ETD Collection
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Item Signal transduction pathways controlling the induction of bone formation by macroporous biomimetic matrices(2015-03-27) Klar, Roland ManfredIn spite of vigorous research efforts to date the induction of bone formation by macroporous coral-derived constructs when implanted heterotopically in the rectus abdominis muscle of the non-human primate Chacma baboon Papio ursinus has not yet been resolved and needs to be assigned. More importantly, the apparent redundancy of molecular signals singly initiating the induction of bone formation in primate species and the heterotopic induction of endochondral bone formation by the mammalian recombinant human transforming growth factor –β3 (rhTGF-β3) isoform have not yet been assigned and need to be mechanistically resolved. Using the rectus abdominis muscle of Papio ursinus the study sought to molecularly determine how coral-derived macroporous constructs and doses of the hTGF-β3 isoform initiate the induction of bone formation. To elucidate the function of osteoclastogenesis and Ca2+, biomimetic coral-derived 7% hydroxyapatite/calcium carbonate (7% HA/CC) devices were supplemented either with 240 μg zoledronate bisphosphonate, an osteoclast binding antagonist, or 500 μg of the calcium channel blocker verapamil hydrochloride. Additionally but in separate coralderived bioreactors, 125 μg rhTGF-β3 and/or 125 μg hNoggin were added to answer the question of how TGF-β3 induces bone formation. All devices were then subsequently implanted within heterotopic sites of the rectus abdominis muscle of 6 Papio ursinus and left in vivo for 15, 60 and 90 days. Harvested specimens were subjected to histomorphometrical and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. Collagen Type IV expression supported by extensive vascularisation was detected and observed respectively in all implants after 15 days in vivo. Importantly the zoledronate treated specimens possessed delayed tissue patterning and morphogenesis,Item Fractures and bone mass in urban South African children of different ethnic backgrounds(2014-08-25) Thandrayen, KebashniAims: 1) To determine the incidence or rates of fractures, the common sites of fractures, the causes of fractures and grades of trauma causing fractures in urban South African children of different ethnic groups from birth until 17/18 years of age. 2) To investigate the association between fracture prevalence, bone mass and physical activity in South African children. 3) To assess associations of fracture prevalence and bone mass in adolescents with maternal fracture history and bone mass and sibling fracture history. Design: Using the Birth to Twenty longitudinal cohort of children, we obtained retrospective information on fractures and their sites from birth to 14.9 years of age on 2031 participants. The ethnic breakdown of the children was black (B) 78%, white (W) 9%, mixed ancestry (MA) 10.5% and Indian (I) 1.5%. Using the Bone Health cohort of the Birth to Twenty longitudinal study, we retrospectively obtained information of lifetime fractures until age 14.9 years in 533 subjects. Bone mass (measured by DXA), anthropometric data, physical activity scores and skeletal maturity were obtained at age 10 and 15 years. Comparisons were made between those who did and did not fracture within the same sex and ethnic groups. The third component of the thesis utilized data from 1389 adolescent-biological mother pairs of the Birth to Twenty (Bt20) longitudinal study. Questionnaires were completed on adolescent fractures until 17/18 years of age and on sibling fractures. Biological mothers completed questionnaires on their own fractures prior to the age of 18 years. Anthropometric and bone mass data on adolescent-biological mother pairs were collected. Results: Twenty two percent of children had sustained a fracture one or more times during the first 15 years of life (males 27.5% and females 16.3%; p<0.001). The percentage of children fracturing differed between the ethnic groups (W 41.5%, B 19%, MA 21%, I 30%; p<0.001). Of the children reporting fractures, 20% sustained multiple fractures. The most common site of fracture was the upper limb (57%). In the second component of the thesis, white males who fractured were found to be significantly taller (10 years p < 0.05), more physically active (15 years p < 0.01) and had higher lean body mass (10 years p=0.001; 15 years p<0.05) than those who did not fracture; while white females, who fractured, were fatter (10 and 15 years p< 0.05), than their nonfracturing peers. White males who fractured had greater BA (bone area) and BMC (bone mineral content) at most sites at 10 and 15 years; BA and BMC were no different between fracturing and non-fracturing children in the other ethnic groups. No anthropometric or bone mass differences were found between black children with or without fractures. The third component of the thesis showed that an adolescent’s risk of lifetime fracture decreased with increasing maternal lumbar spine (LS) BMC (24% reduction in fracture risk for every unit increase in maternal LS BMC Z-score) and increased if they were white, male or had a sibling with a history of fracture. Adolescent height, weight, male gender, maternal BA and BMC, and white ethnicity were positive predictors of adolescent bone mass. White adolescents and their mothers had a higher fracture prevalence (adolescents: 42%, mothers: 31%) compared to the black (adolescents: 20%, mothers: 6%) and mixed ancestry (adolescents: 20%, mothers: 16%) groups. Conclusion: More than twice as many South African white children fracture compared to black and mixed ancestry children. This is the first study to show ethnic differences in fracture rates among children; a pattern that is similar to that found in South African postmenopausal women. The factor associated with fractures in white boys appears to be participation in sports activities, while in white girls obesity appears to play a role. We were unable to find any factors that could explain fractures in black children. Unlike the findings of some other studies, fractures in these children were not associated with lower bone mass or reduced skeletal size. Maternal bone mass also appears to play a role in determining fracture incidence in children, as the mother’s bone mass has a significant inverse association with their off-springs’ fracture risk throughout childhood and adolescence. Furthermore, there is a strong familial component in fracture risk among South African adolescents and their siblings, as evidenced by the increased risk of fracture in siblings of index children who have fractured during childhood and adolescence. Differences in fracture rates and bone mass between families and individuals of different ethnic origins may be due to differing lifestyles and/or genetic backgrounds.Item A comparive study into the bone health of South African pre-pubertal children who participate in physical activites with various amounts of skeletal loading(2014-08-25) Meiring, Rebecca MaryOsteoporosis is a disease that may be pre-determined from the condition of bone health during youth. In South Africa, the situation is quite unique in that the population of black people has a reduced fracture rate compared to white people. As lifestyle and dietary patterns change with urbanisation and there is a shift towards westernised diets and sedentary behaviour in youth, fractures in elderly South African blacks may become more prevalent. With these rapid lifestyle changes, it will become increasingly important to prioritise osteoporosis and its related conditions as a major public health concern in South Africa. Very few of the factors influencing osteoporosis have been well studied in children of different ethnic groups. Physical activity in childhood, especially in the prepubertal years, confers residual benefits to the adult skeleton. In this thesis, the associations between ethnicity, history of participation in physical activity and skeletal health were explored in a sample of pre-/early pubertal children from South Africa who participated in four different studies. Furthermore, a novel aspect of the thesis was the use of peripheral quantitative computed tomography (pQCT) to investigate the mechanistic role that physical activity plays on bone health in this unique population. First the use of an existing physical activity questionnaire for the assessment of bone loading had to be validated in a sample of black and white boys and girls (n=38). A bone loading algorithm was used to calculate a peak bone strain score (PBSS) from the physical activity questionnaire. Therefore a bone specific physical activity questionnaire (B3Q) was used in subsequent studies. The PBSS was shown to be reliable and reproducible with significant (p<0.001) intraclass correlation coefficients. There were significant correlations between PBSS and moderate (r=0.38; p=0.02), vigorous (r=0.36; p=0.03) and combined moderate to vigorous intensity activity counts (r=0.38; p=0.02) as measured by accelerometry. The ability of the PBSS algorithm to classify children into high or low weight bearing groups was in moderate agreement with accelerometer derived combined moderate and vigorous activity counts (κ=0.42; p=0.008). PBSS was significantly correlated to body size adjusted bone mineral content at all sites scanned by DXA (r=0.43-0.57; p<0.05). Positive correlations were observed between PBSS and area, density and strength at the radius and tibia (r=0.40-0.64; p<0.05). At the radial metaphysis, significant correlations between moderate activity (r=0.46; p=0.005) and combined moderate and vigorous activity counts (r=0.42; p=0.01) were seen for bone strength. No associations were seen between accelerometer measured physical activity and bone outcomes at the tibial diaphysis. Multiple regression analysis showed that the PBSS was a better predictor of bone mass and structure than was accelerometry. The next study sought to determine whether children who were classified as being high bone loaders for the past two years would present with greater bone mass and strength regardless of their ethnicity. Sixty six children [black boys, 10.4(1.4) yrs, n=15; black girls, 10.1(1.2) yrs, n=27; white boys, 10.1(1.1) yrs, n=7; white girls, 9.6(1.3) yrs, n=17] reported on all their physical activities over the past two years in the interviewer administered bone specific physical activity questionnaire (B3Q). Children were classified as being either high or low bone loaders based on the cohort’s median peak bone strain score estimated from the B3Q. In the low bone loading group, black children had greater femoral neck bone mineral content (BMC) (2.9 (0.08)g) than white children (2.4 (0.11)g; p=0.05). There were no ethnic differences in the high bone loaders for femoral neck BMC. At the cortical sites, the black low bone loaders had a greater radius area (97.3 (1.3) vs 88.8 (2.6) mm2 ; p=0.05) and a greater tibia total area (475.5 (8.7) vs. 397.3 (14.0) mm2 ; p=0.001) and strength (1633.7 (60.1) vs. 1271.8 (98.6) mm3 ; p=0.04) compared to the white low bone loaders. These measures were not different between the black low and high bone loaders or between the black and white high bone loaders. Ethnic differences in bone area and strength apparent between children classified as having a lower bone loading physical activity history appear to have been attenuated when children partaking in high bone loading physical activities were compared. Greater levels of mechanical loading seemed to have no apparent benefits in black children. Cross-sectional studies in black and white pre-pubertal children have observed significant ethnic differences in structural bone outcomes as measured by pQCT but there are a limited number of intervention studies that have been conducted in black children. The cortical bone of black and white children may respond differently to mechanical forces, yet no physical activity interventions and their effects on bone structure in black children have been done. The aim of the third study was to determine whether a weight-bearing physical activity intervention improves measures of bone mass, structure and strength in pre-pubertal black children. Children (9.7 ± 1.1 years) were randomised into an exercise (EX; n=12) and control (CON; n=11) group. The EX children performed a 20-week weightbearing exercise program performed twice a week for 45 minutes per session, while CON children continued their regular activities. Changes in tibial trabecular volumetric bone density, area and strength were greater in the EX than the CON group (all p<0.01). At the cortical site of the tibia, the change in bone density was greater in the EX group than the CON group (all p<0.05). The greater change in tibial periosteal circumference in the EX groups also resulted in a greater change in cortical thickness of the tibia compared to the CON group (p<0.05). The final study assessed whether rates of bone accrual differed over one year between high and low bone loaders and also between black and white South African children. Forty seven children (18 boys, 29 girls) were followed up after one year. High bone loaders tended to have greater baseline BMC at all sites measured by DXA but the difference was only significant at the femoral neck (p=0.03). At the follow up visit, femoral neck BMC remained significantly higher in the high compared to the low bone loaders (p=0.003). Bone strength index (BSI) at the follow up visit was significantly greater in the high bone loaders compared to the low bone loaders (p=0.05). Although there was a trend for the high bone loaders to have greater indices of density and area at the 65% tibia compared to the low bone loaders, this was not significantly different at baseline or at follow up. High bone loaders had greater relative changes in whole body BMC (p=0.002), tibial cortical area (p=0.03), cortical density (p=0.04) and cortical thickness (p=0.03) compared to low bone loaders. There were no significant differences in DXA bone outcomes between black and white children at baseline and follow up. At baseline, total density at the 4% radius was greater in black than in white children (p<0.001) but total density at the follow up visit was not significantly different between black and white children (p=0.06). Trabecular density was greater in the black than in the white children at baseline (p=0.01) as well as at follow up (p=0.04). BSI at baseline was greater in the black than in the white children (p=0.05) but this significance disappeared at follow up. Similar to the 4% radius, cortical density at baseline was significantly greater in the black compared to the white children at the 65% radius (p=0.01) and at the 65% tibia (p=0.04). In conclusion, the PBSS algorithm from the B 3Q can be used to reliably and accurately collect data on previous participation in weight bearing exercise and is able to classify children as being either high or low bone loaders. It appears that in order for White children to reach the same bone mass/health levels as Black children, they may need to participate in higher levels of weight-bearing physical activity. Ethnic differences in bone area and strength apparent between children classified as having a lower bone loading physical activity history appear to have been attenuated when children partaking in high bone loading physical activities were compared. The associations may indicate that a strong environmental influence (i.e. high participation in physical activity) may offer similar or even superior benefits to bone over genetic (ethnic) influences. The use of pQCT appears to be sufficiently sensitive in detecting bone structural changes in response to mechanical loading interventions. As such, pQCT measures were able to determine the efficacy of a weight bearing physical activity intervention on trabecular and cortical sites in black children, and, similar to what has previously been observed in white and Asian children, our knowledge on the attainment of bone in response to an exercise intervention in black children is deepened. Moreover, the bone accrual that occurs in a population of black and white children from a low-middle income country may also differ between ethnicities and may reflect an environmental influence that modifies existing paradigms on physical activity and bone health in children. The promotion of weightbearing physical activity should occur in all youth, to oppose the possible lifestyle induced risks for developing osteoporosis in adulthood.Item Racial differences in the growth of the axial and appendicular skeleton and bone mass in 11 year old South African children.(2014-03-28) Nyati, Howard LukhanyoIntroduction 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.Item Bone mass and bone size in 10 year-old South African children(2013-04-17) Van der Lingen, Linda;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.