New findings with old drugs for osteoporosis

Background : Postmenopausal osteoporosis is common and is associated with stooped posture, loss of height, back pain and fractures. Objectives/methods : This evaluation is of clinical outcome trials with tibolone (Long-Term Intervention of Fractures with Tibolone) and strontium ranelate (Spinal Osteoporosis Therapeutic Intervention) in postmenopausal osteoporosis. Results : Although the Long-Term Intervention of Fractures with Tibolone trial established that tibolone decreased the incidence of vertebral and non-vertebral fractures in postmenopausal osteoporosis, it also showed that tibolone caused a small increase in the incidence of stoke. The Spinal Osteoporosis Therapeutic Intervention trial established that strontium ranelate decreased the incidence of vertebral fractures, but had little effect on the incidence of non-vertebral fractures. Conclusions : As some of the bisphosphonates (alendronate, risedronate, zoledronic acid) have been shown to prevent hip fractures without increasing the incidence of stroke, they should be preferred to tibolone and strontium in the treatment of postmenopausal osteoporosis.

Clinical efficacy and safety of zoledronic acid in prostate and breast cancer

The anti-estrogen treatment for hormone-sensitive breast cancer and the androgen deprivation therapy for prostate cancer can lead to the development of osteoporosis and bone fractures. Metastases associated with prostate and breast cancer can also occur in bone. Bisphosphonates are used in these types of bone dysfunction. Zoledronic acid is the most potent bisphosphonate. In osteoporosis, zoledronic acid inhibits bone reabsorption and increases bone mineral density for at least a year after intravenous administration. The efficacy and safety of zoledronic acid in osteoporosis secondary to hormone-sensitive cancers (prostate and breast), and in the bone metastases associated with these cancers are reviewed.

Good clinical endpoints with denosumab in osteoporosis and cancer

Background: Bone loss associated with low oestrogen levels in postmenopausal women, and with androgen deprivation therapy in men with hormone-sensitive prostate cancer, result in an increased incidence of fractures. Denosumab has been shown to increase bone mineral density in these two conditions. Objectives/methods: The objective of this evaluation is to review the clinical trials that have studied clinical endpoints in these conditions. Results: FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) was an International Phase III clinical trial that measured the clinical endpoints with denosumab in postmenopausal women with osteoporosis. At 36 months, new vertebral fractures had occurred in 7.2% of subjects in the placebo group and this was lowered to 2.3% of subjects treated with denosumab. HALT (Denosumab Hormone Ablation Bone Loss Trial) studied the clinical endpoints in men with non-metastatic prostate cancer receiving androgen-deprivation therapy. The incidence of vertebral fractures was significantly lower in the denosumab group (1.5%) than in the placebo group (3.9%). The incidence of adverse effects with denosumab in both clinical trials was low. Conclusions: Denosumab reduces the incidence of fractures in postmenopausal women with osteoporosis and in men with non-metastatic prostate cancer receiving androgen-deprivation therapy. Denosumab is well tolerated.

Geological control of physiography in Southeast Queensland: A multi-scale analysis using GIS

The study reported here, constitutes a full review of the major geological events that have influenced the morphological development of the southeast Queensland region. Most importantly, it provides evidence that the region’s physiography continues to be geologically ‘active’ and although earthquakes are presently few and of low magnitude, many past events and tectonic regimes continue to be strongly influential over drainage, morphology and topography. Southeast Queensland is typified by highland terrain of metasedimentary and igneous rocks that are parallel and close to younger, lowland coastal terrain. The region is currently situated in a passive margin tectonic setting that is now under compressive stress, although in the past, the region was subject to alternating extensional and compressive regimes. As part of the investigation, the effects of many past geological events upon landscape morphology have been assessed at multiple scales using features such as the location and orientation of drainage channels, topography, faults, fractures, scarps, cleavage, volcanic centres and deposits, and recent earthquake activity. A number of hypotheses for local geological evolution are proposed and discussed. This study has also utilised a geographic information system (GIS) approach that successfully amalgamates the various types and scales of datasets used. A new method of stream ordination has been developed and is used to compare the orientation of channels of similar orders with rock fabric, in a topologically controlled approach that other ordering systems are unable to achieve. Stream pattern analysis has been performed and the results provide evidence that many drainage systems in southeast Queensland are controlled by known geological structures and by past geological events. The results conclude that drainage at a fine scale is controlled by cleavage, joints and faults, and at a broader scale, large river valleys, such as those of the Brisbane River and North Pine River, closely follow the location of faults. These rivers appear to have become entrenched by differential weathering along these planes of weakness. Significantly, stream pattern analysis has also identified some ‘anomalous’ drainage that suggests the orientations of these watercourses are geologically controlled, but by unknown causes. To the north of Brisbane, a ‘coastal drainage divide’ has been recognized and is described here. The divide crosses several lithological units of different age, continues parallel to the coast and prevents drainage from the highlands flowing directly to the coast for its entire length. Diversion of low order streams away from the divide may be evidence that a more recent process may be the driving force. Although there is no conclusive evidence for this at present, it is postulated that the divide may have been generated by uplift or doming associated with mid-Cenozoic volcanism or a blind thrust at depth. Also north of Brisbane, on the D’Aguilar Range, an elevated valley (the ‘Kilcoy Gap’) has been identified that may have once drained towards the coast and now displays reversed drainage that may have resulted from uplift along the coastal drainage divide and of the D’Aguilar blocks. An assessment of the distribution and intensity of recent earthquakes in the region indicates that activity may be associated with ancient faults. However, recent movement on these faults during these events would have been unlikely, given that earthquakes in the region are characteristically of low magnitude. There is, however, evidence that compressive stress is building and being released periodically and ancient faults may be a likely place for this stress to be released. The relationship between ancient fault systems and the Tweed Shield Volcano has also been discussed and it is suggested here that the volcanic activity was associated with renewed faulting on the Great Moreton Fault System during the Cenozoic. The geomorphology and drainage patterns of southeast Queensland have been compared with expected morphological characteristics found at passive and other tectonic settings, both in Australia and globally. Of note are the comparisons with the East Brazilian Highlands, the Gulf of Mexico and the Blue Ridge Escarpment, for example. In conclusion, the results of the study clearly show that, although the region is described as a passive margin, its complex, past geological history and present compressive stress regime provide a more intricate and varied landscape than would be expected along typical passive continental margins. The literature review provides background to the subject and discusses previous work and methods, whilst the findings are presented in three peer-reviewed, published papers. The methods, hypotheses, suggestions and evidence are discussed at length in the final chapter.

Creation of a validated 3D finite element model of an ovine tibia

Introduction Ovine models are widely used in orthopaedic research. To better understand the impact of orthopaedic procedures computer simulations are necessary. 3D finite element (FE) models of bones allow implant designs to be investigated mechanically, thereby reducing mechanical testing. Hypothesis We present the development and validation of an ovine tibia FE model for use in the analysis of tibia fracture fixation plates. Material & Methods Mechanical testing of the tibia consisted of an offset 3-pt bend test with three repetitions of loading to 350N and return to 50N. Tri-axial stacked strain gauges were applied to the anterior and posterior surfaces of the bone and two rigid bodies – consisting of eight infrared active markers, were attached to the ends of the tibia. Positional measurements were taken with a FARO arm 3D digitiser. The FE model was constructed with both geometry and material properties derived from CT images of the bone. The elasticity-density relationship used for material property determination was validated separately using mechanical testing. This model was then transformed to the same coordinate system as the in vitro mechanical test and loads applied. Results Comparison between the mechanical testing and the FE model showed good correlation in surface strains (difference: anterior 2.3%, posterior 3.2%). Discussion & Conclusion This method of model creation provides a simple method for generating subject specific FE models from CT scans. The use of the CT data set for both the geometry and the material properties ensures a more accurate representation of the specific bone. This is reflected in the similarity of the surface strain results.

Development of a multi-scale finite element model of the osteoporotic lumbar vertebral body for the investigation of apparent level vertebra mechanics and micro-level trabecular mechanics.

Osteoporotic spinal fractures are a major concern in ageing Western societies. This study develops a multi-scale finite element (FE) model of the osteoporotic lumbar vertebral body to study the mechanics of vertebral compression fracture at both the apparent (whole vertebral body) and micro-structural (internal trabecular bone core)levels. Model predictions were verified against experimental data, and found to provide a reasonably good representation of the mechanics of the osteoporotic vertebral body. This novel modelling methodology will allow detailed investigation of how trabecular bone loss in osteoporosis affects vertebral stiffness and strength in the lumbar spine.

Modelling of inflatable rescue boats (IRBs) in surf conditions to reduce injuries

The Inflatable Rescue Boat (IRB) is arguably the most effective rescue tool used by the Australian surf lifesavers. The exceptional features of high mobility and rapid response have enabled it to become an icon on Australia's popular beaches. However, the IRB's extensive use within an environment that is as rugged as it is spectacular, has led it to become a danger to those who risk their lives to save others. Epidemiological research revealed lower limb injuries to be predominant, particularly the right leg. The common types of injuries were fractures and dislocations, as well as muscle or ligament strains and tears. The concern expressed by Surf Life Saving Queensland (SLSQ) and Surf Life Saving Australia (SLSA) led to a biomechanical investigation into this unique and relatively unresearched field. The aim of the research was to identify the causes of injury and propose processes that may reduce the instances and severity of injury to surf lifesavers during IRB operation. Following a review of related research, a design analysis of the craft was undertaken as an introduction to the craft, its design and uses. The mechanical characteristics of the vessel were then evaluated and the accelerations applied to the crew in the IRB were established through field tests. The data were then combined and modelled in the 3-D mathematical modelling and simulation package, MADYMO. A tool was created to compare various scenarios of boat design and methods of operation to determine possible mechanisms to reduce injuries. The results of this study showed that under simulated wave loading the boats flex around a pivot point determined by the position of the hinge in the floorboard. It was also found that the accelerations experienced by the crew exhibited similar characteristics to road vehicle accidents. Staged simulations indicated the attributes of an optimum foam in terms of thickness and density. Likewise, modelling of the boat and crew produced simulations that predicted realistic crew response to tested variables. Unfortunately, the observed lack of adherence to the SLSA footstrap Standard has impeded successful epidemiological and modelling outcomes. If uniformity of boat setup can be assured then epidemiological studies will be able to highlight the influence of implementing changes to the boat design. In conclusion, the research provided a tool to successfully link the epidemiology and injury diagnosis to the mechanical engineering design through the use of biomechanics. This was a novel application of the mathematical modelling software MADYMO. Other craft can also be investigated in this manner to provide solutions to the problem identified and therefore reduce risk of injury for the operators.

An alginate-based hybrid system for growth factor delivery in the functional repair of large bone defects

The treatment of challenging fractures and large osseous defects presents a formidable problem for orthopaedic surgeons. Tissue engineering/regenerative medicine approaches seek to solve this problem by delivering osteogenic signals within scaffolding biomaterials. In this study, we introduce a hybrid growth factor delivery system that consists of an electrospun nanofiber mesh tube for guiding bone regeneration combined with peptide-modified alginate hydrogel injected inside the tube for sustained growth factor release. We tested the ability of this system to deliver recombinant bone morphogenetic protein-2 (rhBMP-2) for the repair of critically-sized segmental bone defects in a rat model. Longitudinal [mu]-CT analysis and torsional testing provided quantitative assessment of bone regeneration. Our results indicate that the hybrid delivery system resulted in consistent bony bridging of the challenging bone defects. However, in the absence of rhBMP-2, the use of nanofiber mesh tube and alginate did not result in substantial bone formation. Perforations in the nanofiber mesh accelerated the rhBMP-2 mediated bone repair, and resulted in functional restoration of the regenerated bone. [mu]-CT based angiography indicated that perforations did not significantly affect the revascularization of defects, suggesting that some other interaction with the tissue surrounding the defect such as improved infiltration of osteoprogenitor cells contributed to the observed differences in repair. Overall, our results indicate that the hybrid alginate/nanofiber mesh system is a promising growth factor delivery strategy for the repair of challenging bone injuries.

The relationship between deformity correction and clinical outcomes after thoracoscopic scoliosis surgery : a prospective series of one hundred patients

Prospective clinical case series of 100 patients receiving thoracoscopic anterior scoliosis correction surgery. The objective was to evaluate the relationship between clinical outcomes of thoracoscopic anterior scoliosis surgery and deformity correction using the Scoliosis Research Society (SRS) outcomes instrument questionnaire. The surgical treatment of scoliosis is quantitatively assessed in the clinic using radiographic measures of deformity correction, as well as the rib hump, but it is important to understand the extent to which these quantitative measures correlate with self-reported improvements in patients’ quality of life following surgery. A series of 100 consecutive adolescent idiopathic scoliosis patients received a single anterior rod via a thoracoscopic approach at the Mater Children’s Hospital, Brisbane, Australia. Patients completed SRS outcomes questionnaires pre-operatively and at 24 months post-operatively. There were 94 females and 6 males with a mean age of 16.1 years. The mean Cobb angle improved from 52º pre-operatively to 25º post-operatively (52%) and the mean rib hump improved from 16º to 8º (51%). The mean total SRS score for the cohort was 99.4/120. None of the deformity related parameters in the multiple regression were significant. However, patients with the lowest post-operative major Cobb angles reported significantly higher SRS scores than those with the highest post-operative Cobb angles, but there was no difference on the basis of rib hump correction. There were no significant differences between patients with either rod fractures or screw-related complications compared to those without complications.

Vitamin D and injury prevention

Vitamin D, along with calcium, may help decrease the risk of falls and fractures in older adults. Sunlight and other sources of ultraviolet radiation are not recommended because they increase the risk of skin cancers and sun-induced eye disorders. Rather, vitamin D and calcium needs should be met through foods and dietary supplements. As a preventive measure to reduce the risk of falls and fractures, it is recommended that older adults meet the 2005 Dietary Guidelines and consume 1000 IU of vitamin D, preferably as vitamin D3.

Effect of surgical approach on bone vascularisation, fracture and soft tissue healing : comparison of less invasive to open approach

Over the past ten years, minimally invasive plate osteosynthesis (MIPO) for the fixation of long bone fractures has become a clinically accepted method with good outcomes, when compared to the conventional open surgical approach (open reduction internal fixation, ORIF). However, while MIPO offers some advantages over ORIF, it also has some significant drawbacks, such as a more demanding surgical technique and increased radiation exposure. No clinical or experimental study to date has shown a difference between the healing outcomes in fractures treated with the two surgical approaches. Therefore, a novel, standardised severe trauma model in sheep has been developed and validated in this project to examine the effect of the two surgical approaches on soft tissue and fracture healing. Twenty four sheep were subjected to severe soft tissue damage and a complex distal femur fracture. The fractures were initially stabilised with an external fixator. After five days of soft tissue recovery, internal fixation with a plate was applied, randomised to either MIPO or ORIF. Within the first fourteen days, the soft tissue damage was monitored locally with a compartment pressure sensor and systemically by blood tests. The fracture progress was assessed fortnightly by x-rays. The sheep were sacrificed in two groups after four and eight weeks, and CT scans and mechanical testing performed. Soft tissue monitoring showed significantly higher postoperative Creatine Kinase and Lactate Dehydrogenase values in the ORIF group compared to MIPO. After four weeks, the torsional stiffness was significantly higher in the MIPO group (p=0.018) compared to the ORIF group. The torsional strength also showed increased values for the MIPO technique (p=0.11). The measured total mineralised callus volumes were slightly higher in the ORIF group. However, a newly developed morphological callus bridging score showed significantly higher values for the MIPO technique (p=0.007), with a high correlation to the mechanical properties (R2=0.79). After eight weeks, the same trends continued, but without statistical significance. In summary, this clinically relevant study, using the newly developed severe trauma model in sheep, clearly demonstrates that the minimally invasive technique minimises additional soft tissue damage and improves fracture healing in the early stage compared to the open surgical approach method.

Application of hyperbaric oxygen in bone tissue engineering : effect of hyperbaric oxygen treatment on bone marrow stem cells

and non-union of bony fractures has been proposed since 1966, little has been known about the effect of HBOT on bone marrow stem cells (BMSC). The aim of this study is to investigate the effect of HBO treatment on osteogenetic differentiation of BMSC and potential application in bone tissue engineering. Adhesive stromal cells harvested from bone marrow were characterized by mesenchymal differentiation potential, cell surface markers and their proliferation capacity. Mesenchymal stem cells, which demonstrated osteogenic, chondrogenic and adipogenic differentiation potential and expressed positively for CD 29, CD 44, CD 73, CD 90, CD 105, CD 166 and negatively for CD34 and CD 45, were selected and treated in a laboratory-scale HBO chamber using different oxygen pressures and exposure times. No obvious effect of HBO treatment on BMSC proliferation was noticed. However, cytotoxic effects of HBO were considerably less pronounced when cells were cultured in medium supplemented with 10% FBS in comparison to medium supplemented with 2% FCS, as was evaluated by WST-1 assay. Under HBO treatment, bone nodules were formed in three days, which was clearly revealed by Von Kossa staining. In contrasts, without HBO treatment, bone nodules were not detected until 9-12 days using the same inducing culture media. Calcium deposition was also significantly increased after three days of HBO treatments compared to no HBO treatment. In addition it was also found that oxygen played a direct role in the enhancement of BMSC osteogenic differentiation, which was independent of the effect of air pressure.

Is there a difference between narrowing of the spinal canal and neurological deficits comparing Denis and Magerl classifications?

We have read with great interest the retrospective study by Caffaro and Avanzi1 evaluating the relation between narrowing of the spinal canal and neurological deficits in patients with burst-type fractures of the spine. The authors are to be commended for obtaining detailed neurological and radiological data in a large cohort of 227 patients. The authors conclude: “The percentage of narrowing of the spinal canal proved to be a pre-disposing factor for the severity of the neurological status in thoracolumbar and lumbar burst-type fractures according to the classifications of Denis and Magerl.” Although this conclusion is mainly in accordance with previous findings, we would like to comment on the methodological approach applied in the current study.

Application of an optimisation algorithm to configure an internal fixation device

Fractures of long bones are sometimes treated using various types of fracture fixation devices including internal plate fixators. These are specialised plates which are used to bridge the fracture gap(s) whilst anatomically aligning the bone fragments. The plate is secured in position by screws. The aim of such a device is to support and promote the natural healing of the bone. When using an internal fixation device, it is necessary for the clinician to decide upon many parameters, for example, the type of plate and where to position it; how many and where to position the screws. While there have been a number of experimental and computational studies conducted regarding the configuration of screws in the literature, there is still inadequate information available concerning the influence of screw configuration on fracture healing. Because screw configuration influences the amount of flexibility at the area of fracture, it has a direct influence on the fracture healing process. Therefore, it is important that the chosen screw configuration does not inhibit the healing process. In addition to the impact on the fracture healing process, screw configuration plays an important role in the distribution of stresses in the plate due to the applied loads. A plate that experiences high stresses is prone to early failure. Hence, the screw configuration used should not encourage the occurrence of high stresses. This project develops a computational program in Fortran programming language to perform mathematical optimisation to determine the screw configuration of an internal fixation device within constraints of interfragmentary movement by minimising the corresponding stress in the plate. Thus, the optimal solution suggests the positioning and number of screws which satisfies the predefined constraints of interfragmentary movements. For a set of screw configurations the interfragmentary displacement and the stress occurring in the plate were calculated by the Finite Element Method. The screw configurations were iteratively changed and each time the corresponding interfragmentary displacements were compared with predefined constraints. Additionally, the corresponding stress was compared with the previously calculated stress value to determine if there was a reduction. These processes were continued until an optimal solution was achieved. The optimisation program has been shown to successfully predict the optimal screw configuration in two cases. The first case was a simplified bone construct whereby the screw configuration solution was comparable with those recommended in biomechanical literature. The second case was a femoral construct, of which the resultant screw configuration was shown to be similar to those used in clinical cases. The optimisation method and programming developed in this study has shown that it has potential to be used for further investigations with the improvement of optimisation criteria and the efficiency of the program.

Prospective association between physical activity and falls in community-dwelling older women

Abstract Objective: To explore associations between physical activity and risk of falls and broken or fractured bones in community-dwelling older women. Design, setting and participants: This was a prospective observational survey with 3- and 6-year follow-ups. The sample included 8562 healthy, community-dwelling women, aged 70-75 years in 1996, who completed surveys as participants in the Australian Longitudinal Study on Women’s Health. Outcomes were reports of a fall to the ground, injury from a fall, and broken or fractured bones in 1999 and 2002. The main predictor variable was physical activity level in 1996, categorized based on weekly frequency as none/very low, low, moderate, high, and very high. Covariates were demographic and health-related variables. Logistic regression models were computed separately for each outcome in 1999 and 2002. Main results: In multivariable models, very high physical activity was associated with decreased risk of a fall in 1999 (odds ratio 0.67, 95% CI 0.48 to 0.93) and in 2002 (odds ratio 0.62, 95% CI 0.42 to 0.92). High/very high physical activity was associated with decreased risk of broken or fractured bones in 2002 (odds ratio 0.64, 95% CI 0.42 to 0.96). No significant association was found between physical activity and injury from a fall. Conclusions: The results suggest that at least daily moderate to vigorous physical activity is required for the primary prevention of falls to the ground and broken or fractured bones in women aged 70-75 years.