Bone marrow composition, diabetes, and fracture risk: More bad news for saturated fat

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99083/1/jbmr2013.pd

Variation in Estradiol Level Affects Cortical Bone Growth in Response to Mechanical Loading in Sheep

Although mechanical loading can stimulate cortical bone growth, little is known about how individual physiology affects this response. This study demonstrates that in vivo variation in estradiol (E2) level alters osteoblast sensitivity to exercise-induced strains, affecting cortical bone responses to mechanical loading. Subadult sheep were divided into treatment groups that varied in terms of circulating E2 levels and loading (exercised and sedentary). After 45 days, periosteal cortical bone growth rates and cross-sectional properties were measured at the midshafts of hindlimb bones and compared with strain data. The results indicate significant interactions between E2 and strain. Cortical bone growth in exercised animals with elevated E2 levels was 27% greater in the femur, 6% greater in the tibia, and 14% greater in the metatarsal than in exercised animals with lower E2 levels, or sedentary animals regardless of E2 dose (P<0.05). There was also a trend toward greater resistance to deformation in the tibia, but not the metatarsal, in the exercised, high-E2 group compared to the other treatment groups. These results demonstrate that E2 plays a role in mediating skeletal responses to strain, such that physiological variation in E2 levels among individuals may lead to differential growth responses to similar mechanical loading regimes. Efforts to model the relationship between environmental strain and bone morphology should include the effects of physiological variation in hormone levels.Anthropolog

Trabecular Bone Orientation in Flexed Versus Extended Postures in Guinea Fowl: A Test of Wolff’s Law

Although bipedal locomotion is a hominin synapomorphy, disagreements persist about whether early hominin bipeds were capable of fully extended limb posture, or used a bent-knee, bent-hip gait. Several recent studies have used the orientation of trabecular bone in limb joints to infer posteral differences during bipedal locomotion between early bipeds and later Homo. There analyses depend on the assumption that the orientation of the trabeculae in joint corresponds to the orientation of compressive forces that are transmitted through the joints. However, the hypothesis that trabecular struts will differ in orientation because of differences in the orientation of loads they experience during growth have not been tested. This study experimentally tests the hypothesis that there is a quantifiable relationship between the orientations of trabeculae and joint posture. The experiment included 16 guinea fowl (Numida melegris): 6 extended-posture runners, 6 flexed-posture runners, and 4 sedentary controls. The exercised animals ran 6 days per week at 1.9 mph for 15 minutes, on either a flat treadmill or a treadmill inclined to 20°. Kinematic and ground reaction force data collected as the birds moved on horizontal and inclined substrates confirm that the degree of flexion at the knee at toe-off is 10° greater when moving up inclines relative to level running. Micro-CT scans were analyzed using image analysis software to relate this difference to trabecular and subchondral bone morphology within the distal femoral epiphysis, including subchondral bone thickness, and trabecular orientation, number, thickness, volume, and connectivity.AnthropologyHuman Evolutionary Biolog

Trabecular Bone in the Bird Knee Responds with High Sensitivity to Changes in Load Orientation

Wolff’s law of trajectorial orientation proposes that trabecular struts align with the orientation of dominant compressive loads within a joint. Although widely considered in skeletal biology, Wolff’s law has never been experimentally tested while controlling for ontogenetic stage, activity level, and species differences, all factors that may affect trabecular bone growth. Here we report an experimental test of Wolff’s law using a within-species design in age-matched subjects experiencing physiologically normal levels of bone strain. Two age-matched groups of juvenile guinea fowl Numida meleagris ran on a treadmill set at either 0° (Level group) or 20° (Incline group), for 10·min per day over a 45-day treatment period. Birds running on the 20° inclined treadmill used more-flexed knees than those in the Level group at midstance (the point of peak ground reaction force). This difference in joint posture enabled us to test the sensitivity of trabecular alignment to altered load orientation in the knee. Using a new radon transform-based method for measuring trabecular orientation, our analysis shows that the fine trabecular bone in the distal femur has a high degree of correspondence between changes in joint angle and trabecular orientation. The sensitivity of this response supports the prediction that trabecular bone adapts dynamically to the orientation of peak compressive forces.Anthropolog

Validation of an enzyme- linked immunoassay assay for osteocalcin, a marker of bone formation, in dried blood spots

ObjectivesInvestigating factors that contribute to bone loss and accretion across populations in remote settings is challenging, particularly where diagnostic tools are scarce. To mitigate this challenge, we describe validation of a commercial ELISA assay to measure osteocalcin, a biomarker of bone formation, from dried blood spots (DBS).MethodsWe validated the Osteocalcin Human SimpleStep ELISA kit from Abcam (ab1951214) using 158 matched plasma and DBS samples. Passing- Bablok regression analysis assessed the relationships between plasma and DBS osteocalcin concentrations. Dilutional linearity and spike and recovery experiments determined if the DBS matrix interfered with osteocalcin measurement, and intra- and inter- assay coefficients of variation (CVs) were calculated. Limit of detection, analyte stability, and specific forms of osteocalcin measured by the kit were also investigated.ResultsMean plasma osteocalcin value was 218.2 ng/mL (range 64.6- 618.1 ng/mL). Linear relationships existed between plasma and DBS concentrations of osteocalcin, with no apparent bias in plasma vs DBS concentrations. There was no apparent interference of the DBS matrix with measurement of osteocalcin in DBS. Intra- assay CV for DBS was ~8%, while average inter- assay CV was 14.8%. Limit of detection was 0.34- ng/mL. Osteocalcin concentrations were stable in DBS stored at - 28°C and room temperature, but not those stored at 37°C. This ELISA kit detects total osteocalcin.ConclusionsOsteocalcin, a bone formation biomarker, can be measured from DBS. Combined with a previously validated DBS assay for TRACP- 5b, a bone resorption biomarker, these assays have the potential to help researchers disentangle the many factors contributing to bone strength.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162811/2/ajhb23394.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162811/1/ajhb23394_am.pd

Adults with Cerebral Palsy have Higher Prevalence of Fracture Compared with Adults Without Cerebral Palsy Independent of Osteoporosis and Cardiometabolic Diseases

Individuals with cerebral palsy (CP) have an increased risk of fracture throughout their lifespan based on an underdeveloped musculoskeletal system, excess body fat, diminished mechanical loading, and early development of noncommunicable diseases. However, the epidemiology of fracture among adults with CP is unknown. The purpose of this cross‐sectional study was to determine the prevalence of fracture among a large sample of privately insured adults with CP, as compared with adults without CP. Data were from the Optum Clinformatics Data Mart (Eden Prairie, MN, USA), a deidentified nationwide claims database of beneficiaries from a single private payer. Diagnostic codes were used to identify 18‐ to 64‐year‐old beneficiaries with and without CP and any fracture that consisted of osteoporotic pathological fracture as well as any type of fracture of the head/neck, thoracic, lumbar/pelvic, upper extremity, and lower extremity regions. The prevalence of any fracture was compared between adults with (n = 5,555) and without (n = 5.5 million) CP. Multivariable logistic regression was performed with all‐cause fracture as the outcome and CP group as the primary exposure. Adults with CP had a higher prevalence of all‐cause fracture (6.3% and 2.7%, respectively) and fracture of the head/neck, thoracic, lumbar/pelvic, upper extremity, and lower extremity regions compared with adults without CP (all p < 0.01). After adjusting for sociodemographic and socioeconomic variables, adults with CP had higher odds of all‐cause fracture compared with adults without CP (OR 2.5; 95% CI, 2.2 to 2.7). After further adjusting for cardiometabolic diseases, adults with CP had higher odds of all‐cause fracture compared with adults without CP (OR 2.2; 95% CI, 2.0 to 2.5). After further adjusting for osteoporosis, adults with CP still had higher odds of all‐cause fracture compared with adults without CP (OR 2.0; 95% CI, 1.8 to 2.2). These findings suggest that young and middle‐aged adults with CP have an elevated prevalence of all‐cause fracture compared with adults without CP, which was present even after accounting for cardiometabolic diseases and osteoporosis. © 2019 American Society for Bone and Mineral Research.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150537/1/jbmr3694_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150537/2/jbmr3694.pd

Test–Retest Reliability and Correlates of Vertebral Bone Marrow Lipid Composition by Lipidomics Among Children With Varying Degrees of Bone Fragility

The reliability of lipidomics, an approach to identify the presence and interactions of lipids, to analyze the bone marrow lipid composition among pediatric populations with bone fragility is unknown. The objective of this study was to assess the test–retest reliability, standard error of measurement (SEM), and the minimal detectable change (MDC) of vertebral bone marrow lipid composition determined by targeted lipidomics among children with varying degrees of bone fragility undergoing routine orthopedic surgery. Children aged 10 to 19 years, with a confirmed diagnosis of adolescent idiopathic scoliosis (n = 13) or neuromuscular scoliosis and cerebral palsy (n = 3), undergoing posterior spinal fusion surgery at our institution were included in this study. Transpedicular vertebral body bone marrow samples were taken from thoracic vertebrae (T11, 12) or lumbar vertebrae (L1 to L4). Lipid composition was assessed via targeted lipidomics and all samples were analyzed in the same batch. Lipid composition measures were examined as the saturated, monounsaturated, and polyunsaturated index and as individual fatty acids. Relative and absolute test–retest reliability was assessed using the intraclass correlation coefficient (ICC), SEM, and MDC. Associations between demographics and index measures were explored. The ICC, SEM, and MDC were 0.81 (95% CI, 0.55–0.93), 1.6%, and 4.3%, respectively, for the saturated index, 0.66 (95% CI, 0.25–0.87), 3.5%, and 9.7%, respectively, for the monounsaturated index, and 0.60 (95% CI, 0.17–0.84), 3.6%, and 9.9%, respectively, for the polyunsaturated index. For the individual fatty acids, the ICC showed a considerable range from 0.04 (22:2n‐6) to 0.97 (18:3n‐3). Age was positively correlated with the saturated index (r2 = 0.36; p = 0.014) and negatively correlated with the polyunsaturated index (r2 = 0.26; p = 0.043); there was no difference in index measures by sex (p > 0.58). The test–retest reliability was moderate‐to‐good for index measures and poor to excellent for individual fatty acids; this information can be used to power research studies and identify measures for clinical or research monitoring. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163414/2/jbm410400_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163414/1/jbm410400.pd

Estimating EQ-5D utilities based on the Short-Form Long Term Conditions Questionnaire (LTCQ-8)

Purpose: The aim of this work was to develop a mapping algorithm for estimating EuroQoL 5 Dimension (EQ-5D) utilities from responses to the Long-Term Conditions Questionnaire (LTCQ), thus increasing LTCQ’s potential as a comprehensive outcome measure for evaluating integrated care initiatives. Methods: We combined data from three studies to give a total sample of 1334 responses. In each of the three datasets, we randomly selected 75% of the sample and combined the selected random samples to generate the estimation dataset, which consisted of 1001 patients. The unselected 25% observations from each dataset were combined to generate an internal validation dataset of 333 patients. We used direct mapping models by regressing responses to the LTCQ-8 directly onto EQ-5D-5L and EQ-5D-3L utilities as well as response (or indirect) mapping to predict the response level that patients selected for each of the five EQ-5D-5L domains. Several models were proposed and compared on mean squared error and mean absolute error. Results: A two-part model with OLS was the best performing based on the mean squared error (0.038) and mean absolute error (0.147) when estimating the EQ-5D-5L utilities. A multinomial response mapping model using LTCQ-8 responses was used to predict EQ-5D-5L responses levels. Conclusions: This study provides a mapping algorithm for estimating EQ-5D utilities from LTCQ responses. The results from this study can help broaden the applicability of the LTCQ by producing utility values for use in economic analyses

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population

The “Skinny” on brown fat, obesity, and bone

The discovery that metabolically active brown fat is present in humans throughout ontogeny raises new questions about the interactions between thermoregulatory, metabolic, and skeletal homeostasis. Brown adipose tissue (BAT) is distinct from white adipose tissue (WAT) for its ability to burn, rather than store, energy. BAT uniquely expresses uncoupling protein‐1 (abbreviated as UCP1), which diverts the energy produced by cellular respiration to generate heat. While BAT is found in small mammals, hibernators, and newborns, this depot was thought to regress in humans during early postnatal life. Recent studies revealed that human BAT remains metabolically active throughout childhood and even in adulthood, particularly in response to cold exposure. In addition to the constitutive BAT depots present at birth, BAT cells can be induced within WAT depots under specific metabolic and climatic conditions. These cells, called inducible brown fat, “brite,” or beige fat, are currently the focus of intense investigation as a possible treatment for obesity. Inducible brown fat is associated with higher bone mineral density, suggesting that brown fat interacts with bone growth in previously unrecognized ways. Finally, BAT may have contributed to climatic adaptation in hominins. Here, I review current findings on the role of BAT in thermoregulation, bone growth, and metabolism, describe the potential role of BAT in moderating the obesity epidemic, and outline possible functions of BAT across hominin evolutionary history. Yrbk Phys Anthropol 156:98–115, 2015. © 2014 American Association of Physical AnthropologistsPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110636/1/ajpa22661.pd