Does social deprivation correlate with meningococcal MenACWY, Hib/MenC and 4CMenB/Meningococcal Group B vaccine uptake in Northern Ireland?

BACKGROUND: Several meningococcal vaccines have been recently introduced into the infant and adolescent vaccination schedules in Northern Ireland to promote immunity to Neisseria meningitidis, protecting against meningococcal septicaemia and meningococcal meningitis. Maintained vaccination uptake is vital in securing individual protection as well as herd immunity. Several social factors have been described in influencing vaccine uptake and therefore it was the aim of this study to examine possible correlations between meningococcal vaccine uptake rates and indicators of social deprivation in Northern Ireland. METHODS: Vaccination data was retrieved from the Cover of Vaccination Evaluated Rapidly (COVER) database, for meningococcal vaccines (MenACWY, HiB/MenC & 4CMenB, as well as for MMR vaccine as a non-meningococcal control). Vaccine coverage data assessed included (i). Two doses of MenB by 12 months, (ii). All 3 doses of MenB by 24 months, (iii). HiB/MenC coverage, (iv). MenACWY (Year 12s, for NI) (v). First dose of MMR. Northern Ireland Multiple Deprivation Measures 2017 (NIMDM2017) were examined against 38 indicators in 7 domains. NI HSCT vaccine uptake dataset for each vaccine was correlated with each indicator in the HSCT NIMDM2017 dataset. Regression analysis was performed to determine the relationship between vaccine uptake and deprivation indicators and coefficient of variation (R2) was calculated for each of the indicators. R2 values >0.7 were considered significant. RESULTS: For 4CMenB (all 3 doses by 24 Months), HiB/MenC, MenACWY and for MMR, correlation of variation (R2) values > 0.7, were obtained for 17, 16, 0 and 17 social deprivation indicators, respectively. Significant deprivation indicators were (i) the proportion of 18-21 year olds, who have not enrolled in higher education courses at higher or further education establishments, (ii) the proportion of domestic dwellings that are unfit, (iii) the proportion of domestic dwellings with Local Area Problem Scores, (iv) rate of burglary, (v) rate of vehicle crime, (vi) rate of antisocial behaviour incidents (per 1,000 population), (vii) absenteeism at primary schools and (viii) the proportion of the population aged 65 and over living in households whose equivalised income is below 60% of the NI median. CONCLUSIONS: Within the last two decades, incidence of meningococcal disease has been on the decline. The introduction of meningococcal vaccines has contributed to this decrease and uptake of such vaccines should remain a public health priority to maintain the decline in meningococcal disease. Identifying contributing factors to low vaccine uptake, such as, the association between local deprivation and uptake of meningococcal vaccines, should be of public health importance and acknowledged by local governments and policy makers in their efforts to enhance vaccine uptake, both infant and teenage vaccination. There is a clear correlation with educational deprivation measures such as absenteeism and poor educational attainment and reduced vaccine uptake, perhaps through lack of understanding and willingness to vaccinate. This is where the importance of a clear and coherent public health message surrounding meningococcal vaccination should be prioritised, particularly to establish innovative modalities in a multidisciplinary team approach, to reach out to and increase vaccine uptake rates in socially deprived communities in Northern Ireland.

Vaccination terminology: A revised glossary of key terms including lay person's definitions.

WHAT IS KNOWN AND OBJECTIVE: There has been a paucity of vaccine and vaccine-related definitions within the scientific and medical peer-reviewed literature, particularly with the arrival of COVID-19. Therefore, it was the aim of this commentary to collate definitions to 44 vaccine- and vaccinology-related key terms, from four international and respected sources of information (where available), including (i) the World Health Organisation (WHO), (ii) the US Centers for Disease Control and Prevention (CDC), (iii) The Department of Health, Government of Australia and (iv) the European Union. In addition, it was a further aim to develop a lay person's definition to each of these 44 key terms, to act as a published and citeable reference point for pharmacists and other healthcare professionals, when communicating with patients and other public-facing stakeholders. COMMENT: Definitions are important in health care in order to (i) provide concise insight on a specific topic, (ii) provide a common understanding and (iii) set reference points to allow the adoption of a standard uniform approach. WHAT IS NEW AND CONCLUSION: The collation of definitions of key vaccine terms was compiled from four respected sources of information. A glossary of 44 key terms was produced to help pharmacists and other healthcare professionals explain such terms professionally, as well as to patient stakeholders in lay person's vocabulary. These lay definitions had superior readability metrics than definitions from any of the four professional sources, indicating their suitability for engagement with patient-facing stakeholders. Understanding the barriers to vaccine uptake is crucial for health professionals and policymakers to achieve improved uptake rates. This commentary has aimed at adding value to healthcare professionals and patients, by providing an up-to-date glossary of several professional definitions, from respected sources, as well as an accompanying lay definition to support the healthcare professional-patient communicative interface. Vaccines have become an important preventative tool, particularly in the context of the COVID-19 pandemic, to help mitigate disease severity and to help control the pandemic locally, nationally and internationally. Accessible and robust definitions help inform the dialogue to achieve this goal and the avoidance of obscurum per obscurius.

The value of evaluating the abdominal aorta in patients <50 years of age presenting for abdominal ultrasound.

INTRODUCTION: Practitioners of US routinely include a survey of the abdominal aorta during abdominal US in accordance with international guidelines. Such practice is of uncertain value in younger patients. METHODOLOGY: This study was a retrospective review of 2000 abdominal US examinations which included visualisation of the aorta in patients <50 years of age. Patient demographics and referral details were recorded, and US images and reports were reviewed for the presence of aortic and periaortic pathology. RESULTS: The most common indications for US were abdominal pain (1337, 44%), deranged liver function tests (453, 15%), nausea and/or vomiting (229, 8%), elevated inflammatory markers (146, 5%), pancreatitis (134, 4%) and pyrexia (127, 4%). Fewer than half (977, 49%) of the reports contained a comment regarding the aorta. Aortic pathology was reported in 2 (0.1%) cases. Both were reported as aortic ectasia and both represented a false-positive diagnosis. One male patient had a known abdominal aortic aneurysm with endovascular aortic repair. No new aortic aneurysms were found. All cases of atherosclerotic disease were ignored, and none were reported. Periaortic pathology was encountered on 1 patient, but this was known. No case of new periaortic pathology was detected. CONCLUSION: Routine and indiscriminate imaging of the abdominal aorta during abdominal US in patients <50 years of age is not evidence based. No new case of abdominal aortic aneurysm or new para-aortic pathology was detected, all cases of atherosclerosis were ignored, and two false-positive diagnoses of aortic ectasia were made.

Improving meningococcal MenACWY and 4CMenB/meningococcal group B vaccine-related health literacy in patients: Importance of readability of pharmaceutical Patient Leaflets.

WHAT IS KNOWN AND OBJECTIVE: Patient information leaflets (PILs) or Patient Leaflets (PLs) formally accompany dispensed medicines and are intended to provide the patient with information on how to use the medicine safely. To date, there have been no studies that have examined the readability of meningococcal vaccine patient-facing information, including information contained within the vaccine PIL. Given the role of pharmacists in presenting PILs to patients, it was, therefore, the aim of this study to quantitatively analyse the readability of Patient Leaflets, which accompany licensed meningococcal vaccines in the UK and US and to compare PILs to vaccine pharmaceutical manufacturers' summary of product characteristics (SPC), as well as other patient-facing vaccine-related information. METHODS: Five sources of meningococcal vaccine information were examined for the licensed meningococcal vaccines in the UK (Bexsero, Menveo, Menitorix, Trumenba, Nimenrix & NeisVac-C) and in the United States (Bexsero, Menveo, Trumenba, Menactra, Menomune-A/C/Y/W-135, Menquadfi), including as follows: (i) SPC (Electronic Medicines Compendium, UK), (ii) Package Insert (FDA; USA), (iii) Patient Leaflet (Electronic Medicines Compendium, UK), (iv) Vaccine pharmaceutical websites and (v) government web resources. Readability was examined employing 10 readability metrics, including the Flesch Reading Ease and the Flesch-Kincaid Grade level. RESULTS AND DISCUSSION: The information source with the greatest readability scores was the UK Patient Leaflet, which had a mean Flesch Reading Ease score of 58.1 and a mean Flesch-Kincaid Grade score of 7.3, followed by the US Department of Health & Human Services patient-facing website for vaccines (55.9 & 8, respectively), followed by the US Centers for Disease Control and Prevention Vaccine Information Statement (47.3 & 9.4, respectively). Pharmaceutical patient-facing websites for meningococcal vaccines had mean scores of 44.6 and 9.9, respectively. When compared with UK Patient Leaflets, pharmaceutical websites were statistically different with poorer readability with both Flesch Reading Ease and Flesch-Kincaid Grade Level indices (p = 0.02 & p = 0.04, respectively). WHAT IS NEW AND CONCLUSION: Pharmaceutical meningococcal vaccine PILs were easily read and had statistically significant good readability scores in comparison with vaccine SPCs and US Package Inserts, pharmaceutical product websites and other government patient-facing meningococcal vaccine information. Preparation of patient-facing materials of a complex topic, such as describing meningococcal vaccines, is difficult to accomplish. Although there is a plurality of sources of information through websites and social media, PILs are one of the few sources that are provided directly to patients. This underpins the potential importance of PILs and the importance of their readability. Adoption of readability calculators and scrutiny of materials for their readability will help authors develop materials with improved understanding for vaccine recipients, potentially leading to improved health literacy and vaccine uptake. Renewed efforts should be sought to promote the information within the PIL, thereby maximizing the value of this resource with vaccine recipients, their carers and family.

The value of surveying the kidneys during pelvic ultrasound examinations.

INTRODUCTION: Pelvic ultrasounds are commonly performed for various clinical indications in female patients presenting to the hospital. A survey of the kidneys is routinely included as part of the examination, but there is limited justification for their inclusion in the assessment of every female presenting for a pelvic ultrasound. METHOD: We examined the utility of surveying the kidney ultrasound during pelvic ultrasonography by reviewing the records of 1009 pelvic ultrasound examinations in 1000 women. RESULTS: In total, 46 incidental findings were identified, but 91% of these were clinically inconsequential. Only four patients had incidental findings of high clinical priority requiring specialist treatment. Of these, two patients were symptomatic and had urinary tract obstruction due to stones. The other two patients harboured asymptomatic renal cell carcinomas. The overall incidence of renal incidental findings of high clinical priority in asymptomatic patients was two in 1009 examinations (1999 kidneys). CONCLUSION: Indiscriminate uncritical screening of the kidneys in women presenting for pelvic ultrasound is not evidence-based and represents a low-yield examination with extremely low rate of incidental findings of clinical significance.

Raman spectroscopy predicts the link between claw keratin and bone collagen structure in a rodent model of oestrogen deficiency.

Osteoporosis is a common disease characterised by reduced bone mass and an increased risk of fragility fractures. Low bone mineral density is known to significantly increase the risk of osteoporotic fractures, however, the majority of non-traumatic fractures occur in individuals with a bone mineral density too high to be classified as osteoporotic. Therefore, there is an urgent need to investigate aspects of bone health, other than bone mass, that can predict the risk of fracture. Here, we successfully predicted association between bone collagen and nail keratin in relation to bone loss due to oestrogen deficiency using Raman spectroscopy. Raman signal signature successfully discriminated between ovariectomised rats and their sham controls with a high degree of accuracy for the bone (sensitivity 89%, specificity 91%) and claw tissue (sensitivity 89%, specificity 82%). When tested in an independent set of claw samples the classifier gave 92% sensitivity and 85% specificity. Comparison of the spectral changes occurring in the bone tissue with the changes occurring in the keratin showed a number of common features that could be attributed to common changes in the structure of bone collagen and claw keratin. This study established that systemic oestrogen deficiency mediates parallel structural changes in both the claw (primarily keratin) and bone proteins (primarily collagen). This strengthens the hypothesis that nail keratin can act as a surrogate marker of bone protein status where systemic processes induce changes.

A Natural, Calcium-Rich Marine Multi-mineral Complex Preserves Bone Structure, Composition and Strength in an Ovariectomised Rat Model of Osteoporosis.

Calcium supplements are used as an aid in the prevention of osteopenia and osteoporosis and also for the treatment of patients when used along with medication. Many of these supplements are calcium carbonate based. This study compared a calcium-rich, marine multi-mineral complex (Aquamin) to calcium carbonate in an ovariectomised rat model of osteoporosis in order to assess Aquamin's efficacy in preventing the onset of bone loss. Animals were randomly assigned to either non-ovariectomy control (Control), ovariectomy (OVX) plus calcium carbonate, ovariectomy plus Aquamin or ovariectomy plus Aquamin delay where Aquamin treatment started 8 weeks post OVX. At the end of the 20-week study, the trabecular architecture was measured using micro computed tomography, bone composition was assessed using Fourier transform infrared spectroscopy and the mechanical properties were assessed using nanoindentation and three-point bend testing. The study demonstrates that oral ingestion of Aquamin results in less deterioration of trabecular bone structure, mineral composition and tissue level biomechanical properties in the tibia of rats following ovariectomy than calcium carbonate. This study has shown that in an animal model of osteoporosis, Aquamin is superior to calcium carbonate at slowing down the onset of bone loss.

Incorporation of the natural marine multi-mineral dietary supplement Aquamin enhances osteogenesis and improves the mechanical properties of a collagen-based bone graft substitute.

Aquamin is a commercially-available supplement derived from the algae species Lithothamnion, which has proven osteogenic potential. By harnessing this potential and combining Aquamin with a collagen scaffold, with architecture and composition optimised for bone repair, the aim of this study was to develop a natural osteo-stimulative bone graft substitute. A fabrication process was developed to incorporate Aquamin into scaffolds to produce collagen-Aquamin (CollAqua) scaffolds at two different Aquamin concentrations, 100F or 500F (equivalent weight% of collagen or five times the weight of collagen respectively). CollAqua constructs had improved mechanical properties which were achieved without reducing the scaffold׳s permeability or porosity below the minimum level required for successful bone tissue engineering. The fabrication process produced a homogenous Aquamin distribution throughout the scaffold. Release kinetics revealed that in the first 12h, the entire Aquamin content was released from the 100F however, less than half of Aquamin in the 500F was released with the remainder released approximately 21 days later giving an initial burst release followed by a delayed release. Osteoblasts cultured on the CollAqua scaffolds showed improved osteogenesis as measured by alkaline phosphatase, osteopontin and osteocalcin expression. This was confirmed by increased mineralisation as determined by von Kossa and Alizarin red staining. In conclusion, a cell and growth factor free collagen-based bone graft substitute with enhanced mechanical properties has been developed. The addition of Aquamin to the collagen biomaterial significantly improved mineralisation by osteoblasts and results in a new product which may be capable of enhancing osteogenesis to facilitate bone repair in vivo.

Encapsulation of cardiac stem cells in superoxide dismutase-loaded alginate prevents doxorubicin-mediated toxicity.

Anthracyclines are powerful drugs available for the treatment of neoplastic diseases. Unfortunately, these chemotherapy agents cause cardiomyopathy and congestive heart failure. Doxorubicin (DOX) is a widely used anthracycline and evidence indicates that DOX-induced cardiotoxicity can be viewed as a stem cell disease, whereby the formation of reactive oxygen species (ROS) by DOX is seen to predominantly hinder cardiac stem cell (CSC) regenerative capability. Acute, early-onset and late-onset cardiotoxicity have been described and this may be reversible by the local administration of CSCs, which regenerate myocardial tissue and rescue the failing heart. CSCs are, however, particularly sensitive to oxidative stress and die rapidly by apoptosis in such adverse conditions. Therefore, this study aims to enhance CSC survival by encapsulation in an alginate hydrogel formulation containing superoxide dismutase (SOD), a reactive oxygen species scavenger. Cell survival was qualitatively and quantitatively assessed by fluorescent microscopy and assays measuring metabolic activity, cell viability, cytotoxicity and apoptosis. CSCs were cultured in DOX-conditioned cell culture medium and displayed reduced live cell numbers as well as high levels of apoptosis. Encapsulation of CSCs in alginate alone failed to prevent apoptosis. Encapsulation in SOD-loaded alginate reduced apoptosis to near-normal levels, whilst metabolic activity was returned to baseline. In conclusion, this study demonstrates that encapsulation of CSCs in SOD-loaded alginate hydrogel enhances CSC survival in the presence of DOX, raising the possibility of its application as a novel therapy for the treatment of acute and early onset DOX-induced cardiotoxicity.

Temporal changes in bone composition, architecture, and strength following estrogen deficiency in osteoporosis.

Using an ovariectomized (OVX) ovine model, we provide an analysis of the timing of changes in bone following estrogen deficiency. The expression of genes known to regulate osteoclastogenesis, matrix production, and mineralization, as measured by real-time RT-PCR, was significantly increased by 12 months; and increased expression was maintained through to 31 months post-OVX compared to controls. FTIR spectroscopy confirmed that mineralized crystals were less mature than in controls 12 months post-OVX and were even less so by 31 months. The mineral-to-matrix ratio was significantly reduced by 31 months, while the ratio of mature to immature collagen cross-linking was initially increased at 12 months and subsequently reduced at 31 months post-OVX. In contrast, trabecular number, thickness, and separation were unchanged at 12 months. Significant reductions in trabecular number and thickness and a significant increase in trabecular separation were observed 31 months after OVX. Most notably perhaps these combined changes led to a significant reduction in the compressive strength of trabecular bone after 31 months. The results indicate that there is an initial increase in bone turnover, which is accompanied by a change in bone composition. This is followed by a continued increase in bone resorption and relative reduction in bone formation, leading to deterioration in bone microarchitecture. Ultimately, these cumulative changes led to a significant reduction in the compressive strength of bones following 31 months of estrogen deficiency. These findings provide important insight into the time sequence of changes during osteoporosis.

The marine-derived, multi-mineral formula, Aquamin, enhances mineralisation of osteoblast cells in vitro.

Osteoporosis is a global health problem characterized by low bone mass and an increase in bone fragility. It is now well accepted that dietary factors play a central role in bone development and health. Diet that lacks adequate minerals is considered to be a risk factor for osteoporosis. The food supplement, Aquamin, is a natural, multi-mineral derived from the red algae Lithothamnion corallioides, rich in calcium, magnesium and 72 other trace minerals. The aim of this study was to evaluate the effect of Aquamin on osteoblastic behaviour and mineralisation in a pre-osteoblastic cell line. Cell number and metabolic activity were assessed using Hoescht DNA and AlamarBlue assays respectively. Osteogenic differentiation was measured using an alkaline phosphatase assay while mineralisation was determined using von Kossa and alizarin red staining. It is reported here that Aquamin promotes increased mineralisation in osteoblast cell culture. These data suggest that the nutritional supplement Aquamin plays an important role in promoting bone formation and may be useful in treating bone diseases such as osteoporosis.

Effects of estrogen deficiency and bisphosphonate therapy on osteocyte viability and microdamage accumulation in an ovine model of osteoporosis.

It has been proposed that osteocyte viability plays an important role in bone integrity, and that bone loss in osteoporosis may be partially due to osteocyte cell death following estrogen depletion. Osteoporosis treatments such as bisphosphonates can inhibit osteocyte apoptosis which in turn may also reduce remodeling. Consequently, microcracks in bone which are normally repaired by bone remodeling may accumulate. This study used an ovine model of osteoporosis to examine the effects of estrogen depletion and bisphosphonates on osteocyte apoptosis and microdamage accumulation. Skeletally mature ewes were randomly assigned into two equal groups; ovariectomy (OVX) and a non-treatment group (control). Half of these animals were sacrificed 12 months post-OVX. Twenty months post-OVX, a number of OVX animals were randomly selected and each received a supra-pharmacological dose of the bisphosphonate, zoledronic acid (Zol). This group and all the remaining animals were sacrificed 31 months post-OVX. A compact bone specimen was removed from the left metacarpal of each animal; half was used for osteocyte apoptosis detection and the remainder for microdamage analysis. Estrogen deficiency resulted in significant increases in the levels of osteocyte apoptosis while zoledronic acid significantly reduced the level of apoptosis in osteocytes. Zoledronic acid treatment resulted in the formation of more microcracks. However, these cracks were shorter than in control or OVX groups which may provide one explanation as to why increased damage levels following bisphosphonate treatment have not lead to increased fractures. This study also provides additional evidence of the importance of estrogen in preserving the osteocyte network.

Structural adaptation and intracortical bone turnover in an ovine model of osteoporosis.

Compact bone makes up approximately 80% of the human skeletal mass. This study examines the effect of estrogen deficiency on compact bone turnover and associated geometrical structural adaptation over a 31-month period in a large animal model. Twenty-seven skeletally mature sheep were divided into control (n = 16) and ovariectomy group (OVX, n = 11). Animals were administered five different fluorochrome dyes to label intracortical bone turnover, and sacrificed at 31 months. Compact bone samples were analyzed for cortical geometry, intracortical turnover at five time points, resorption cavities, porosity, and compressive strength. Intracortical bone turnover was significantly increased in OVX, which demonstrated seasonal variation. Cross-sectional area in OVX was significantly greater than control and was associated with an increased section modulus. Intracortical porosity was significantly increased in OVX, however, there was no significant difference in ultimate compressive strength between the groups. Our results demonstrate increased intracortical bone turnover, resportion spaces, and porosity in OVX, without adversely affecting compressive strength. Our results also support the hypothesis of geometrical adaptation of compact bone in response to estrogen deficiency. These results suggest an early structural compensatory response in compact bone, despite increased intracortical turnover.

Variation of trabecular microarchitectural parameters in cranial, caudal and mid-vertebral regions of the ovine L3 vertebra.

The lumbar vertebrae are major load-bearing structures within the spinal column. The current understanding of the microstructure of these bodies and their full role in load-bearing is incomplete. There is a need to develop our understanding of these issues to improve fracture prediction in musculoskeletal diseases such as osteoporosis. The lumbar vertebrae consist primarily of trabecular bone enclosed in a thin cortical shell, but little is known about how microstructural parameters vary within these structures, particularly in relation to the trabecular compartment. The specific aim of this study was to use micro-computed tomography to characterize the trabecular microarchitecture of the ovine L3 vertebra in cranial, mid-vertebra and caudal regions. The L3 vertebra was obtained from skeletally mature ewes (n = 18) more than 4 years old. Three-dimensional reconstructions of three pre-defined regions were obtained and microarchitectural parameters were calculated. Whereas there was no difference in bone volume fraction or structural model index between regions, trabecular number, thickness, spacing, connectivity density, degree of anisotropy and bone mineral density all displayed significant regional variations. The observed differences were consistent with the biomechanical hypothesis that in vivo loads are distributed differently at the endplates compared with the mid-vertebra. Thus, a more integrative approach combining biomechanical theory and anatomical features may improve fracture risk assessment in the future.

Effects of ovariectomy on bone turnover, porosity, and biomechanical properties in ovine compact bone 12 months postsurgery.

Compact bone makes up approximately 80% of the human skeleton by mass; but there are little data available on the effects of increased bone turnover on compact bone mechanical and material properties. This study addresses this question by measuring intracortical remodeling, resorption cavity number, and porosity in an ovariectomized (OVX) sheep model, and measures changes in biomechanical properties. Thirty-eight sheep were divided into two groups. Group 1 were controls (n = 19), and Group 2 were ovariectomized (OVX; n = 19). Fluorochrome dyes were administered intravenously to both groups at five time points over 12 months post-OVX to label sites of bone turnover. At 12 months post-OVX all animals were euthanized. Samples were harvested from the left metatarsal and were analyzed for intracortical bone turnover at five time points, the number of resorption cavities, and the level of intracortical porosity. The effects of these parameters on bone biomechanical properties were then measured. Bone turnover was increased in the OVX group at 6, 9, and 12 months (p < 0.05). Resorption was also higher in the OVX group at 12 months (p < 0.05). Furthermore, porosity was significantly increased in the OVX group at 12 months (p < 0.05). Stiffness and yield strength were reduced in the OVX group compared to controls (p = 0.05). Ultimate compressive strength and work to fracture did not differ between groups. These findings provide new insights into the mechanisms and effects of increased bone turnover on bone material and microstructural properties.

Effects of high bone turnover on the biomechanical properties of the L3 vertebra in an ovine model of early stage osteoporosis.

STUDY DESIGN: Investigations of the effects of high bone turnover on the L3 vertebra were carried out, using an ovariectomized (OVX) ovine model of early stage osteoporosis. OBJECTIVE: To assess the contribution of bone turnover to the biomechanics of L3. SUMMARY OF BACKGROUND DATA: Clinically, dual energy x-ray absorptiometry (DEXA) is used to measure bone mineral density (BMD). However, this can only predict 60% to 70% of bone strength; the remainder is due to bone quality. There is currently little information available on how strength is affected by changes in bone quality parameters, particularly bone turnover. Turnover can be assessed clinically using biochemical markers; however, this provides systemic values, whereas localized values are required to predict site-specific fracture risk. METHODS: Thirty-eight sheep were assigned to 2 groups (control, n = 19; OVX, n = 19). Both groups were intravenously administered a fluorochrome dye on the day of surgery and 3, 6, 9, and 12 months thereafter, to label sites of bone turnover. After 12 months, animals were killed and the spinal columns harvested. L3 vertebrae were scanned using DEXA. Bone turnover was quantified using epifluorescence microscopy, and microarchitecture was assessed by microCT scanning. Compressive testing was used to characterize the mechanical properties of the vertebrae. RESULTS: BMD and microarchitecture were unchanged in OVX compared with controls. However, bone turnover, as measured by fluorochrome labeled sites, was significantly increased in the OVX group in cortical and trabecular compartments. As a consequence, the biomechanical properties were significantly reduced in that group. CONCLUSION: These findings show that OVX resulted in changes in bone turnover, which reduced biomechanical properties in a model of early stage osteoporosis. These differences were present despite microarchitecture or BMD remaining unchanged. In the future, the ability to assess site-specific bone turnover would greatly enhance the accuracy with which fracture risk could be predicted.

The effects of increased intracortical remodeling on microcrack behaviour in compact bone.

The behaviour of microdamage in bone is related to its microstructural features and thus has an important role in tissue structural properties. However, it is not known how cracks behave in areas of increased intracortical remodeling. More remodeling creates wider variation in the properties of the primary microstructural features of cortical bone, namely osteons. This situation may occur after treatment involving parathyroid hormone or events such as menopause/ovariectomy. High turnover was modeled in this study by using ovariectomy (OVX) to induce surgical menopause in sheep. We hypothesized that osteon age would influence microcrack behaviour during propagation. Five fluorochrome dyes were administered intravenously at different time-points over 12 months post-OVX to label remodeling sites and all animals were then euthanized. Compact bone specimens (2x2x36 mm) were harvested from the right metatarsal. Samples were cyclically loaded to failure and then histological analyses were carried out. Cracks were categorized by length into three groups; short (<100 mum), intermediate (100-300 mum) and long (>300 mum). Numerical crack density (Cr.Dn) of long cracks was greater in controls compared with OVX. Controls also displayed a higher crack surface density (Cr.S.Dn) compared with OVX (p<0.05). The behaviour of short cracks did not differ between old and new osteons, but intermediate and long cracks preferentially stopped at newer osteons compared with older ones (p<0.05). This mechanism may have an important role in terms of prolonging fatigue life. We conclude that recently formed secondary osteons have a unique influence on propagating microcracks compared with older osteons. Therefore localized remodeling levels should be considered when studying microcrack behaviour in bone.

The behaviour of fatigue-induced microdamage in compact bone samples from control and ovariectomised sheep.

This study investigates the effect of microdamage on bone quality in osteoporosis using an ovariectomised (OVX) sheep model of osteoporosis. Thirty-four sheep were divided into an OVX group (n=16) and a control group (n=18). Fluorochromes were administered intravenously at 3 monthly intervals after surgery to label bone turnover. After sacrifice, beams were removed from the metatarsal and tested in three-point bending. Following failure, microcracks were identified and quantified in terms of region, location and interaction with osteons. Number of cycles to failure (Nf) was lower in the OVX group relative to controls by approximately 7%. Crack density (CrDn) was higher in the OVX group compared to controls. CrDn was 2.5 and 3.5 times greater in the compressive region compared to tensile in control and OVX bone respectively. Combined results from both groups showed that 91% of cracks remained in interstitial bone, approximately 8% of cracks penetrated unlabelled osteons and less than 1% penetrated into labelled osteons. All cases of labelled osteon penetration occurred in controls. Crack surface density (CrSDn), was 25% higher in the control group compared to OVX. It is known that crack behaviour on meeting microstructural features such as osteons will depend on crack length. We have shown that osteon age also affects crack propagation. Long cracks penetrated unlabelled osteons but not labelled ones. Some cracks in the control group did penetrate labelled osteons. This may be due the fact that control bone is more highly mineralized. CrSDn was increased by 25% in the control group compared to OVX. Further study of these fracture mechanisms will help determine the effect of microdamage on bone quality and how this contributes to bone fragility.

Microcracks in cortical bone: how do they affect bone biology?

Microcrack accumulation in cortical bone has been implicated in skeletal fragility and stress fractures. These cracks have also been shown to affect the mechanical and material properties of cortical bone. Their growth has been linked to osteocyte apoptosis and the initiation of the remodeling process, which also has a role in their repair. Clinically, osteoporosis is diagnosed using dual energy x-ray absorptiometry. However, evidence now indicates that bone mass alone is insufficient to satisfactorily explain the skeletal fragility of osteoporosis and consideration needs to be given to bone quality in the diagnosis and treatment of the disease. Bone quality includes parameters such as trabecular and cortical microarchitecture, morphology, bone turnover, degree of mineralization of the bone matrix, and significantly, the amount of microdamage present in the bone. Current clinical treatments concentrate on the inhibition of osteoclast activity to maintain bone mass in osteoporotic patients. However, these cells have a major role in removing existing microcracks from the bone matrix, and hence the use of bone resorption- inhibiting drugs may lead to insufficient bone repair and therefore an increase in microdamage accumulation and loss of bone quality.