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Vertebral Bone Mineral Density (vertebral + bone_mineral_density)
Selected AbstractsA nonsecosteroidal vitamin D receptor ligand with improved therapeutic window of bone efficacy over hypercalcemiaJOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2010Masahiko Sato Abstract Vitamin D3 analogues were shown to be beneficial for osteoporosis and other indications, but their narrow therapeutic window between efficacy and hypercalcemia has limited their clinical utility. A nonsecosteroidal, tissue-selective, orally bioavailable, vitamin D receptor (VDR) ligand was ascertained to be efficacious in bone while having modest calcemic effects in vivo. This compound (VDRM2) potently induced Retinoid X Receptor alpha (RXR)-VDR heterodimerization (EC50,=,7.1,±,1.6,nM) and induced osteocalcin promoter activity (EC50,=,1.9,±,1.6,nM). VDRM2 was less potent in inducing Ca2+ channel transient receptor potential cation channel, subfamily V, member 6 (TRPV6) expression (EC50,=,37,±,12,nM). VDRM2 then was evaluated in osteopenic ovariectomized (OVX) rats and shown to dose-dependently restore vertebral bone mineral density (BMD) from OVX to sham levels at 0.08,µg/kg per day. Hypercalcemia was observed at a dose of 4.6,µg/kg per day of VDRM2, suggesting a safety margin of 57 [90% confidence interval (CI) 35,91]. 1,,25-dihydroxyvitamin D3 [1,,25(OH)2D], ED71, and alfacalcidol restored BMD at 0.030, 0.0055, and 0.046,µg/kg per day, respectively, whereas hypercalcemia was observed at 0.22, 0.027, and 0.23,µg/kg per day, indicating a safety margin of 7.3, 4.9, and 5.0, respectively (90% CIs 4.1,13, 3.2,7.7, and 3.5,6.7, respectively). Histomorphometry showed that VDRM2 increased cortical bone area and stimulated the periosteal bone-formation rate relative to OVX at doses below the hypercalcemic dose. By contrast, ED71 increased the periosteal bone-formation rate only above the hypercalcemic dose. VDRM2 suppressed eroded surface on trabecular bone surfaces at normal serum calcium dosage levels, suggesting dual anabolic and antiresorptive activity. In summary, vitamin D analogues were more potent than VDRM2, but VDRM2 had a greater safety margin, suggesting possible therapeutic potential. © 2010 American Society for Bone and Mineral Research [source] Full-length bovine spp24 [spp24 (24-203)] inhibits BMP-2 induced bone formation,JOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2008Chananit Sintuu Abstract Secreted phosphoprotein 24 kDa (spp24) is a bone matrix protein. It contains a TGF-, receptor II homology 1 (TRH1) domain. A cyclic, synthetic 19 amino acid peptide (bone morphogenetic protein binding peptide or BBP) based on the sequence of the TRH1 domain enhances BMP-2 induced osteogenesis. Many observations suggest that different size forms of this protein have very different effects (inhibiting or enhancing) on BMP-2 induced osteogenesis. Using the stable recombinant Met(His)6 -tagged secretory form of full-length (fl) bovine spp24 [Met(His)6 -spp24 (residues 24,203)] and transgenic (TG) mice expressing fl bovine spp24 (residues 1,203), we have demonstrated that spp24 inhibits BMP-2 induced bone formation. The effects of Met(His)6 -spp24 (24,203) were determined in the ectopic bone-forming bioassay in male mice. Implantation of 5 µg of BMP-2 stimulated bone formation, assessed densitometrically as bone area and mineral content. When Met(His)6 -spp24 (24,203) was implanted with BMP-2, it elicited a dose-dependent decrease in BMP-2-medicated ectopic bone formation. When added at a 50-fold excess (w/w), Met(His)6 -spp24 (24,203) completely ablated the effects of BMP-2, while addition of a 10-fold excess had no effect. Constitutive expression of fl bovine spp24 (1,203) under the control of the osteocalcin promoter in TG female mice reduced femoral and vertebral bone mineral density at 3 months of age and reduced femoral BMD at 8 months of age, but had no effects in male mice, which can exhibit less osteocalcin-promoter driven gene transcription than females. Histomorphometric analysis demonstrated that bone volume and trabecular thickness were lower in TG female mice at 3 months of age than in sex- and age-matched wild type (WT) controls. Thus, fl spp24 and its secretory isoform (Met(His)6 -spp24 [24,203]), which contain a BMP-binding or TRH1 motif, inhibit ectopic bone formation in male mice and adversely affects BMD and histological parameters related to bone mass and formation in female mice expressing the human transgene. Under these conditions, fl spp24 acts as a BMP antagonist in vivo. © 2008 Orthopaedic Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:753,758, 2008 [source] Measuring and interpreting age-related loss of vertebral bone mineral density in a medieval populationAMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue 2 2009Sabrina C. Agarwal Abstract This study investigates the age- and sex-related patterns in vertebral bone mineral density (BMD) and the relationship between BMD and vertebral osteophytosis (VO), using a specialized peripheral densitometer in a skeletal sample excavated from the British medieval village Wharram Percy. A total of 58 individuals were divided by sex into three broad age categories (18,29, 30,49, 50+ years.). Each fourth intact vertebral centra was scored for VO and 5-mm thick coronal sections scanned in a specialized peripheral densitometer (GE Lunar Piximus DXA). Changes in BMD associated with age, sex, and VO severity were examined in the whole vertebral section, a strictly trabecular region, and a primarily cortical region of bone separately. Significant change in vertebral BMD was found to occur by middle age with little or no statistical change in BMD between middle and old age. Females appear to suffer greater bone loss at an earlier age with no change in BMD between middle and old age, whereas males show a more steady loss of BMD across the age groups. The bone mineral content and BMD of the cortical region is higher in individuals with pronounced/severe osteophytosis. The unusual age- and sex-related patterns of change in vertebral BMD at Wharram Percy are compared with the patterns of age-related change from recent longitudinal population-based studies. The results emphasize the different pattern of bone loss in young adulthood seen in trabecular regions of the skeleton and highlight the importance of consideration of degenerative joint disease in BMD studies. The influence of lifestyle factors on vertebral BMD in this medieval population is also discussed. Am J Phys Anthropol 2009. © 2009 Wiley-Liss, Inc. 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