Browsing by Subject "Bone strength"
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Item 6820 Assessing The Efficacy And Safety Of Setrusumab For Osteogenesis Imperfecta: Updated Phase 2 Data From The Phase 2/3 Orbit Study(Oxford University Press, 2024-10-05) Gottesman, G. S.; Carpenter, T. O.; Wallace, M.; Smith, P.; Imel, E. A.; Wang, H.; Byers, H. M.; Krolczyk, S.; Lewiecki, E. M.; Medicine, School of MedicineOsteogenesis imperfecta (OI) is a rare genetic disorder characterized by bone fragility and low bone mass with no universally accepted treatment. Setrusumab is a fully human anti-sclerostin monoclonal antibody that improved bone mineral density (BMD), bone strength, and bone turnover markers in adults with OI (ASTEROID; NCT03118570). In the ongoing Phase 2/3 Orbit study (NCT05125809), Phase 2 evaluated the efficacy and safety of setrusumab in pediatric and young-adult cohorts with OI based on PK/PD, safety, and BMD data, to determine the dosing strategy for the Phase 3 portion. Subjects with OI Types I, III, or IV, ages 5 to <26 years, were randomized 1:1 to receive 20 or 40 mg/kg setrusumab intravenously monthly. Six-month data as of August 2023 are presented. Twenty-four subjects (50% female, 75% <18 years of age) with OI Type I (n=17/24, 71%) or III/IV (n=7/24, 29%) were enrolled and randomized to receive 20 mg/kg (n=14/24) or 40 mg/kg (n=10/24) of setrusumab. The mean (SD) baseline-corrected area under the effect curve (AUEC) for serum P1NP in the 20 mg/kg setrusumab group was 4153 (4407) µg/(L*day) over month one of treatment, and 5256 (5521) µg/(L*day) in the 40 mg/kg group. Mean (SE) change from baseline in lumbar spine BMD in the 20 mg/kg group was 9.1% (1.8%) and 12.8% (2.5%) at M3 and M6, respectively (all p<0.05 vs baseline) and 9.3% (2.4%) and 16.1% (3.9%) in the 40 mg/kg group (M6 p<0.05 vs baseline). Mean (SE) baseline BMD Z-score in the 20 mg/kg group of 2.1 (0.8) improved by 0.6 (0.8) at M3 and 0.9 (0.8) at M6, and improved from 1.1 (0.4) at baseline by 0.5 (0.4) and 0.9 (0.4) at M3 and M6, respectively, in the 40 mg/kg group (all p<0.05 vs baseline). The median annualized fracture rate (excluding fingers, toes, face, and skull) was reduced significantly from 0.7 to 0 (p=0.042) after setrusumab initiation (calculated reduction of 67%). No new radiographically confirmed fractures excluding fingers, toes, face, and skull were reported in 20/24 (83%) subjects after starting setrusumab, while only 4/24 (17%) reported fractures (precipitating events: one subject: slipped on ice, stubbed toe, one subject each: fell off of tricycle, bending over in bed, tripped and fell). Setrusumab treatment resulted in no unexpected adverse events. Treatment-related adverse events included infusion-related reaction (7/24, 29%), headache (3/24, 13%) infusion site pain, bone pain, and upper respiratory tract infection (each 1/24, 4%). In Orbit Phase 2, we observed significant improvements from baseline in lumbar spine BMD at M3 and M6 at both 20 and 40 mg/kg doses, with no marked differences between dose groups. Fracture rates significantly decreased with setrusumab initiation, with 83% of subjects reporting no new fractures.Item Am I big boned? Bone length scaled reference data for HRpQCT measures of the radial and tibial diaphysis in White adults(Elsevier, 2024-01-06) Warden, Stuart J.; Fuchs, Robyn K.; Liu, Ziyue; Toloday, Katelynn R.; Surowiec, Rachel; Moe, Sharon M.; Physical Therapy, School of Health and Human SciencesCross-sectional size of a long bone shaft influences its mechanical properties. We recently used high-resolution peripheral quantitative computed tomography (HRpQCT) to create reference data for size measures of the radial and tibial diaphyses. However, data did not take into account the impact of bone length. Human bone exhibits relatively isometric allometry whereby cross-sectional area increases proportionally with bone length. The consequence is that taller than average individuals will generally have larger z-scores for bone size outcomes when length is not considered. The goal of the current work was to develop a means of determining whether an individual's cross-sectional bone size is suitable for their bone length. HRpQCT scans performed at 30 % of bone length proximal from the distal end of the radius and tibia were acquired from 1034 White females (age = 18.0 to 85.3 y) and 392 White males (age = 18.4 to 83.6 y). Positive relationships were confirmed between bone length and cross-sectional areas and estimated mechanical properties. Scaling factors were calculated and used to scale HRpQCT outcomes to bone length. Centile curves were generated for both raw and bone length scaled HRpQCT data using the LMS approach. Excel-based calculators are provided to facilitate calculation of z-scores for both raw and bone length scaled HRpQCT outcomes. The raw z-scores indicate the magnitude that an individual's HRpQCT outcomes differ relative to expected sex- and age-specific values, with the scaled z-scores also considering bone length. The latter enables it to be determined whether an individual or population of interest has normal sized bones for their length, which may have implications for injury risk. In addition to providing a means of expressing HRpQCT bone size outcomes relative to bone length, the current study also provides centile curves for outcomes previously without reference data, including tissue mineral density and moments of inertia.Item Differential changes in bone strength of two inbred mouse strains following administration of a sclerostin-neutralizing antibody during growth(PLOS, 2019-04-04) Mathis, Noah J.; Adaniya, Emily N.; Smith, Lauren M.; Robling, Alexander G.; Jepsen, Karl J.; Schlecht, Stephen H.; Anatomy and Cell Biology, IU School of MedicineAdministration of sclerostin-neutralizing antibody (Scl-Ab) treatment has been shown to elicit an anabolic bone response in growing and adult mice. Prior work characterized the response of individual mouse strains but did not establish whether the impact of Scl-Ab on whole bone strength would vary across different inbred mouse strains. Herein, we tested the hypothesis that two inbred mouse strains (A/J and C57BL/6J (B6)) will show different whole bone strength outcomes following sclerostin-neutralizing antibody (Scl-Ab) treatment during growth (4.5-8.5 weeks of age). Treated B6 femurs showed a significantly greater stiffness (S) (68.8% vs. 46.0%) and maximum load (ML) (84.7% vs. 44.8%) compared to A/J. Although treated A/J and B6 femurs showed greater cortical area (Ct.Ar) similarly relative to their controls (37.7% in A/J and 41.1% in B6), the location of new bone deposition responsible for the greater mass differed between strains and may explain the greater whole bone strength observed in treated B6 mice. A/J femurs showed periosteal expansion and endocortical infilling, while B6 femurs showed periosteal expansion. Post-yield displacement (PYD) was smaller in treated A/J femurs (-61.2%, p < 0.001) resulting in greater brittleness compared to controls; an effect not present in B6 mice. Inter-strain differences in S, ML, and PYD led to divergent changes in work-to-fracture (Work). Work was 27.2% (p = 0.366) lower in treated A/J mice and 66.2% (p < 0.001) greater in treated B6 mice relative to controls. Our data confirmed the anabolic response to Scl-Ab shown by others, and provided evidence suggesting the mechanical benefits of Scl-Ab administration may be modulated by genetic background, with intrinsic growth patterns of these mice guiding the location of new bone deposition. Whether these differential outcomes will persist in adult and elderly mice remains to be determined.Item Fine mapping of bone structure and strength QTLs in heterogeneous stock rat(Elsevier, 2015-12) Alam, Imranul; Koller, Daniel L.; Cañete, Toni; Blázquez, Gloria; Mont-Cardona, Carme; López-Aumatell, Regina; Martínez-Membrives, Esther; Díaz-Morán, Sira; Tobeña, Adolf; Fernández-Teruel, Alberto; Stridh, Pernilla; Diez, Margarita; Olsson, Tomas; Johannesson, Martina; Baud, Amelie; Econs, Michael J.; Foroud, Tatiana; Department of Medicine, IU School of MedicineWe previously demonstrated that skeletal structure and strength phenotypes vary considerably in heterogeneous stock (HS) rats. These phenotypes were found to be strongly heritable, suggesting that the HS rat model represents a unique genetic resource for dissecting the complex genetic etiology underlying bone fragility. The purpose of this study was to identify and localize genes associated with bone structure and strength phenotypes using 1524 adult male and female HS rats between 17 to 20 weeks of age. Structure measures included femur length, neck width, head width; femur and lumbar spine (L3-5) areas obtained by DXA; and cross-sectional areas (CSA) at the midshaft, distal femur and femoral neck, and the 5th lumbar vertebra measured by CT. In addition, measures of strength of the whole femur and femoral neck were obtained. Approximately 70,000 polymorphic SNPs distributed throughout the rat genome were selected for genotyping, with a mean linkage disequilibrium coefficient between neighboring SNPs of 0.95. Haplotypes were estimated across the entire genome for each rat using a multipoint haplotype reconstruction method, which calculates the probability of descent at each locus from each of the 8 HS founder strains. The haplotypes were then tested for association with each structure and strength phenotype via a mixed model with covariate adjustment. We identified quantitative trait loci (QTLs) for structure phenotypes on chromosomes 3, 8, 10, 12, 17 and 20, and QTLs for strength phenotypes on chromosomes 5, 10 and 11 that met a conservative genome-wide empiric significance threshold (FDR=5%; P<3×10(-6)). Importantly, most QTLs were localized to very narrow genomic regions (as small as 0.3 Mb and up to 3 Mb), each harboring a small set of candidate genes, both novel and previously shown to have roles in skeletal development and homeostasis.Item Racial Differences in Cortical Bone Mass, Size and Estimated Strength at the Tibial Diaphysis in Early Pubertal Children(Office of the Vice Chancellor for Research, 2012-04-13) Warden, Stuart J.; Ferira, Ashley J.; Laing, Emma M.; Hill, Kathleen M.; Martin, Berdine R.; Weaver, Connie M.; Peacock, Munro; Lewis, Richard D.Osteoporotic fracture rates differ according to race, with blacks having up to half the rate of whites. The reduced fracture rate in blacks has been suggested to be due to their superior bone mass; however, mass is not the sole determinant of bone strength. Bone strength, and consequent fracture risk, is also influenced by how bone material is distributed or structured. It is likely bone structure also contributes to the lower incidence of fractures in blacks and that racial differences in bone structure have roots in childhood. The aim of this study was to assess the influence of race on pQCT-derived cortical bone mass, size and estimated strength at the tibial diaphysis in early pubertal children. 160 children were recruited, with equal subjects according to race (black, n=80; white, n=80) and sex (female, n=80; male, n=80). Subjects were at sexual maturation stages 2 or 3. Tomographic slices of the tibial diaphysis at 66% proximal from the medial malleolus were acquired using pQCT. Slices were assessed for cortical volumetric BMD (Ct.vBMD), cortical BMC (Ct.BMC), total (Tt.Ar) and cortical (Ct.Ar) area, density weighted maximum (IMAX) and minimum (IMIN) second moments of area, density-weighted polar strength-strain index (SSIP), and muscle cross-sectional area (mCSA). Group differences were assessed by two-way analysis of covariance, with race (black vs. white) and sex (female vs. male) as independent variables. Covariates included predicted years from peak height velocity (maturity offset), tibial length and mCSA. There were no interactions between race and sex (all P=0.50-0.98) or main effect for sex (all P=0.08-0.45). Blacks had 15.7% more Ct.BMC, and 10.8-11.8% larger Tt.Ar and Ct.Ar than whites (all P<0.001). The greater enhancement of Ct.BMC relative to Ct.Ar resulted in blacks having 3.6% greater Ct.vBMD than whites (P<0.001). The combination of increased cortical bone mass, size and density in blacks contributed to enhanced estimated bone strength, with IMAX, IMIN and SSIP being 20.0%, 34.5% and 25.2% greater in blacks than whites, respectively (all P<0.001). These data indicate that early pubertal black children have enhanced bone mass, size and estimated bone strength at the tibial diaphysis versus whites, independent of tibial length and mCSA. They suggest bone structural differences may contribute to observed racial differences in fracture rates and that structural divergence between races develops during childhood.Item Reference data and calculators for second-generation HR-pQCT measures of the radius and tibia at anatomically standardized regions in White adults(Springer, 2022) Warden, Stuart J.; Liu, Ziyue; Fuchs, Robyn K.; van Rietbergen, Bert; Moe, Sharon M.; Physical Therapy, School of Health and Human SciencesPurpose: To provide age- and sex-specific reference data for high-resolution peripheral quantitative computed tomography (HR-pQCT) measures of the distal and diaphyseal radius and tibia acquired using a second-generation scanner and percent-of-length offsets proximal from the end of the bone. Methods: Data were acquired in White adults (aged 18-80 years) living in the Midwest region of the USA. HR-pQCT scans were performed at the 4% distal radius, 30% diaphyseal radius, 7.3% distal tibia, and 30% diaphyseal tibia. Centile curves were fit to the data using the LMS approach. Results: Scans of 867 females and 317 males were included. The fitted centile curves reveal HR-pQCT differences between ages, sexes, and sites. They also indicate differences when compared to data obtained by others using fixed length offsets. Excel-based calculators based on the current data were developed and are provided to enable computation of subject-specific percentiles, z-scores, and t-scores and to plot an individual's outcomes on the fitted curves. In addition, regression equations are provided to convert estimated failure load acquired with the conventional criteria utilized with first-generation scanners and those specifically developed for second-generation scanners. Conclusion: The current study provides unique data and resources. The combination of the reference data and calculators provide clinicians and investigators an ability to assess HR-pQCT outcomes in an individual or population of interest, when using the described scanning and analysis procedure. Ultimately, the expectation is these data will be expanded over time so the wealth of information HR-pQCT provides becomes increasingly interpretable and utilized.