Multiple Skeletal Sites Research Articles

Dietary Intakes of Copper and Selenium in Association with Bone Mineral Density.

The important trace elements, copper and selenium, have diverse effects on human health. As well as other important roles in living tissues, these trace elements are toxic at high levels but are key constituents of various enzymes and proteins essential for maintaining physiological health. However, links between dietary intakes of these elements, particularly copper, and bone mineral density (BMD) in humans remain uncertain. This study aimed to investigate whether dietary intakes of copper and selenium are associated with BMD in women. Dietary intakes of copper and selenium were assessed for 575 women in the Geelong Osteoporosis Study, using a detailed semi-quantitative food frequency questionnaire in conjunction with nutrition composition databases. Participants taking oral multivitamin preparations were excluded from analyses; 522 participants (ages 20-88 y) met the eligibility criteria. BMD at multiple skeletal sites was measured by dual energy X-ray absorptiometry (Lunar DPX-L). Separate multivariable regression models were developed to identify associations between copper and selenium intakes and BMD, after adjustments for age, anthropometry, other dietary factors, medication use, and lifestyle factors. Median (interquartile range) daily intake for copper was 1.5 mg (1.2-1.9) and for selenium, 72 μg (57-90). Low intakes (lowest tertile versus pooled upper tertiles) of copper and selenium were consistently associated with lower BMD at multiple skeletal sites. Fully adjusted models identified small but statistically significant differences in BMD, ranging from 1.8% to 4.0% for low copper intakes and 1.4% to 4.0% for low selenium intakes. Low dietary intakes of copper and selenium were both independently associated with lower BMD, at least in this sample of women. The results contribute to the evidence base for informing dietary recommendations for these trace elements with respect to their contributions to optimal bone health.

Multi-site phantomless bone mineral density from clinical quantitative computed tomography in males.

Volumetric bone mineral density (vBMD) is commonly assessed using QCT. Although standard vBMD calculation methods require phantom rods that may not be available, internal-reference phantomless (IPL) and direct measurements of Hounsfield units (HU) can be used to calculate vBMD in their absence. Yet, neither approach has been systemically assessed across skeletal sites, and HU need further validation as a vBMD proxy. This study evaluated the accuracy of phantomless methods, including IPL and regression-based phantomless (RPL) calibration using HU to calculate vBMD, compared to phantom-based (PB) methods. vBMD from QCT scans of 100 male post-mortem human subjects (PMHS) was calculated using site-specific PB calibration at multiple skeletal sites throughout the body. A development sample of 50/100 PMHS was used to determine site-specific reference material density for IPL calibration and RPL equations. Reference densities and equations from the development sample were used to calculate IPL and RPL vBMD on the remaining 50/100 PMHS for method validation. PB and IPL/RPL vBMD were not significantly different (p > .05). Univariate regressions between PB and IPL/RPL vBMD were universally significant (p < 0.05), except for IPL Rad-30 (p = 0.078), with a percent difference across all sites of 6.97% ± 5.95% and 5.22% ± 4.59% between PB and IPL/RPL vBMD, respectively. As vBMD increased, there were weaker relationships and larger differences between PB vBMD and IPL/RPL vBMD. IPL and RPL vBMD had strong relationships with PB vBMD across sites (R2 = 97.99, R2 = 99.17%, respectively), but larger residual differences were found for IPL vBMD. As the accuracy of IPL/RPL vBMD varied between sites, phantomless methods should be site-specific to provide values more comparable to PB vBMD. Overall, this study suggests that RPL calibration may better represent PB vBMD compared to IPL calibration, increases the utility of opportunistic QCT, and provides insight into bone quality and fracture risk.

Specific Uptake in the Bone Marrow Causes High Absorbed Red Marrow Doses During [177Lu]Lu-DOTATATE Treatment.

Bone marrow suppression is a common side effect after [177Lu]Lu-DOTATATE treatment of neuroendocrine neoplasms. Neuroendocrine neoplasms share expression of somatostatin receptor type 2 with CD34-positive hematopoietic progenitor cells, potentially leading to active uptake in the radiosensitive red marrow region where these cells are located. This study aimed to identify and quantify specific red marrow uptake using SPECT/CT images collected after the first treatment cycle. Methods: Seventeen patients diagnosed with neuroendocrine neoplasms were treated with [177Lu]Lu-DOTATATE. Seven of them had confirmed bone metastases. After the first treatment cycle, each patient went through 4 SPECT/CT imaging sessions 4, 24, 48, and 168 h after administration. Monte Carlo-based reconstructions were used to quantify activity concentrations in tumors and multiple skeletal sites presumed to house red marrow: the T9-L5 vertebrae and the ilium portion of the hip bones. The activity concentration from the descending aorta was used as input in a compartment model intended to establish a pure red marrow biodistribution by separating the nonspecific blood-based contribution from the specific activity concentration in red marrow. The biodistributions from the compartment model were used to perform red marrow dosimetry at each skeletal site. Results: Increased uptake of [177Lu]Lu-DOTATATE was observed in the T9-L5 vertebrae and hip bones in all 17 patients compared with activity concentrations in the aorta. The mean specific red marrow uptake was 49% (range, 0%-93%) higher than the nonspecific uptake. The median (±SD) total absorbed dose to the red marrow was 0.056 ± 0.023 Gy/GBq and 0.043 ± 0.022 Gy/GBq for the mean of all vertebrae and hip bones, respectively. The patients with bone metastases had an absorbed dose of 0.085 ± 0.046 Gy/GBq and 0.069 ± 0.033 Gy/GBq for the vertebrae and hip bones, respectively. The red marrow elimination phase was statistically slower in patients with fast tumor elimination, which is in line with transferrin transport of 177Lu back to the red marrow. Conclusion: Our results suggest that specific red marrow uptake of [177Lu]Lu-DOTATATE is in line with observations of somatostatin receptor type 2-expressing hematopoietic progenitor cells within the bone marrow. Blood-based dosimetry methods fail to account for the prolonged elimination of specific uptake and underestimate the absorbed dose to red marrow.

Decreased bone mass in adolescents with bone fragility fracture but not in young children: a case-control study.

The incidence of distal forearm fracture due to minimal/moderate trauma shows a bimodal distribution for age at event, with one peak occurring during early adolescence, in both boys and girls and the other one in postmenopausal females. The aim of this study was, therefore, to document whether the relationship between bone mineral density and fracture is different in young children compared with adolescents. A matched-pair, case-control study has been conducted to evaluate bone mineral density in 469 young children and 387 adolescents of both sexes, with/without fracture due to minimal/moderate trauma with assurance that the compared groups were equally susceptible to the outcome event. All fractures were radiographically confirmed. The study utilized bone mineral areal density of the total body, spine, hips, and forearm; volumetric bone mineral density of the forearm; and metacarpal radiogrammetry measurements. The study controlled for skeletal development, bone geometry, body composition, hand grip strength, calcium intake, and vitamin D status. Adolescents with distal forearm fracture have reduced bone mineral density at multiple skeletal regions of interest. This was documented by the bone mineral areal density measurements at multiple skeletal sites (p < 0.001), volumetric bone mineral density measurements of the forearm (p < 0.0001), and metacarpal radiogrammetry (p < 0.001). Adolescent females with fracture had reduced cross-sectional areas of the radius and metacarpals. The bone status of young female and male children with fracture was no different to its controls. Increased body fatness was more prevalent among fracture cases than in controls. Around 72% of young female and male children with fracture had serum 25-hydroxyvitamin D levels below the threshold of 31 ng/ml, compared with only 42% of female controls and to 51% of male controls. Adolescents with bone fragility fracture had reduced bone mineral density at multiple skeletal regions of interest, whereas this was not the case with younger children. The results of the study may have implications for the prevention of bone fragility in this segment of the pediatric population.

Opportunistic measures of bone mineral density at multiple skeletal sites during whole-body CT in polytrauma patients.

Whole-body CT (WBCT) in polytrauma patients enables the detection of numerous incidental findings, such as estimates of bone mineral density (BMD) at multiple skeletal sites. This could help in better understanding of age- and sex-related changes in BMD through skeleton. Data were retrospectively retrieved from the WBCTs requested during a 2-year period. BMD, expressed in CT Hounsfield units (HU), was measured at frontal and occipital bone, four vertebrae (C4, Th7, L4, and S2), iliac bone, and proximal humerus and femur. Measurements were done on native and postcontrast scans. The population sample was age-, sex-, and visceral fat volume adjusted for analysis. A total of 296 patients were included, with a median age of 51years. BMD varied from the highest HU in cranial bones (629 HU) to the lowest HU in the pelvic bones (114 HU), P < 0.001. Sex differences were independent predictors of BMD in cranial bones and proximal humerus. The age-related decline in BMD was significant in all other bones, but the association with age differed among the measurement's sites. Visceral fat showed the strongest correlation with the lumbar spine and iliac wing, although multivariate analysis revealed it was not an independent predictor of bone density, such as age and sex. BMD varies through skeleton, being the highest in the proximal axial skeleton. Age-related changes in BMD are significant and more pronounced than sex-related changes in almost all bones. Cranial bones do not follow the same pattern compared to other bones.

Association between serum uric acid level and bone mineral density at multiple skeletal sites in middle-aged and elderly men: a cross-sectional study of a healthy population in Taiwan.

Previous studies have reported an association between serum uric acid (sUA) levels and bone mineral density (BMD). However, their findings are controversial and limited to adult men in the general population. This study was aimed at examining the association between sUA levels and BMD at multiple skeletal sites in middle-aged and elderly men. A cross-sectional analysis of BMD at different skeletal sites and sUA levels was conducted on 918 men (age: 50.83 ± 7.95) using data from the Ditmanson Research Database. The participants were categorized into four groups based on quartiles of the sUA level, and BMD were assessed using dual-energy X-ray absorptiometry. Multivariate linear regression models were utilized to investigate the association between sUA levels and BMD. Further, subgroup analyses were performed. After adjusting for potential confounding factors, sUA as a continuous variable was significantly associated with BMD at the femoral neck only (β, 95% confidence interval: 0.007 [0.001-0.013]). However, in the categorical analysis, no significant differences were detected in terms of BMD at different skeletal sites across the different sUA quartile groups. Moreover, if the body mass index (BMI) was < 24kg/m2 for each unit increase in sUA level, the spine, femoral neck, and total hip BMD increased by 0.014, 0.013, and 0.015g/cm2, respectively. The sUA level was not associated with BMD at different skeletal sites in middle-aged and elderly men. Nevertheless, a positive association was only found between sUA levels and BMD at all skeletal sites in the normal weight group.

Cortical porosity occurs at varying degrees throughout the skeleton in rats with chronic kidney disease

Cortical porosity develops in chronic kidney disease (CKD) and increases with progressing disease. Cortical porosity is likely a prominent contributor to skeletal fragility/fracture. The degree to which cortical porosity occurs throughout the skeleton is not fully known. In this study, we assessed cortical bone porosity via micro-computed tomography at multiple skeletal sites in rats with progressive chronic kidney disease. We hypothesized that cortical porosity would occur in long bones throughout the body, but to a lesser degree in flat bones and irregular bones. Porosity was measured, using micro-CT, at 17 different skeletal sites in 6 male rats with CKD. Varying degrees of porosity were seen throughout the skeleton with higher porosity in flat and irregular bone (i.e. parietal bone, mandible) vs. long bones (p = 0.01) and in non-weightbearing bones vs. weightbearing bones (p = 0.01). Porosity was also higher in proximal sites vs. distal sites in long bones (p < 0.01 in all comparisons). There was large heterogeneity in porosity within skeletal sites across rats and within the same rat across skeletal sites. Correlations showed cortical porosity of the proximal tibia was positively associated with porosity at the other sites with the strongest correlation to the parietal bone and the weakest to the ulna. Overall, our data demonstrates varying and significant cortical bone porosity across the skeleton of animals with chronic kidney disease. These data point to careful selection of skeletal sites to assess porosity in pre-clinical studies and the potential for fractures at multiple skeletal sites in patients with CKD.

Compartment-specific effects of muscle strength on bone microarchitecture in women at high risk of osteoporosis.

BackgroundIt is well known that skeletal integrity is influenced by the musculature. Poor muscle strength (i.e. sarcopenia) is considered a major predictor of fragility fractures. While this observation appears particularly relevant for older women with increased risk of osteoporosis, there has been no comprehensive investigation to determine the influence of muscle performance on compartment‐specific bone microarchitecture in multiple body regions.MethodsWe retrospectively analysed data from different muscle performance and bone microarchitecture assessments in 230 women (aged 21 to 87 years) at high risk of osteoporosis. Muscle performance tests included grip strength and chair rising test (CRT) combined with mechanography. Balance was determined by Romberg posturography. Areal bone mineral density (BMD) was measured by dual‐energy X‐ray absorptiometry (DXA) at the hip and lumbar spine. Compartment‐specific volumetric BMD, microarchitecture, and geometry were assessed by second‐generation high‐resolution peripheral quantitative computed tomography (HR‐pQCT) at multiple skeletal sites (distal radius, tibia, and fibula). Regression models were applied to test for interactions between muscle and bone parameters. Subgroups were defined to compare women with osteoporosis and osteosarcopenia regarding BMD and microarchitecture.ResultsWhile osteoporosis was diagnosed in 115/230 (50.0%) women, sarcopenia was detected in 38/230 (16.5%). Positive associations of both grip strength and CRT maximum force with cortical geometric and microarchitectural parameters were detected at all measured sites, with the strongest effect applying to CRT maximum force and tibial parameters (e.g. tibial cortical area R 2 = 0.36, P < 0.0001, and tibial cortical thickness R 2 = 0.26, P < 0.0001). Balance parameters showed much weaker or no associations with HR‐pQCT parameters. Major associations between muscle strength and trabecular parameters could not be confirmed. Age and body mass index were confirmed as negative and positive predictors for several microarchitectural parameters, respectively. An independent predictive value of grip strength on radial, tibial, and fibular (all P < 0.01) cortical area and of CRT maximum relative force on cortical thickness (all P < 0.05) was revealed. Women with osteosarcopenia showed significantly reduced cortical HR‐pQCT parameters but no differences in DXA values compared with women with osteoporosis but no sarcopenia. Stratification by fracture and treatment status revealed that vertebral fractures and denosumab treatment altered the muscle–bone interaction.ConclusionsA systemic interaction between muscle strength and bone microarchitecture was demonstrated, and this interaction appears to be primarily with the cortical bone compartment. The value of muscle assessments in fracture risk evaluation may be partly mediated by their effects on bone microarchitecture.

Histologic Severity of Nonalcoholic Fatty Liver Disease Associates with Reduced Bone Mineral Density in Children.

Lower whole body bone mineral density (BMD) has been reported in children with nonalcoholic fatty liver disease (NAFLD), but potential mediators remain uncertain. To assess BMD at multiple skeletal sites in children with confirmed NAFLD and controls with obesity, adjusting for known determinants of BMD, and examine potential mediators. We assessed age-, sex-, and race-specific, and height-adjusted BMD z-scores of whole body, lumbar spine, hip, femoral neck and forearm by dual-energy-x-ray absorptiometry in 79 children, 8-19years old: 46 with biopsy-confirmed NAFLD [29 steatohepatitis (NASH)/17 fatty liver (NAFL)] and 33 controls without liver disease. We compared BMD z-scores by multivariable regression, adjusting for known BMD determinants and potential mediators (inflammatory and insulin resistance measures). Unadjusted mean BMD z-scores in NAFLD were similar to controls, but significantly lower in NASH vs. NAFL at all sites. After covariate adjustment, mean forearm BMD z-score was higher in NAFL (β 0.60 ± SE 0.30, p < 0.05) and lower in NASH (β -0.49 ± SE 0.26, p = 0.06) vs. controls (p = 0.002 for group), with similar trends at whole body and total hip; hs-CRP negatively associated with whole body and forearm BMD z-scores (p < 0.05), while visceral fat area negatively associated with femoral neck (p < 0.05). Only three children had clinically low whole body BMD z-scores (< -2), one per group (control, NAFL and NASH). NASH, but not NAFL, may be associated with increased risk of reduced BMD in children. Systemic inflammation, independent of body composition and load bearing, may mediate reduction in BMD in NASH.

Reference Ranges for Bone Mineral Content and Density by Dual Energy X-Ray Absorptiometry for Young Children.

Assessment of bone health in young children has been hampered by limited reference values for bone mineral content (BMC) and areal bone mineral density (aBMD) by dual energy X-ray absorptiometry (DXA). To identify age, sex, and population ancestry effects on BMC and aBMD and develop smoothed reference ranges for BMC and aBMD in young children. To quantify precision of bone measurements and influence of height-for-age Z-scores on bone Z-scores. We recruited 484 healthy children ages 1 to 2 years or 4.5 to 5 years at 2 clinical centers, who were seen once or up to 7 times over a 3-year period. Lumbar spine, distal forearm, and whole-body subtotal (ages ≥ 3 years) BMC and aBMD were measured by DXA. These data were combined with data from the Bone Mineral Density in Childhood Study from children ages 5 to 8.9 years to create the smoothed reference curves. For 1- to 5-year-olds, BMC and aBMD at all skeletal sites increased with age. Age trends differed by sex for BMC and aBMD of the spine, distal one-third radius, ultradistal radius, and by ancestry (Black vs non-Black) for all measures. BMC and aBMD precision (% coefficient of variation) ranged from 1.0% to 4.4%. Height Z-scores were positively associated with bone Z-scores and accounted for 4% to 45% of the variance. We demonstrate the feasibility of bone density measurements in young children and provide robust reference ranges and stature adjustments for calculation of bone Z-scores at multiple skeletal sites to enable bone health assessments.

Advanced ankylosing spondylitis: a multisite, multimodality densitometric analysis for investigation of bone loss in the axial and appendicular skeleton

The aim of this study was to investigate if there is a bias in bone mineral density measurements among major densitometric techniques across multiple skeletal sites. In 25 advanced ankylosing spondylitis patients, bone mineral density measurements were acquired in the lumbar spine, the hip, and the forearm. In total, 60% of patients had a bone mineral density Z-score of -2 or less at one or more skeletal sites. Dedicated loss of cortical bone was identified at the distal forearm (60% of patients). Differences in bone mineral density measurements across all densitometric techniques were highly significant (p≤0.001). Bone loss was more striking in spinal trabecular bone by three-dimensional quantitative computed tomography [Z-score -2.1] versus dual-energy X-ray absorptiometry [Z-score 0]. A trabecular bone loss quantified by quantitative computed tomography was about twice as much as a cortical bone loss by single-energy X-ray absorptiometry (p=0.001). Low bone mineral density is prevalent in advanced ankylosing spondylitis patients, predominating in the spine. Bone mineral density measurements have systematic differences when compared to each other. Knowledge of these offsets is useful for improved diagnosis of regional bone loss that allows for targeted treatment of osteoporosis. Three-dimensional quantitative computed tomography is more suitable for evaluating spinal osteoporosis in advanced ankylosing spondylitis than dual-energy X-ray absorptiometry, which rather underestimates bone loss.

Serum Uric Acid Level Is Positively Associated With Higher Bone Mineral Density at Multiple Skeletal Sites Among Healthy Qataris.

BackgroundOxidative stress has been implicated as a fundamental mechanism in the decline of bone mass. Although serum uric acid (SUA) has potent antioxidant properties, the findings of many epidemiological and experimental studies couldn’t draw a clear conclusion on the relation between SUA and bone health. We aim to investigate the association between SUA and bone mineral density (BMD) at different skeletal sites among healthy Qataris.MethodologyA cross-sectional analysis including total-body and site-specific bone mineral density scores and other serological markers of 2981 healthy Qatari adults (36.4 ± 11.1 years) from the Qatar biobank database was conducted. The study participants were divided into quartiles based on the level of SUA, and the BMD was measured using dual-energy X-ray absorptiometry (DXA). Multiple regression analyses were applied to investigate the association between SUA and BMD adjusting for multiple confounding factors.ResultsHigh levels of SUA were significantly associated with the increased bone mineral density of the total body and at site-specific skeletal locations after adjusting for age and gender (p-value < 0.001). Further adjustment for body mass index (BMI), smoking, vitamin D, alkaline phosphatase, and estimated glomerular filtration rate (eGFR) levels attenuated the association but the association remained significant for individuals with high SUA levels (p-value ≤ 0.01).The association between SUA and BMD was not significant in non-obese, females, young adults, and smokers. However, no interaction was found between SUA and age, gender, BMI and smoking.ConclusionHigher SUA levels are associated with a high bone density among healthy Qatari adults. However, such observation demands further investigations to outline the underlying mechanisms.

Abstract 1737: Nanotherapeutic targeting of drug resistant multiple myeloma cells through VLA4-contact facilitated drug-delivery of camptothecin prodrug

Abstract Multiple Myeloma (MM) is a recurring-relapsing plasma cell malignancy, which invariably develops drug resistance. Acquired resistance often involves mutation of drug targets or activation of compensatory pathways, making new targets in high demand. Physical contact of MM cells (MMC) with the bone microenvironment further protects MMC, via cell adhesion mediated-drug resistance (CAM-DR). Integrin α4β1 (Very Late Antigen 4; VLA4), mediates adhesion of MMC both to fibronectin in the matrix and to stromal cells expressing VCAM1, providing survival signals and protection from cell death upon drug treatment.Aiming to treat resistant cells, we proposed to utilize nanotechnology to safely deliver a drug whose target would not be lost in refractory MMC and to exploit, rather than bypassing, CAM-DR by introducing selective pressure for VLA4 overexpression then targeting it with drug-carrying nanoparticles (VLA4-NP). In particular, we hypothesized that, in combination treatments, VLA4-NP carrying a camptothecin prodrug (CPT-PD) would target drug-resistant MMC, reducing tumor burden and prolonging survival. Camptothecin (CPT) is a potent but poorly bioavailable topoisomerase 1 (TOP1) inhibitor. In vitro, CPT reduced proliferation and induced apoptosis in a panel of MM cell lines, including sub-lines resistant to other agents. RNAseq showed that MM cells from patients with relapsing or refractory MM had high levels of TOP1 expression. We modified CPT into an inactive lipase-sensitive prodrug (CPT-PD) that stabilizes the compound in micellar nanoparticles until enzymatically liberated in the MM cytosol (VLA4-CPT-PD-NP, 20 nm). In vitro and in vivo fluorescence tracking experiments showed that VLA4-NP binding increased in drug-resistant MM cells with minimal off-target delivery. In vitro, VLA4-CPT-PD-NP reduced MM cell proliferation and enhanced the effects of free drugs (melphalan, dexamethasone, lenalidomide). When MMC were co-cultured with primary bone marrow stroma from MM donors, MMC adhering to stroma survived free drug treatment, while VLA4-CPT-PD-NP had strong toxic effects on the myeloma cells and spared the stroma. In the KaLwRij/5TGM1 mouse model, melphalan resistant MMC are adherent to the bone. In these mice, uptake of fluorescently labeled VLA4-NP by MMC increased after melphalan treatment, while co-treatment with VLA4-CPT-PD-NP and free melphalan reduced tumor burden at multiple skeletal sites (p&amp;lt;0.01) and the M-protein levels by SPEP (p&amp;lt;0.01) relative to melphalan alone. Further, treatment with VLA4-CPT-PD and melphalan prolonged survival even after drug withdrawal (p&amp;lt;0.001), without added toxicity to the kidneys, liver or gut. This work provides proof of principle that CAM-DR can be exploited to safely deliver chemortherapeutics to resistant cells and effectively enhance treatment in myeloma. Citation Format: Francesca Fontana, Michael J. Scott, John S. Allen, Grace Cui, Xiaoxia Yang, Julie O'Neal, Steven Fletcher, Noriko Yanaba, Anne H. Schmieder, Michael P. Rettig, Julie Ritchey, Mark A. Fiala, Ravi Vij, Gregory M. Lanza. Nanotherapeutic targeting of drug resistant multiple myeloma cells through VLA4-contact facilitated drug-delivery of camptothecin prodrug [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1737.

Metachronous Osteosarcoma: A Rare Case Report

Introduction: Osteosarcoma is a common primary sarcoma of the bone, constituting approximately 0.07% of all neoplasms. Rarely, some patients with osteosarcoma have multiple skeletal sites involvement, either synchronous or metachronous. Metachronous osteosarcoma is a rare form of osteosarcoma in which osteosarcomatous lesions occur distant from the primary osteosarcoma site more than 6 months after the initial treatment without pulmonary manifestation. Case Report: We present a case of metachronous osteosarcoma in a 16-year-old female who was initially treated for non-metastatic osteosarcoma of the left distal femur with neoadjuvant chemotherapy, wide excision, endoprosthesis and followed by adjuvant chemotherapy. Serial follow-up did not show evidence of distant metastasis. Nevertheless, she presented 3 years later with a progressively enlarging left proximal forearm mass and re-staging revealed an osteosarcoma of the same histological type. She underwent combination of chemo- and radio- therapy but subsequently succumbed to the disease due to lung metastasis. Conclusion: With the advent of diagnostic and therapeutic techniques, the 5-year survival rate of nonmetastatic osteosarcoma ranges around 60-70%. Albeit it is rare, a metachronous osteosarcoma can present difficult challenges to the treating physician.

Genetic variants affecting bone mineral density and bone mineral content at multiple skeletal sites in Hispanic children.

Osteoporosis is a major public health burden with significant economic costs. However, the correlates of bone health in Hispanic children are understudied. We aimed to identify genetic variants associated with bone mineral density (BMD) and bone mineral content (BMC) at multiple skeletal sites in Hispanic children. We conducted a cross-sectional genome-wide linkage analysis, genome-wide and exome-wide association analysis of BMD and BMC. The Viva La Familia Study is a family-based cohort with a total of 1030 Hispanic children (4-19years old at baseline) conducted in Houston, TX. BMD and BMC were measured by Dual-energy X-ray absorptiometry. Significant heritability were observed for BMC and BMD at multiple skeletal sites ranging between 44 and 68% (P<2.8×10-9). Significant evidence for linkage was found for BMD of pelvis and left leg on chromosome 7p14, lumbar spine on 20q13 and left rib on 6p21, and BMC of pelvis on chromosome 20q12 and total body on 14q22-23 (logarithm of odds score>3). We found genome-wide significant association between BMC of right arm and rs762920 at PVALB (P=4.6×10-8), and between pelvis BMD and rs7000615 at PTK2B (P=7.4×10-8). Exome-wide association analysis revealed novel association of variants at MEGF10 and ABRAXAS2 with left arm and lumber spine BMC, respectively (P<9×10-7). We identified novel loci associated with BMC and BMD in Hispanic children, with strongest evidence for PTK2B. These findings provide better understanding of bone genetics and shed light on biological mechanisms underlying BMD and BMC variation.

Reproducibility and Radiation Effect of High-Resolution In Vivo Micro Computed Tomography Imaging of the Mouse Lumbar Vertebra and Long Bone.

A moderate radiation dose, in vivo µCT scanning protocol was developed and validated for long-term monitoring of multiple skeletal sites (femur, tibia, vertebra) in mice. A customized, 3D printed mouse holder was designed and utilized to minimize error associated with animal repositioning, resulting in good to excellent reproducibility in most cortical and trabecular bone microarchitecture and density parameters except for connectivity density. Repeated in vivo µCT scans of mice were performed at the right distal femur and the 4th lumbar vertebra every 3weeks until euthanized at 9weeks after the baseline scan. Comparing to the non-radiated counterparts, no radiation effect was found on trabecular bone volume fraction, osteoblast and osteoblast number/surface, or bone formation rate at any skeletal site. However, trabecular number, thickness, and separation, and structure model index were sensitive to ionizing radiation associated with the µCT scans, resulting in subtle but significant changes over multiple scans. Although the extent of radiation damage on most trabecular bone microarchitecture measures are comparable or far less than the age-related changes during the monitoring period, additional considerations need to be taken to minimize the confounding radiation factors when designing experiments using in vivo µCT imaging for long-term monitoring of mouse bone.

Letter to the Editor.

Letter to the Editor.

Bone measurements at multiple skeletal sites in adolescent idiopathic scoliosis-an in vivo correlation study using DXA, HR-pQCT and QCT.

Low bone mass is an important feature of adolescent idiopathic scoliosis (AIS), which is a complex 3D spinal deformity that affects girls during puberty. However, no clinical imaging modality is suitable for regular monitoring on their spinal bone qualities in rapid growth period. Therefore, we investigated whether bone mineral density (BMD) and bone microstructure at non-spinal sites correlated with BMD and mechanical property in the spine in AIS patients. Thirty-two AIS girls (16.7 ± 3.5years old with mean Cobb angle of 67 ± 11°) who underwent pre-operative spine CT examination for navigation surgery were recruited. Volumetric BMD (vBMD) of lumbar spine (LS) was measured by quantitative computed tomography (QCT), vBMD and bone microstructure of distal radius (DR) by high-resolution peripheral QCT (HR-pQCT) and areal BMDs of total hip (TH) and femoral necks (FN) by dual-energy X-ray absorptiometry (DXA). Biomechanical properties of the DR and LS were estimated by finite element analysis (FEA). Pearson correlation was performed to study the correlation between bone parameters at these three sites. LS vBMD correlated significantly with both FN and TH aBMD (R = 0.663-0.725, both p< 0.01) and with DR microstructural parameters (R = 0.380-0.576, all p < 0.05). Mechanical properties of LS and DR were also correlated (R = 0.398, p= 0.039). Bone measurement at proximal femur and distal radius could provide an additional predictive power in estimating the bone changes at spine, which is the primary site of deformity in AIS patients. Our result indicated that DXA and HR-pQCT could provide a valid surrogate for spine bone measurements in AIS patients.

NOTUM inhibition increases endocortical bone formation and bone strength

The disability, mortality and costs caused by non-vertebral osteoporotic fractures are enormous. Existing osteoporosis therapies are highly effective at reducing vertebral but not non-vertebral fractures. Cortical bone is a major determinant of non-vertebral bone strength. To identify novel osteoporosis drug targets, we phenotyped cortical bone of 3 366 viable mouse strains with global knockouts of druggable genes. Cortical bone thickness was substantially elevated in Notum−/− mice. NOTUM is a secreted WNT lipase and we observed high NOTUM expression in cortical bone and osteoblasts but not osteoclasts. Three orally active small molecules and a neutralizing antibody inhibiting NOTUM lipase activity were developed. They increased cortical bone thickness and strength at multiple skeletal sites in both gonadal intact and ovariectomized rodents by stimulating endocortical bone formation. Thus, inhibition of NOTUM activity is a potential novel anabolic therapy for strengthening cortical bone and preventing non-vertebral fractures.

The presence of large focal lesions is a strong independent prognostic factor in multiple myeloma

AbstractSpatial intratumor heterogeneity is frequently seen in multiple myeloma (MM) and poses a significant challenge for risk classifiers, which rely on tumor samples from the iliac crest. Because biopsy-based assessment of multiple skeletal sites is difficult, alternative strategies for risk stratification are required. Recently, the size of focal lesions (FLs) was shown to be a surrogate marker for spatial heterogeneity, suggesting that data from medical imaging could be used to improve risk stratification approaches. Here, we investigated the prognostic value of FL size in 404 transplant-eligible, newly diagnosed MM patients. Using diffusion-weighted magnetic resonance imaging with background suppression, we identified the presence of multiple large FLs as a strong prognostic factor. Patients with at least 3 large FLs with a product of the perpendicular diameters >5 cm2 were associated with poor progression-free survival (PFS) and overall survival (OS; median, 2.3 and 3.6 years, respectively). This pattern, seen in 13.8% of patients, was independent of the Revised International Staging System (RISS), gene expression profiling (GEP)–based risk score, gain(1q), or extramedullary disease (hazard ratio, 2.7 and 2.2 for PFS and OS in multivariate analysis, respectively). The number of FLs lost its negative impact on outcome after adjusting for FL size. In conclusion, the presence of at least 3 large FL is a feature of high risk, which can be used to refine the diagnosis of this type of disease behavior and as an entry criterion for risk-stratified trials.