral Versus Medial Femoral Condyle Oval Grafts Versus 2 Overlapping Circular Grafts.

BACKGROUND: Studies have demonstrated the acceptability of using a contralateral nonorthotopic lateral femoral condyle (LFC) graft for a circular medial femoral condyle (MFC) osteochondral defect up to 20 to 25 mm in diameter. Larger oblong defects can now be managed using either overlapping circle grafts or a single oblong-shaped osteochondral allograft (OCA). PURPOSE: To determine if an oblong contralateral nonorthotopic LFC OCA can attain an acceptable surface contour match compared with an oblong ipsilateral MFC OCA or an overlapping circle technique for large oblong defects of the MFC. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 120 fresh-frozen human femoral condyles were matched by tibial width into 30 groups of 4 condyles (1 recipient MFC, 3 donor condyles). The recipient MFC was initially imaged using nano-computed tomography (nano-CT). A 17 × 36-mm oblong defect was created in the recipient MFC. Overall, 3 donor groups were formed: MFC oblong, LFC nonorthotopic oblong, LFC or MFC overlapping circles. After each transplant, the recipient condyle underwent nano-CT and was digitally reconstructed, which was superimposed on the initial nano-CT scan of the native recipient condyle. Dragonfly 3D software was used to determine the root mean square (RMS) of both the surface height deviation and the circumferential step-off height deviation between the native and donor cartilage surfaces for each graft. RESULTS: RMS surface height deviations were as follows: 0.59 mm for MFC oblong grafts, 0.58 mm for LFC oblong grafts, and 0.78 mm for overlapping circle grafts. The MFC and LFC oblong grafts had significantly less surface height deviation than the overlapping circle grafts (P = .004 and P = .002, respectively). RMS step-off height deviations were as follows: 0.68 mm for MFC oblong grafts, 0.70 mm for LFC oblong grafts, and 0.85 mm for overlapping circle grafts. The MFC and LFC oblong grafts had significantly less step-off height deviation than the overlapping circle grafts (P < .001 and P = .002, respectively). The majority of this difference was on the medial segment of the overlapping circle grafts. CONCLUSION: Oblong ipsilateral MFC OCAs and oblong contralateral nonorthotopic LFC OCAs produced a significantly better surface contour match to the native MFC than overlapping circle grafts for oblong defects 17 × 36 mm in size. CLINICAL RELEVANCE: Size-matched contralateral nonorthotopic LFC grafts are acceptable for MFC defects, which may allow for a quicker match, earlier patient care, and less wastage of valuable donor tissue.

Sex and External Size Specific Limitations in Assessing Bone Health From Adult Hand Radiographs.

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.

External Bone Size Is a Key Determinant of Strength-Decline Trajectories of Aging Male Radii.

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.

Femoral Neck External Size but not aBMD Predicts Structural and Mass Changes for Women Transitioning Through Menopause.

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.