Abstract The goal of this study is to investigate the causes of skeletal fragility in Type 1 Diabetic (T1D) women. We hypothesize that bone fragility in diabetic individuals is partly due to changes in mineral and/or intrinsic material properties in the osteocyte lacunar/peri-lacunar regions of bone tissue. Studies of bone material properties in T1D are limited, and bone mineral density (BMD) alone does not explain the elevated fracture risk in T1D women (Cases). Innovative instruments with nanoscale resolution, including a laser scanning microscope (LSM), an atomic force microscope that is integrated with infrared spectroscopy (AFM-IR), and a nanoindenter were used for the characterization of the material properties surrounding osteocyte lacunae. In trabecular bone tissue, the compositional mineral matrix and Mineral Matrix Peak ratios (MMA, MMP for both near- & far-lacunae) along with material strength variables (Modulus, Hardness for both near- & far-lacunae) were lower in T1D compared to Controls. While material compositional ratio of mineral maturity crystallinity area (MMCA) was higher, the mineral maturity crystallinity peak (MMCP) and hardness tended to be higher in “lacunae-near” than “lacunae-far” for all the biopsies. Furthermore, the higher mineral matrix (MMA) and material strength (modulus, hardness) in peri-lacunar regions of Controls may suggest its increased brittleness or differences in properties as compared to T1D. We postulate that difference between Cases (T1D) and Controls in modulus and hardness could be due to the variation in mineral exchange (diffusion) rate within the peri lacunar space.

INTRODUCTION:Race-specific reference ranges for pediatric areal bone mineral density (BMD) are widely used, but the value of race-based clinical algorithms has been questioned. We developed race-neutral pediatric reference ranges for areal BMD and bone mineral apparent density (BMAD) and compared race-specific vs race-neutral Z-scores in their ability to predict prospective fractures. MATERIAL AND METHODS:This secondary analysis of the Bone Mineral Density in Childhood Study used longitudinal BMD data of the spine, hip, forearm, and total body less head and BMAD from dual-energy x-ray absorptiometry (DXA) scans. Race/ethnicity, dietary calcium, physical activity, and prospective fractures were assessed by questionnaire. Race-neutral reference ranges and height-for-age Z-score adjustment equations were created using the lambda-sigma-mu method. Race-neutral and race-specific Z-scores were compared using linear mixed-effect modeling. Cox proportional hazard modeling was used to test whether race-neutral Z-scores associated with fracture. RESULTS:Race-neutral BMD and BMAD Z-scores were 0.5 to 0.7 SD greater than race-specific Z-scores for Black children but only ∼0.1 SD lower for children from other race/ethnicity groups. Growth and lifestyle factors modified group differences. One SD increase in race-neutral Z-scores was associated with a 12% to 18% reduced risk of fracture. CONCLUSION:We present the first race-neutral pediatric reference ranges for BMD and BMAD that are weighted to be representative of the US population and demonstrate that these Z-scores associate with fracture risk. Adoption of these new reference ranges should be considered, with thoughtful implementation for patients previously monitored with race-specific reference ranges, especially among children who identify as Black.

Pregnancy and lactation-associated osteoporosis (PLO) is a rare presentation of early-onset osteoporosis characterized by low trauma and spontaneous fractures during late pregnancy/lactation. Herein, we report areal BMD (aBMD) by DXA and volumetric BMD (vBMD), microarchitecture, and strength at the distal radius and tibia by HR-pQCT in 59 women with PLO-in comparison to both healthy premenopausal controls (n = 28) and premenopausal women with idiopathic osteoporotic fractures not associated with pregnancy/lactation (non-PLO IOP; n = 50). Women with PLO (aged 34 ± 6 yr) had a more severe clinical presentation than non-PLO IOP: 80% had vertebral and 92% had multiple fractures (p<.001). They had lower DXA aBMD at all sites vs Controls (all p<.001) and non-PLO IOP (all p<.05). By HR-pQCT, PLO had deficits in all radial/tibial density and most microarchitecture parameters and lower bone strength than controls (all p<.001). Compared to non-PLO IOP, PLO had lower total and trabecular density at radius and tibia (all p ≤ .01) and significant deficits in trabecular microstructure and cortical thickness at the radius only. We studied PLO subgroups with clinical factors potentially related to bone physiology: Within PLO, women with vertebral fractures had lower spine aBMD and higher tibial cortical porosity but were otherwise structurally similar to the nonvertebral group. Those with prior heparin exposure had larger bone size and trabecular area, and those with renal stones had smaller bone size and lower 1/3 radius aBMD. We also compared groups based on postpartum timing: Recent PLO (n = 25) evaluated ≤12 M postpartum, before expected recovery of pregnancy/lactation bone loss, had significantly lower aBMD than distant PLO (n = 34) evaluated >12 M postpartum. However, radial/tibial HR-pQCT measures did not differ, suggesting pre-existing and/or persistent structural deficits. This structural study increases our mechanistic understanding of the severe bone fragility presentation that characterizes PLO and also highlights areas of potential mechanistic heterogeneity that require additional investigation.

Vitamin D status has long been related to falls risk. In this planned secondary analysis of a vitamin supplementation trial in postmenopausal women, standardized 25-hydroxyvitamin D concentration up to 60 ng/mL was not associated with increased falls. Women with 25(OH)D ≥ 60 ng/mL had higher odds of ≥ 2 falls. Falls are common and cause fractures. High circulating 25(OH)D may increase falls risk; thus, recent guidance recommends 25(OH)D not exceed 50 ng/mL. Prior falls studies have not reported standardized 25(OH)D (s25D) data. The purpose of this planned secondary analysis of a 4-year calcium/vitamin D supplementation trial was to evaluate the association of s25D with falls. This study recruited 2,303 postmenopausal women. The analytic dataset consisted of pooled concatenated data from years 2–4 (NTotal = 5,732). Serum 25(OH)D was measured annually and subsequently retrospectively standardized using Vitamin D Standardization Program methods. Falls were recorded by diary. Incidence for ≥ 1 fall and ≥ 2 falls was assessed by s25D group (≤ 20, 20- < 30, 30- < 40, 40- < 50, 50- < 60 and ≥ 60 ng/mL) using multivariable logistic regression. Mean (SD) baseline s25D was 32.6 ng/mL (8.3) with no difference between supplement and placebo groups. s25D increased to 41.3 ng/mL at year 2 in the supplement group then remained stable. By s25D group, incidence for ≥ 1 fall varied from 22–32

Background Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. Results Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. Conclusion We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single “optimal” pubertal growth pattern.

Context: We previously reported that sequential teriparatide followed by denosumab substantially increases bone mineral density (BMD) in premenopausal idiopathic osteoporosis (PremenIOP). Objective: To determine whether administration of bisphosphonates after denosumab cessation is associated with stable BMD in PremenIOP Design: Open-label extension study. Participants: Twenty-four PremenIOP Teriparatide-Denosumab Study participants. Interventions: Oral alendronate (ALN), 70 mg weekly, or intravenous zoledronic acid (ZOL), 5 mg once (patient choice), was administered 7 months (M) after final denosumab dose. Outcomes: BMD by dual-energy x-ray absorptiometry and serum C-telopeptide (CTX) q6M; Vertebral Fracture Assessment (VFA), and high-resolution peripheral quantitative computed tomography (HR-pQCT) q12 M. Results: Twenty-four women with PremenIOP (aged 43 +/- 8 years), severely affected with low trauma adult fractures (range 0-12; 9 with vertebral fractures) and/or very low BMD, had large BMD increases on sequential teriparatide-denosumab (spine: 25 +/- 9%; total hip: 11 +/- 6%). During the Bisphosphonate Extension, mean BMD and CTX changes in the entire group were small and not statistically significant at 6 or 12 M. Women choosing ZOL (n = 6) vs ALN (n = 18) did not differ by baseline age, body mass index, fractures, BMD, or CTX. On ZOL, there were small lumbar spine BMD declines and CTX increases, particularly between 6 M and 12 M, while greater stability was observed on ALN. Changes in BMD and CTX did not differ by duration of denosumab (36 M vs <36 M) or between 20 women who remained premenopausal and 4 who transitioned into menopause. Higher pre-teriparatide CTX, likely reflecting baseline remodeling status, predicted more spine and hip bone loss. No new vertebral (clinical or vertebral fraction assessment screening) or nonvertebral fractures occurred. Conclusion: BMD remained stable in women with PremenIOP who received bisphosphonates after sequential teriparatide-denosumab therapy.

Background: Body composition assessment aids evaluation of energy stores and the impact of diseases and interventions on child growth. Current United States pediatric reference ranges from the National Health and Nutrition Examination Survey (NHANES) include 20% of children with obesity, body mass index of >= 95th percentile. Objectives: This study aimed to develop dual energy X-ray absorptiometry (DXA) based reference ranges in a diverse cohort with low-obesity prevalence from the Bone Mineral Density in Childhood Study (BMDCS). Methods: This is a secondary analysis of a longitudinal, prospective, observational cohort. Healthy children (height and BMI within 3rd to 97th per-centiles, ages 5-19 y at enrollment), from 5 United States centers were measured annually for <7 visits. Whole body scans were acquired using Hologic scanners. A subsample underwent repeat measurements to determine precision. We generated reference ranges for appendicular and total lean soft tissue mass index (LSTM Index), fat mass index (FMI), and other body composition measures. Resulting curves were compared to NHANES and across subgroups. Sex and age-specific equations were developed to adjust body composition Z-scores for height Z score. Results: We obtained 9846 scans of 2011 participants (51% female, 22% Black, 17% Hispanic, 48% White, 7% Asian/Pacific Islander, and 6% with obesity). Precision (percent coefficient of variation) ranged from 0.7% to 1.96%. Median and-2 standard deviation curves for BMDCS and NHANES were similar, but NHANES +2 standard deviation LSTM Index and FMI curves were distinctly greater than the respective BMDCS curves. Subgroup differences were more extreme for appendicular LSTM Index-Z (mean +/- SD: Asian -0.52 +/- 0.93 compared with Black 0.77 +/- 0.87) than for FMI-Z (Hispanic 0.29 +/- 0.98 compared with Black -0.14 +/- 1.1) and were smaller for Z-scores adjusted for height Z-score. Conclusions: These reference ranges add to sparse normative data regarding body composition in children and adolescents and are based on a cohort with an obesity prevalence similar to current BMI charts. Awareness of subgroup differences aids in interpreting results.

Premenopausal women with idiopathic osteoporosis (PreMenIOP) have marked deficits in skeletal microstructure. We have reported that sequential treatment with teriparatide and denosumab improves central skeletal bone mineral density (BMD) by dual‐energy X‐ray absorptiometry and central QCT in PreMenIOP. We conducted preplanned analyses of high‐resolution peripheral quantitative computed tomography (HR‐pQCT) scans from teriparatide and denosumab extension studies to measure effects on volumetric BMD (vBMD), microarchitecture, and estimated strength at the distal radius and tibia. Of 41 women enrolled in the parent teriparatide study (20 mcg daily), 34 enrolled in the HR‐pQCT study. HR‐pQCT participants initially received teriparatide (N = 24) or placebo (N = 10) for 6 months; all then received teriparatide for 24 months. After teriparatide, 26 enrolled in the phase 2B denosumab extension (60 mg q6M) for 24 months. Primary outcomes were percentage change in vBMD, microstructure, and stiffness after teriparatide and after denosumab. Changes after sequential teriparatide and denosumab were secondary outcomes. After teriparatide, significant improvements were seen in tibial trabecular number (3.3%, p = 0.01), cortical area and thickness (both 2.7%, p < 0.001), and radial trabecular microarchitecture (number: 6.8%, thickness: 2.2%, separation: −5.1%, all p < 0.02). Despite increases in cortical porosity and decreases in cortical density, whole‐bone stiffness and failure load increased at both sites. After denosumab, increases in total (3.5%, p < 0.001 and 3.3%, p = 0.02) and cortical vBMD (1.7% and 3.2%; both p < 0.01), and failure load (1.1% and 3.6%; both p < 0.05) were seen at tibia and radius, respectively. Trabecular density (3.5%, p < 0.001) and number (2.4%, p = 0.03) increased at the tibia, while thickness (3.0%, p = 0.02) increased at the radius. After 48 months of sequential treatment, significant increases in total vBMD (tibia: p < 0.001; radius: p = 0.01), trabecular microstructure (p < 0.05), cortical thickness (tibia: p < 0.001; radius: p = 0.02), and whole bone strength (p < 0.02) were seen at both sites. Significant increases in total vBMD and bone strength parameters after sequential treatment with teriparatide followed by denosumab support the use of this regimen in PreMenIOP. © 2022 American Society for Bone and Mineral Research (ASBMR).

Inflammation plays a key role in cancer development. As an important modulator of inflammation, the role of diet should be explored. The purpose of this study was to determine the association between diets with a higher inflammatory potential, as measured by the Dietary Inflammatory Index (DII®), and cancer development in a cohort of rural post-menopausal women. Dietary intake from a randomized controlled trial cohort of rural, post-menopausal women in Nebraska was used to compute energy-adjusted DII (E-DIITM) scores at baseline and four years later (visit 9). A linear mixed model analysis and multivariate logistic regression evaluated the association between E-DII scores (baseline, visit 9, change score) and cancer status. Of 1977 eligible participants, those who developed cancer (n = 91, 4.6%) had a significantly larger, pro-inflammatory change in E-DII scores (Non-cancer: Δ 0.19 ± 1.43 vs. Cancer: Δ 0.55 ± 1.43, p = 0.02). After adjustment, odds of cancer development were over 20% higher in those with a larger change (more pro-inflammatory) in E-DII scores than those with smaller E-DII changes (OR = 1.21, 95% CI [1.02, 1.42], p = 0.02). Shifting to a more pro-inflammatory diet pattern over four years was associated with increased odds of cancer development, but not with E-DII at baseline or visit 9 alone.

The goal of this study is to investigate the causes of osteoporosis-related skeletal fragility in postmenopausal women. We hypothesize that bone fragility in these individuals is largely due to mineral, and/or intrinsic material properties in the osteocyte lacunar/peri-lacunar regions of bone tissue. Innovative measurements with nanoscale resolution, including scanning electron microscope (SEM), an atomic force microscope that is integrated with infrared spectroscopy (AFM-IR), and nanoindentation, were used to characterize osteocyte lacunar and peri-lacunar properties in bone biopsies from fracturing (Cases) and matched (Age, BMD), non-fracturing (Controls) postmenopausal healthy women. In the peri-lacunar space, the nanoindentation results show that the modulus and hardness of the Controls are lower than the Cases. The AFM-IR results conclusively show that the mineral matrix, maturity (peak) (except in outer/far regions in Controls) were greater in Controls than in Cases. Furthermore, these results indicated that while mineral-to-matrix area ratio tended to be greater, the mineral maturity and crystallinity peak ratio 'near' lacunae is greater than at regions 'far' or more distance from lacunae in the Controls only. Due to the heterogeneity of bone structure, additional measurements are needed to provide more convincing evidence of altered lacunar characteristics and changes in the peri-lacunar bone as mechanisms related to postmenopausal women and fragility. Such findings would motivate new osteocyte-targeted treatments to reduce fragility fracture risks in these groups.

Macro- and microarchitectural, bone material property, dynamic histomorphometric, and bone turnover marker data were studied in normal bone mineral density (BMD) post-menopausal women with fragility fracture. Women with fracture had thinner iliac cortices and more homogeneous bone material properties in cortical bone than age/BMD-matched non-fracture women. Low cortical thickness and bone tissue heterogeneity in normal BMD women are associated with prevalent fragility fracture. Bone mass (bone mineral density, (BMD)) of the spine and hip is today’s best single measurement for evaluating future fragility fracture risk. However, the majority of fragility fractures occur in women with BMD T-score above the WHO osteoporotic BMD threshold of − 2.5, indicating that non-BMD endpoints may play a role in their fragility fractures. We hypothesize that in non-osteoporotic women, bone micoarchitecture, bone material properties, dynamic histomorphometric endpoints, and bone turnover markers are related to fragility fracture. Two groups (N = 60 each) of post-menopausal women with total hip BMD T-score ranging from + 0.3 to –2.49 were recruited: fragility fracture and age/BMD-matched, non-fragility fracture women. Normal (T-score >  − 0.99) and osteopenic (T-score ≤  − 1.0) BMD cohorts were designated within both the fracture and non-fracture groups. Transiliac biopsy specimens were obtained to evaluate dynamic histomorphometric and microarchitectural endpoints and bone material properties by static and dynamic nanoindentation testing. All variables for fracture and non-fracture women within each BMD cohort were compared by the Wilcoxon signed-rank test (P < 0.01). Compared to non-fracture/normal BMD women, fracture/normal BMD women display lower iliac cortical thickness (− 12%, P = 0.0041) and lower heterogeneity of hardness (− 27%, P = 0.0068), elastic modulus (− 35%, P = 0.0009), and storage modulus (− 23%, P = 0.0054) in the cortical bone tissue, and lower heterogeneity of hardness (− 13%, P = 0.0088) in the trabecular bone tissue. Osteopenic women had no abnormalities related to fracture status. Post-menopausal women with normal BMD and fragility fracture have low cortical thickness and heterogeneity of several bone material properties in cortical and trabecular mineralized bone tissue. These differences may explain a portion of the excess bone fragility in women with normal BMD and fragility fracture.