Study of the embryology and ossification of modern bones predicts that fossil intermembranous bones (which ossify from connective tissue) will exhibit greater size variability than endochondral bones (which are formed from embryological cartilaginous precursors), because intermembranous bones are less tightly constrained by joints and articular surfaces. To evaluate this hypothesis, we measured multiple dimensions of 989 intermembranous bones (patellae and other sesamoids) of the saber-toothed cat Smilodon fatalis, the Ice Age lion Panthera atrox, the bison Bison antiquus, the horse Equus occidentalis, the camel Camelops hesternus, the ground sloths Paramylodon (=Glossotherium) harlani and Nothrotheriops shastensis from Rancho La Brea and from the late Pleistocene San Josecito Cave in Nuevo Leon, Mexico. These were compared to measurements of 811 endochondral bones (primarily astragali) of comparable size. Through statistical analyses (coefficients of variation, ANOVA, modified Levene's test, and t-tests) we found slight evidence of higher variability in many of the intermembranous bones of these taxa (21 out of 27 CVs were higher for intermembranous bones than endochondral bones), although this trend is not found in all taxa. Using a modified Levene's test, only Smilodon and some of the dimensions of horse and bison patellae are significantly more variable than the corresponding dimensions of the astragali. Although the results are mixed, at least some data show that intermembranous bones are not as tightly constrained by growth and by adjacent tissues as are endochondral bones. This evidence of relative variability is important in assessing how much variability is typical of a single species, and thus has taxonomic implications.

Indiana University-Purdue University Indianapolis (IUPUI) / Chronic kidney disease (CKD) results in an increased fracture risk, partially due to elevations in parathyroid hormone (PTH) that lead to substantial bone loss. On its own, bone loss does not explain bone fragility in CKD, suggesting that changes in skeletal tissue (bone quality) may also be present. Understanding the factors that lead to fracture in these patients will have a substantial impact on patient care and could lead to a better understanding of how to reduce their fracture risk. Due to their suppression of PTH, calcitriol and its analogues are the current standard of care for bone disease in CKD. Yet, surprisingly little is known of their effects on bone. Agents effective in treating osteoporosis are not recommended in advanced CKD due to the lack of data regarding their efficacy and safety in these patients. The goals of the current study were to determine (1) the impact of CKD on bone quality, (2) the ability of calcitriol to improve skeletal parameters, and (3) the efficacy of various pharmacological interventions (calcium, bisphosphonates, anti-sclerostin antibody, and raloxifene) on bone mass, quality, and mechanical properties in CKD bone disease. Using a slowly progressive rat model of CKD, renal and mineral metabolism, bone morphology, bone quality, and bone mechanics (at several length scales) were assessed. Primarily due to elevated PTH, mechanical testing and tissue-level assessments revealed compromised bone quantity (high cortical porosity and low trabecular volume) and quality (high collagen cross-linking and low matrix bound water). Despite clinically relevant reductions in PTH, calcitriol treatment had no positive impact on skeletal properties. Most agents were only effective when PTH levels were normal. Raloxifene, however, led to greater whole bone and material toughness (the ability of bone to tolerate existing damage) despite modest PTH suppression. While the examination of bone quality in CKD is still in its infancy, these results indicate that enhancing bone quality with raloxifene may be an effective means to compensate for bone loss in CKD.

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There is a need for an improved bone mineral density measurement procedure for neonates. Currently, measurements are made using single photon absorptiometry (SPA). The poor reproducibility of this method means that it has little direct clinical diagnostic application and is therefore not suitable for diagnosing disease in individual patients. A technique using digital radiography has been developed to measure bone mineral density. Digital images of phantoms and chicken bones were acquired at two kvp settings of a digital angiographic unit. Digital information from water, aluminum and lucite phantoms were used to calculate effective mass attenuation coefficients of the phantom materials. These values were subsequently used in bone mineral density calculations of sections of the chicken bones. The bone mineral densities of the chicken bones obtained from the digital radiography method were compared to SPA measurements. The digital radiography method gave consistently higher bone mineral densities for the bones than SPA. This could be due to the differences in measurement technique as SPA scans a single slice whereas digital radiography images a large area of the bone. / Thesis / Master of Science (MSc)

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No description available.

The nitrogen-containing bisphosphonates (NBPs) are the most widely used treatment for diseases involving excessive osteoclastic bone resorption, such as osteoporosis. The clinical efficacy of NBPs is due in large part to their affinity for bone mineral, but it has been suggested that lowering affinity may have benefits due to altered distribution and duration of action possibly allowing direct anti-tumour effects. In addition, the phosphonocarboxylate (PC) analogues inhibit prenylation more selectively through a different enzyme target, Rab geranylgeranyl transferase (RGGT), which may offer additional benefits by reducing side-effects associated with farnesyl diphosphate synthase (FPPS) inhibition. Using fluorescent analogues of PCs and NBPs demonstrated that mineral affinity not only affects initial bone-binding, but also influences desorption, reattachment and penetration at the bone surface, suggesting that lower affinity compounds have lower retention and increased access to other cell types, such as tumour cells. The work presented aimed to investigate the potential of low affinity analogues by characterising their intracellular potency for inhibiting their target enzymes. The results showed that modification to the phosphonate groups to produce phosphonoalkylphosphinate analogues reduced potency for inhibiting FPPS. By contrast, removal of one of the phosphonate groups to give a monophosphonate changed the target enzyme to RGGT. Modifications to the R1 side-chain (substituting with hydrogen or a halogen) of both NBPs and PCs were studied and showed contrasting results, modifications to the R1 side-chain of NBPs affect their ability to inhibit FPPS whereas the same modification to PCs is insignificant for inhibiting RGGT. This showed the distinction between the structural requirements for inhibition of RGGT and FPPS and furthers the understanding of the structure-activity relationships of both NBPs and PCs which could guide future drug design. Within this thesis the most potent inhibitor of RGGT to date, 3-IPEHPC, was characterised which in addition to having therapeutic potential may be used as tool to investigate the importance of Rab prenylation for cellular function.

Introduction Ethnic differences in bone growth and proportions have previously been investigated in relation to bone fragility. Differential growth in the axial and appendicular skeletons has been suggested to predispose to differential susceptibility to fracture. The developmental origins of bone size and osteoporosis have also been investigated. However, the impact of foetal programming on body proportions and limb lengths in unknown. Objectives The aim of this study was to investigate the presence of ethnic and sex differences in axial and appendicular growth. Additionally, it was to investigate the impact of early life factors on skeletal dimensions and proportions in childhood . Methods Anthropometric measurements of stature, weight, sitting height and limb lengths were taken on 368 black and white, male and female 9 year old children. DXA scans of the distal ulna;distal radius; hip and lumbar spine were also obtained. The same measurements were obtained for 197 of the black children who had birthweight and weight and length data at 1 year. For the first part of the analyses, Analyses of Covariance were performed to assess differences in limb lengths adjusted for differences in stature. Multiple regression analyses were used to assess significant predictors of site-specific bone mass. Comparisons were made after adjustment for weight, weight and stature and weight and regional segment lengths. For the second part of the analyses, Analyses of Covariance were performed to assess differences in stature and regional segment lengths at different tertiles of birthweight, and weight and height at 1 year. Stepwise multiple regressions were performed with early life growth patterns to assess significant predictors of stature and regional segment lengths at 10 years. Results Black children had longer limbs but shorter trunks than white children. Regional segment length were a more significant predictor of site-specific bone mass than stature. In black boys birthweight had positive but weak associations with stature and regional segment length while in girls the association were marginal. In contrast, weight and height at 1yr had strong associations with stature and regional segment lengths. Conclusion There is a differential effect of ethnicity and sex on the growth of the axial and appendicular skeletons, and regional segment length is a better predictor of site-specific bone mass than stature. Early life growth has a long-term influence on stature, as well as on regional segment lengths but marginal effect on body proportions.

A research report submitted to the School of Oral Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Dentistry in the branch Maxillofacial and Oral Surgery. Johannesburg 2014 / The reconstruction of osseous mandibular defects remains a significant challenge. The use of autologous bone for mandibular reconstruction is associated with numerous limitations, and alternatives to autologous bone would provide significant benefits for patients. The aim of this study was to evaluate and compare binary application of recombinant human bone morphogenetic protein 7 (rhBMP-7) and recombinant human transforming growth factor  (rhTGF-3) to solo application of recombinant human bone morphogenetic protein 7 (rhBMP-7) in full-thickness mandibular defects in the non-human primate Papio ursinus. In four baboons, a 2.5cm segmental defect was created in the mandible and stabilized with a 2.7mm titanium reconstruction plate. Two defects were implanted with rhBMP-7 solo, and the other two with binary application rhBMP-7 and rhTGF-3 at a ratio of 20:1. All four baboons were euthanazed at 180 days post implantation. All four specimens were radiographed prior to sectioning. Tissue processing and histomorphometry were done on the undecalcified sections prepared from the harvested mandible specimens. In all defects bone regeneration re-established bony continuity at six months. The mean area of the regenerate was 336 ± 107.5 mm2 (range 229-444.7) in the solo specimens, and 312 ± 63.5mm2 (range 249-376.6) in the binary specimens. Radiographic examination confirmed complete bone healing in all defects but variable restitution of defect volume. The regenerated bone had a trabecular pattern consistent with mature mandibular bone and the defect interfaces were indiscernible. Due to the small sample size no performance advantage could be identified between the two treatment groups. These results confirm that successful bone regeneration by tissue induction in surgically created mandibular defects can be achieved with osteogenic proteins of the transforming growth factor- superfamily.

Thesis (Ph.D.)--University of the Witwatersrand, Faculty of Health Sciences, 2012 / Osteoporosis has been described as a paediatric disease with geriatric consequences. This thesis explored the associations between proximal, historical and predictive genetic and environmental factors affecting bone mass and bone size in socio-economically- and environmentally-disadvantaged black and -advantaged white pre- and early-pubertal South African children. Data were collected from 476 children (182 black boys, 72 white boys, 158 black girls, 64 white girls) of mean age 10.6 years (range: 10.0-10.9), 406 biological mothers and 100 biological fathers. The main findings were that black children and their parents compared to white, had greater DXA-measured BMC at the femoral neck regardless of the way in which BMC was corrected for size (height, weight, BA and/or BAPC) and greater bone strength. Lumbar spine BMC was greater or similar depending on which measures were used to correct BMC for size. At the whole body, mid radius and distal one third of the radius, BMC varied between children, and between their parents, and were dependent on which measures were used to correct BMC for size. Weight at 1 year (WT1), length at 1 year (LT1) and birth weight (BW), were significant predictors of BMC of the femoral neck (P<0.05-0.01) after correcting BA and BMC for race/ethnicity, gender, age, socioeconomic status, bone age, height and weight at 10 years. Maternal and paternal heritability was estimated to each be ~30% in both black and white subjects. The main conclusion was that ethnicity is the single most important proximal factor affecting bone mass and bone size in 10 year old South African children. Black children demonstrate a superior bone mass and bone strength at the femoral neck. Historical and predictive factors however indicate that black children have not been programmed for optimal bone health in utero and early life, nor are contemporary environmental factors favourable for the maximisation of peak bone mass. This cohort may be at risk of developing osteoporosis as an elderly population, particularly at the lumbar spine and forearm.