Medicine (Austin & Northern Health) - Theses
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ItemApplication of High Resolution Peripheral Quantitative Computed Tomography to the Study of Bone Microstructure and Matrix Mineral Density in Health and Disease( 2023-06)Longevity increases the proportion of elderly persons in the community. Advancing age is accompanied by bone loss which compromises the volume, microarchitecture, and strength of both cortical and trabecular bone, particularly in women after menopause. Increasing fragility fracture risk is likely to be due to trabeculae thinning, perforation of trabeculae or reduction of trabecular numbers, thinning of the cortex and increased cortical porosity. Bone also becomes fragile due to changes in the material composition such as increased matrix mineral density, glycation of collagen and accumulation of unrepaired microdamage. These changes impact the mechanical properties of bone and make bones less able to resist loading, leading to an increased risk of fragility fractures. The diagnosis of bone fragility is currently based on evaluation of clinical risk factor and with measurement of areal bone mineral density (aBMD) of the lumbar spine, and proximal hip using dual-energy X-ray absorptiometry (DXA). BMD is normally distributed. Over 10% of people in the community have ‘so-called’ normal BMD (T-score more than - 1.0 SD), around 60% of persons have osteopenia (T-score - 1.0 to -2.5 SD) and around 30% have a BMD T-score less than - 2.5 SD below the young normal mean, the diagnostic threshold for ‘osteoporosis’. Because of the population distribution of BMD, most patients with fragility fractures in the community and most patients with diseases affecting the skeleton such as chronic kidney disease who suffer fragility fractures have osteopenia or normal BMD, not osteoporosis, so the use of aBMD threshold of less than – 2.5 SD has led to underestimation of the burden of bone fragility in the community. High-Resolution peripheral Quantitative Computed Tomography (HR-pQCT) with 82 or 61-micron isotropic voxel size is an in-vivo imaging modality. HR-pQCT enables quantifying bone microarchitecture, distinguishing trabecular and cortical compartments, and measuring cortical and trabecular microarchitecture with minimal radiation exposure (5 micro-Sv, equivalent to one day of background radiation) has made it an important modality to identify bone fragility in persons independent of their BMD level. HR-pQCT is used in musculoskeletal research to quantify bone microstructure of appendicular regions of interest, both in normal and pathological conditions. However, there are limitations in the application of this imaging method and in the interpretation of findings, that need to be recognised such as accurate segmentation of cortical from trabecular bone using threshold or non- threshold-based image analysis algorithms and challenges in the correct choice of a region of interest (ROI) which is chosen as a fixed distance from the distal joint line. This region differs in persons differing in arm length; it is more distal in taller individuals, more proximal in shorter individuals. For this reason, sex differences, racial differences and growth related differences in microarchitecture may be the result of differences in the positioning of the region of interest. The aim of this thesis was to address several of these technical limitations in methodology by using a non-threshold-based HR-pQCT image analysis and standardising the location of the ROI, so that sex- and race-specific differences in bone morphology could be correctly determined free of positioning errors. This method was applied in various disease states to establish the effects of disease on bone microarchitecture. We investigated distal radius bone morphology of 158 healthy Asians and Caucasian women and men aged from 21 to 53 years using HR-pQCT. Errors in positioning the region of interest misrepresents accurate quantification of bone microarchitecture because it varies point by point (slice-by slice) along the length of a bone. For example, adjusting the scanned ROI resulted in a 0.51 SD higher cortical porosity in Asian women and 0.32 SD higher cortical porosity in Caucasian women. Failure to correct the ROI overestimated porosity by 0.21 SD in Asian men and by 0.39 SD in Caucasian men. Failure to correct the ROI comparing older Caucasian women, 33 postmenopausal women aged from 73 to 95 years, underestimate the age-related increase in porosity by 0.40 SD. We investigated the effects of spinal paralysis on bone microstructure of distal radius and distal tibia and fibula of individuals with spinal cord injury. In this study, 32 men, 12 with tetraplegia and 20 with paraplegia, that were within 0.5 to 18.5 years of paralysis, were scanned by HR-pQCT. We report that following unloading caused by spinal cord injury, weight bearing regions adapted to accommodate greater peak strains, and strain rates changes had more severe microarchitectural deterioration than non-weight bearing regions that are normally adapted to lower peak strains and strain rates prior injury. These observations highlight the site specificity of the strain thresholds regulating the cellular activity of mechano-transduction. The rapidity of the change and irreversible microarchitectural deterioration suggest prompt intervention with antiresorptive, anabolic therapy, or both, warrants consideration. We also studied the effect of chronic kidney disease (CKD) on bone microstructure of 128 patients with CKD and compared them with 275 age- and sex-matched controls. We report that most patients with CKD stages 4-5D and kidney transplant recipients had osteopenia or normal femoral neck BMD, not osteoporosis. Despite these modest deficits in femoral neck BMD, distal tibial and distal radial microarchitecture and estimated failure load were compromised, even in patients with normal BMD. Cortical and trabecular distal tibia and distal radius microarchitecture, not femoral neck BMD, were independently associated with estimated failure load and accounted for over 85% of the variance in failure load estimated at these metaphyseal locations. Resistance to fracture is achieved by modelling and remodelling adding bone to, or removing bone from, its periosteal (external) and endocortical, intracortical, and trabecular components of its endosteal (internal) surfaces. Quantification of macro/micro-structure of 18 radii and 5 femora human post-mortem specimens show that bone mass is constant along the radius, femur, and femoral neck. Along the metaphyseal regions, the constant mass was fashioned with a large void volume and high surface area/matrix volume forming mainly trabecular bone. At the middiaphyseal regions the same mass was fashioned with small intracortical and medullary void volumes and low surface area/matrix volume forming cortical bone. In addition, quantification of distal radius and tibia of 94 women, using HR-pQCT, showed that bigger bones are assemble with relatively less cortical mass of higher porosity and lower matrix mineral density. In conclusion, the aging population is at higher risk of fragility fractures due to age-related bone loss and deteriorated bone microstructure. HR-pQCT provides three-dimensional bone microstructure analysis of human extremities as in-vivo, with minimal radiation exposure and high-resolution images. We offered a methodological solution for standardizing positioning and scanning of ROI and accurately quantifying bone microarchitecture, and in pathological conditions. We investigated the impact of spinal cord injury on bone microstructure and the effects of chronic kidney disease on bone strength, highlighting the significance of cortical and trabecular microarchitecture in assessing bone health.
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ItemBiological Actions of Estradiol in Men( 2022)ABSTRACT Context: Accumulating evidence suggests that many of the biological actions of testosterone (T) in men are dependent on endogenous aromatisation of T to estradiol (E2). However, few studies have been designed to measure effects of E2 in men directly, in the absence of T. The most prevalent contemporary cause of severe hypogonadism in older men is the use of gonadotrophin-releasing hormone analogs (GnRHa) as androgen deprivation therapy (ADT) for prostate cancer. ADT represents a unique situation in which the usual clinical and ethical imperative to treat severe male hypogonadism with T is absent. Men receiving ADT experience accelerated osteoporosis leading to fractures, accumulation of fat mass, loss of muscle mass, sexual dysfunction, hot flushes, and, reportedly, adverse neuropsychological effects. This thesis reports on a project designed to test the hypothesis that low dose E2 treatment of men receiving GnRHa for prostate cancer would mitigate some of the adverse effects of the induced hypogonadism, by restoring E2 action (E2 ‘add-back’). There were two overarching aims: first, to directly examine the isolated effects of E2 in men in the absence of T in order to provide new information on the biological role of E2 in men; and second, to test the efficacy of transdermal E2, a readily available and cheap therapeutic, for the mitigation of ADT-induced side effects. Methods: Two randomised controlled trials (RCTs) were conducted in men undergoing ADT for prostate cancer. These trials tested the hypotheses that transdermal E2 would: 1. Reduce the ADT-associated unbalanced and accelerated bone remodelling, leading to better maintenance of volumetric bone mineral density (vBMD). 2. Reduce the ADT-associated increase in fat mass. 3. Reduce ADT-associated changes in cognition. 4. Reduce hot flushes and thereby improve quality of life. Trial 1 aimed to assess the effects of two low doses of transdermal E2 on serum E2 concentrations and to assess the effects of E2 add-back on bone remodelling markers and hot flushes. This trial was a 28-day RCT, randomising 37 participants to transdermal E2 0.9mg/d, 1.8mg/d, or matching placebos. Fasting morning pre-dose serum sex steroids were measured by liquid chromatography mass spectrometry. Hot flushes were measured by prospective 7-day diary. Carboxyl-terminal type 1 collagen telopeptide (CTX) and pro collagen type 1 amino-terminal propeptide (P1NP) were measured by electrochemiluminescence. Trial 2 aimed to assess the efficacy of transdermal E2 0.9mg/d on total vBMD at the tibia and total fat mass (co-primary endpoints), as well as on cognition, hot flushes, and quality of life. This trial was a 6-month RCT, randomising 78 participants to transdermal E2 0.9mg/d, or matching placebo. Total vBMD was measured by high resolution peripheral quantitative CT at baseline and study end. Body composition was measured by dual x-ray absorptiometry at baseline, month 3 and month 6. At each visit, sex steroids, bone remodelling markers, and hot flushes were measured as per trial 1. Quality of life was measured by the Functional Assessment of Cancer Therapy – Prostate and the Aging Males’ Symptom Scale instruments. Cognition was assessed by a validated, tablet computer-based cognitive battery. Results: In trial 1, transdermal E2 0.9-1.8 mg daily increased median serum E2 concentrations into the reference range reported for healthy men, but with substantial variability. Day 28 serum E2 concentrations ranged from 106 to 870 pmol/L in the 0.9mg dose group (median 208 pmol/L; interquartile range: 157-332) and 96-1814 pmol/L in the 1.8mg dose group (median 200 pmol/L; interquartile range 144-660). Over 28 days, transdermal E2 reduced serum CTX, increased serum P1NP, and reduced hot flushes. In trial 2, serum E2 increased in the E2 group over 6 months compared to the placebo group, mean adjusted difference (MAD) 207 pmol/L (95% CI 123-292), p<0.001. E2 add-back did not significantly change total vBMD at the distal tibia, MAD 2.0 mg hydroxyapatite per cm3 (95% CI -0.8 – 4.8), p=0.17. E2 increased cortical vBMD at the distal radius, and estimated failure load at the tibia and radius, and reduced CTX and P1NP. E2 add-back did not significantly change total fat mass, although the confidence interval suggested a likely increase in the E2 group, MAD 1007g (95% CI 124-1891), p=0.09. E2 increased android fat, MAD 164 g (95% CI 41-286), p=0.04. E2 did not change performance over time in any pre-defined cognitive domain. E2 reduced daily hot flush frequency, mean adjusted difference (MAD) -1.6 hot flushes per day (95% CI -2.7 to -0.5), p=0.04. but had no significant effect on quality of life. Conclusion: These two trials offer new insights into the biological actions of E2 in men by providing direct observations of E2 effects, in the absence of T. Over 6 months, E2 add-back reduced the bone remodelling rate, and had beneficial effects on bone to increase aBMD at lumbar spine and ultra-distal radius, cortical vBMD at radius, and estimated failure load, a measure of bone strength, at both radius and tibia. Contrary to the hypothesis, these data suggest that E2, in the absence of T, increases fat mass, suggesting that the effect of E2 on fat might be more complex than reported in studies inferring E2 effects to reduce fat from paradigms in which T is present. E2 had no observed effect on cognition, suggesting that any short-term effects of E2 on cognition in men, are likely to be subtle. Transdermal E2 add-back durably reduced hot flushes, thus providing high quality evidence for this intervention to be used clinically.
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ItemThe effect of gender-affirming hormone therapy on the health and well-being of transgender Australians( 2021)There is increasing demand for gender-affirming hormone therapy, used by transgender individuals to align physical characteristics with their gender identity. Although hormone therapy improves quality of life and psychological functioning, significant barriers to accessing appropriate healthcare persist. Hormone therapy is often started at a young age and continued lifelong, yet little is known about the long-term effects on metabolic and bone health, both highly regulated by sex hormones. Our aim was to understand the sociodemographic characteristics of transgender Australians, the level of training and confidence of Endocrinologists in transgender health, and the prescribing practices of experienced medical practitioners. We report findings from a series of surveys. Transgender adults (n=928) reported alarmingly high rates of self-harm (63%), attempted suicide (43%) and discrimination within healthcare settings (26%). Barriers included difficulties navigating the healthcare system and finding doctors to prescribe. Better training for doctors was a priority with only 4% of Endocrinologists and trainees (n=147) reporting any training in transgender health during medical school, 91% desired more training. Experienced prescribers (n=35) displayed uniformity in prescribing practices, despite a lack of local guidelines. We then investigated the effects of hormone therapy on cardiovascular risk and bone microstructure. Transgender individuals face higher metabolic risk due to sex hormone mediated changes in body composition and insulin resistance. Bone morphology may be compromised as estradiol is a key regulator of bone remodelling. Transgender adults on established hormone therapy, and control participants, underwent body composition scanning (dual energy X-ray absorptiometry) and quantification of bone microstructure (high-resolution peripheral quantitative CT). Trans men (n=43) had higher mean lean mass, +7.8kg (4.0, 11.5) p<0.001, similar total fat mass but higher android:gynoid fat ratio when compared to female controls (n=48). Insulin resistance was similar, indicating a protective effect of higher lean mass. Conversely, trans women (n=41) had lower mean lean mass, -6.9kg (-10.6, -3.1), p<0.001, higher fat mass, +9.8kg (3.9, 14.5), p=0.001, and lower android:gynoid fat ratio when compared to male controls (n=30). Although android fat correlated more strongly with insulin resistance, trans women had higher insulin resistance likely due to higher overall fat mass. Bone microarchitecture was not compromised in trans men (n=41), as aromatisation of administered testosterone to estradiol likely prevented bone loss. Trans men had higher distal tibial total volumetric bone density (vBMD), 0.71 SD (0.30, 1.12), p<0.01, preserved cortical morphology and trabecular bone volume fraction relative to female controls (n=71). Despite estradiol administration, trans women (n=40) were not protected from microarchitectural deterioration, indicating the dose was insufficient to offset reduced aromatisable testosterone. Trans women had -0.55 SD lower distal tibial total vBMD (-1.01, -0.08), p=0.02 due to higher cortical porosity, 0.63 SD (0.19, 1.07), p=0.01 and lower trabecular bone volume fraction relative to male controls (n=51). Our survey findings informed new Australian clinical practice guidelines and a new gender service. Our cross-sectional study not only provide new and important insights into sex hormone action but are also highly clinically significant, given proactive measures can be implemented to mitigate fat gain and bone loss, particularly in trans women.