Angiogenesis, Metabolism, Endothelial and Platelet Markers in Diabetes and Cardiovascular Disease.

Introduction: Diabetes is a leading risk factor for cardiovascular disease (CVD), the pathophysiology of both being linked to metabolic, endothelial, renal, angiogenic and platelet abnormalities. We hypothesised that abnormalities in these systems are more adverse in those whose CVD is compounded by diabetes, compared to those with diabetes or CVD alone. Materials and methods: Serum or plasma from 66 patients with diabetes alone, 76 with CVD alone, and 70 with both diabetes and CVD i.e. diabetic cardiovascular disease, was probed for markers of angiogenesis [angiopoietin 1 and 2, vascular endothelial growth factor (VEGF) and endoglin], metabolic [soluble receptor for advanced glycation products (sRAGE), leptin, lipocalin-2, interleukin-8, and cystatin-C], the endothelium (von Willebrand factor, endothelial microparticles and soluble E selectin)], and the platelet (platelet microparticles and soluble P selectin) by ELISA, Luminex or flow cytometry. Results: VEGF (p = 0.04), von Willebrand factor (p = 0.001) and endothelial microparticles (p = 0.042) were all higher in diabetic cardiovascular disease than in diabetes alone and cardiovascular disease alone. Soluble E selectin was higher in diabetic cardiovascular disease than in diabetes alone (p = 0.045), whilst cystatin-C (p = 0.004) and soluble P selectin (p < 0.001) were higher in diabetes and diabetic cardiovascular disease than in cardiovascular disease alone. There were no differences in angiopoietin 1 or 2, endoglin, sRAGE, leptin, lipocalin-2, or interleukin-8. Conclusion: Angiopoietin 1 or 2, endoglin, sRAGE, leptin, lipocalin-2, interleukin-8, and cystatin-c cannot differentiate diabetes from cardiovascular disease, or both conditions combined. Our data point to a more adverse endothelial (von Willebrand factor, endothelial microparticles), and angiogenic profile (VEGF) in those with diabetic cardiovascular disease, supporting the view that this group should be targeted more aggressively.

Landscape distribution and abundance of animal-associated adult filth flies on commercial swine facilities in North Carolina, US.

Filth flies associated with animal production transmit pathogens to humans and animals, propagate antimicrobial resistance in microbial communities and provoke nuisance litigation. Although dispersal of flies from facilities is often responsible for these negative effects, filth fly research on swine facilities has been limited to within the barns. Filth fly adaptations in space and time, as well as influences of abiotic and biotic factors impact distribution and abundance of animal-associated filth flies on swine production facilities. In this study, fly surveillance was conducted around four swine facilities in Bladen County, North Carolina, U.S.A. from January 2019 to October 2019. Traps were replaced weekly and animal-associated filth flies were identified. Flies were grouped for comparison based on biology and differences in pest management strategies. There were distinct differences in abundance and spatial distribution of different filth fly groups on the swine facilities, which are likely linked to environmental factors like spatial relation to crop production and species phenology. The impact of the observed temporal and spatial distribution and abundance is discussed in the context of filth fly management.

Consequences for Norway from a hypothetical accident at the Sellafield reprocessing plant: Atmospheric transport of radionuclides.

The potential consequences for Norway should a nuclear accident at the Sellafield nuclear site occur, have been of concern for Norwegian authorities for several decades. Meteorological data from a 33-year period and the dispersion model 'SNAP' were used to evaluate meteorological conditions for which atmospheric transport of radionuclides from Sellafield to Norway would lead to the most severe impacts. The worst-case meteorological scenario for Norway, was found on 25th June 1989 for a low elevation (0-800 m) release and on 29th June 2001 for a higher elevation (800-1600 m) release. In both cases the western part of Norway was most affected. In general, the probability for depositions (>10 Bq/m2 of 137Cs) increased about 40% during the autumn and winter compared to the spring and summer months. An influence of climate change on the depositions was analysed, but not verified. Results from a number of simulations were also compared to identify how factors such as radioactive particle characteristics and initial release conditions could affect the predicted radionuclide deposition. The impact on predicted total depositions as well as hot-spot depositions by varying particle density and size as well as release elevation in worst-case scenario simulations amounted to about 40%-50%.

Management of bone metastasis and cancer treatment-induced bone loss during the COVID-19 pandemic: An international perspective and recommendations.

Optimum management of patients with cancer during the COVID-19 pandemic has proved extremely challenging. Patients, clinicians and hospital authorities have had to balance the risks to patients of attending hospital, many of whom are especially vulnerable, with the risks of delaying or modifying cancer treatment. Those whose care has been significantly impacted include patients suffering from the effects of cancer on bone, where delivering the usual standard of care for bone support has often not been possible and clinicians have been forced to seek alternative options for adequate management. At a virtual meeting of the Cancer and Bone Society in July 2020, an expert group shared experiences and solutions to this challenge, following which a questionnaire was sent internationally to the symposium's participants, to explore the issues faced and solutions offered. 70 respondents, from 9 countries (majority USA, 39%, followed by UK, 19%) included 50 clinicians, spread across a diverse range of specialties (but with a high proportion, 64%, of medical oncologists) and 20 who classified themselves as non-clinical (solely lab-based). Spread of clinician specialty across tumour types was breast (65%), prostate (27%), followed by renal, myeloma and melanoma. Analysis showed that management of metastatic bone disease in all solid tumour types and myeloma, adjuvant bisphosphonate breast cancer therapy and cancer treatment induced bone loss, was substantially impacted. Respondents reported delays to routine CT scans (58%), standard bone scans (48%) and MRI scans (46%), though emergency scans were less affected. Delays in palliative radiotherapy for bone pain were reported by 31% of respondents with treatments often involving only a single dose without fractionation. Delays to, or cancellation of, prophylactic surgery for bone pain were reported by 35% of respondents. Access to treatments with intravenous bisphosphonates and subcutaneous denosumab was a major problem, mitigated by provision of drug administration at home or in a local clinic, reduced frequency of administration or switching to oral bisphosphonates taken at home. The questionnaire also revealed damaging delays or complete stopping of both clinical and laboratory research. In addition to an analysis of the questionnaire, this paper presents a rationale and recommendations for adaptation of the normal guidelines for protection of bone health during the pandemic.

Resistant Starch Production and Glucose Release from Pre-Prepared Chilled Food: The SPUD Project.

With an increasing prevalence of diabetes worldwide, effective dietary strategies for blood glucose control are crucial. As carbohydrates make up approximately 50% of the diet, it is neither practical nor advisable to avoid them altogether. Most of the carbohydrate in the diet is derived from starch, found in potatoes, pasta, rice and bread. These foods are often processed in some way before consumption, yet little is known about the effects processing, such as chilling and reheating, has on the glycaemic response, particularly when the food is consumed in the context of a mixed meal. This article introduces the SPUD project, a BBSRC DRINC-funded initiative. Taking the potato as the model carbohydrate, this project will investigate, via in vitro and in vivo studies, the effects of domestic food processing techniques on the glycaemic response. A final study, utilising intrinsically labelled potato and a dual stable isotope methodology, will model glucose flux data to determine the underlying mechanisms of action.

"The use of bisphosphonates to treat skeletal complications in solid tumours".

The skeleton is the most common site of secondary disease in breast cancer and prostate cancer, with up to 80% of patients with advanced disease developing bone metastases (BM). The proportion is also substantial in advanced lung cancer (20%-40%). Because of the high prevalence of cancers of the breast, prostate and lung, these cancers account for more than 80% of cases of metastatic bone disease occurring in solid tumours. Metastatic bone disease is associated with greatly increased bone resorption by osteoclasts, leading to moderate to severe pain and other skeletal complications, with major impact on quality of life (QoL). Skeletal Related Events (SREs) have been defined as: pathological long bone or vertebral fractures; spinal cord compression; need for radiation for pain relief or to prevent fracture/spinal cord compression, need for surgery to bone and hypercalcaemia. More recently, Symptomatic Skeletal Events (SSEs) have been defined to monitor QoL. Although there are currently no curative treatments for metastatic bone disease, patients with breast or prostate cancer and BM are now surviving for several years and sometimes longer, and prevention of SREs is the key aim to optimization of QoL. Since their discovery 50 years ago and their introduction more than 30 years ago into the field of metastatic bone disease, a range of oral and intravenous bisphosphonate drugs have made a major contribution to prevention of SREs. Large trials have clearly demonstrated the clinical value of different bisphosphonate-based drugs (including the oral drugs ibandronate and clodronate and intravenous agents such as zoledronate and pamidronate), in treatment of hypercalcaemia of malignancy and the reduction of SREs and SSEs in a range of cancers. Despite the success of denosumab in reducing osteolysis, bisphosphonates also remain mainstay drugs for treatment of metastatic bone disease. Recognizing the 50th Anniversary of the discovery of bisphosphonates, this review focuses on their continuing value in BM treatment and their future potential, for example in providing a bone-targeting vehicle for cytotoxic drugs.

Using a chain of models to predict health and environmental impacts in Norway from a hypothetical nuclear accident at the Sellafield site.

When a nuclear accident occurs, decision makers in the affected country/countries would need to act promptly to protect people, the environment and societal interests from harmful impacts of radioactive fallout. The decisions are usually based on a combination of model prognoses, measurements, and expert judgements within in an emergency decision support system (DSS). Large scale nuclear accidents would need predictive models for the atmospheric, terrestrial, freshwater, and marine ecosystems, for the connections between these in terms of radionuclide fluxes, and for the various exposure pathways to both humans and biota. Our study showed that eight different models and DSS modules could be linked to assess the total human and environmental consequences in Norway from a hypothetical nuclear accident, here chosen to be the Sellafield nuclear reprocessing plant. Activity concentrations and dose rates from 137Cs for both humans and the environment via various exposure routes were successfully modelled. The study showed that a release of 1% of the total inventory of 137Cs in the Highly Active Liquor Tanks at Sellafield Ltd is predicted to severely impact humans and the environment in Norway if strong winds are blowing towards the country at the time of an accidental atmospheric release. Furthermore, since the models did not have built-in uncertainty ranges when this Sellafield study was performed, investigations were conducted to identify the key factors contributing to uncertainty in various models and prioritise the ones to focus on in future research.

The drugs don't work: evaluation of educational theatre to gauge and influence public opinion on antimicrobial resistance.

Increased public awareness of antimicrobial resistance (AMR) is a key component of effective antimicrobial stewardship strategies. Educational theatre combined with an expert panel was used to engage the public about AMR through delivery of a play entitled 'The drugs don't work'. Audience knowledge and understanding of AMR were measured by pre- and post-play questionnaires. Performance of the play and discussion with the expert panel significantly improved audience knowledge and understanding of AMR, including antibiotic misuse and prescribing. Educational theatre provides a positive learning experience and is an innovative method of public engagement to disseminate important public health messages.

Exploring taxonomic and phylogenetic relationships to predict radiocaesium transfer to marine biota.

One potentially useful approach to fill data gaps for concentration ratios, CRs, is based upon the hypothesis that an underlying taxonomic and/or phylogenetic relationship exists for radionuclide transfer. The objective of this study was to explore whether these relationships could be used to explain variation in the transfer of radiocaesium to a wide range of marine organisms. CR data for 137Cs were classified in relation to taxonomic family, order, class and phylum. A Residual Maximum Likelihood (REML) mixed-model regression modelling approach was adopted. The existence of any patterns were then explored using phylogenetic trees constructed with mitochondrial COI gene sequences from various biota groups and mapping the REML residual means onto these trees. A comparison of the predictions made using REML with blind datasets allowed the efficacy of the procedure to be tested. The only significant correlation between predicted and measured activity concentrations was revealed at the taxonomic level of order when comparing REML analysis output with data from the Barents Sea Region. For this single case a correlation 0.80 (Spearman rank) was derived which was significant at the 0.01 level (1-tailed test) although this was not the case once a (Bonferroni) correction was applied. The application of the REML approach to marine datasets has met with limited success, and the phylogenetic trees illustrate complications of using predictions based on values from different levels of taxonomic organization, where predicted values for the order level can mask the values at lower taxonomic levels. Any influence of taxonomy and phylogeny on transfer is not immediately conspicuous and categorizing marine organisms in this way is limited in providing a potentially robust prognostic extrapolation tool. Other factors may plausibly affect transfer to a much greater degree in marine systems, such as quite diverse life histories and different diets, which may confound any phylogenetic pattern.

Communication of prostate cancer cells with bone cells via extracellular vesicle RNA; a potential mechanism of metastasis.

The role of extracellular vesicles (EVs) as vehicles for cell-to-cell communication between a tumour and its environment is a relatively new concept. The hypothesis that EVs may be critical in co-opting tissues by tumours to generate distant metastatic niches is particularly pertinent to prostate cancer (PCa), where metastatic-tropism to bone predominates over other tissue types. The potential role of EVs as a means of communication between PCa cells and cells of the bone stroma such as osteoblasts, is yet to be fully explored. In this study, we demonstrate that PCa cell EVs both enhance osteoblast viability and produce a significantly more supportive growth environment for PCa cells when grown in co-culture with EV-treated osteoblasts (p < 0.005). Characterisation of the RNA cargo of EVs produced by the bone-metastatic PCa cell line PC3, highlights the EV-RNA cargo is significantly enriched in genes relating to cell surface signalling, cell-cell interaction, and protein translation (p < 0.01). Using novel techniques to track RNA, we demonstrate the delivery of a set of PCa-RNAs to osteoblast via PCa-EVs and show the effect on osteoblast endogenous transcript abundance. Taken together, by using proof-of-concept studies we demonstrate for the first time the contribution of the RNA element of the PCa EV cargo, providing evidence to support PCa EV communication via RNA molecules as a potential novel route to mediate bone metastasis. We propose targeting PCa EVs could offer a potentially important preventative therapy for men at risk of metastatic PCa.

Benefits and risks of adjuvant treatment with zoledronic acid in stage II/III breast cancer. 10 years follow-up of the AZURE randomized clinical trial (BIG 01/04).

Adjuvant bisphosphonates improve disease outcomes in postmenopausal early breast cancer (EBC) but the long-term effects are poorly described. The AZURE trial (ISRCTN79831382) was designed to determine whether adjuvant zoledronic acid (ZOL) improves disease outcomes in EBC. Previous analyses showed no effect on overall outcomes but identified benefits in postmenopausal women. Here we present the long-term risks and benefits of adjuvant ZOL with 10-years follow-up. PATIENTS AND METHODS: 3360 patients with stage II/III breast cancer were included in an academic, international, phase III, randomized, open label trial. Patients were followed up on a regular schedule until 10 years. Patients were randomized on a 1:1 basis to standard adjuvant systemic therapy +/- intravenous ZOL 4 mg every 3-4 weeks x6, and then at reduced frequency to complete 5 years treatment. The primary outcome was disease free survival (DFS). Secondary outcomes included invasive DFS (IDFS), overall survival (OS), sites of recurrence, skeletal morbidity and treatment outcomes according to primary tumor amplification of the transcription factor, MAF. Pre-planned subgroup analyses focused on interactions between menopausal status and treatment effects. RESULTS: With a median follow up of 117 months [IQR 70.4-120.4), DFS and IDFS were similar in both arms (HRDFS  = 0.94, 95%CI = 0.84-1.06, p = 0.340; HRIDFS  = 0.91, 95%CI = 0.82-1.02, p = 0.116). However, outcomes remain improved with ZOL in postmenopausal women (HRDFS  = 0.82, 95%CI = 0.67-1.00; HRIDFS  = 0.78, 95%CI = 0.64-0.94). In the 79% of tested women with a MAF FISH negative tumor, ZOL improved IDFS (HRIDFS  = 0.75, 95%CI = 0.58-0.97) and OS HROS  = 0.69, 95%CI = 0.50-0.94), irrespective of menopause. ZOL did not improve disease outcomes in MAF FISH + tumors. Bone metastases as a first DFS recurrence (BDFS) were reduced with ZOL (HRB-DFS  = 0.76, 95%CI = 0.63-0.92, p = 0.005). ZOL reduced skeletal morbidity with fewer fractures and skeletal events after disease recurrence. 30 cases of osteonecrosis of the jaw in the ZOL arm (1.8%) have occurred. CONCLUSIONS: Disease benefits with adjuvant ZOL in postmenopausal early breast cancer persist at 10 years of follow-up. The biomarker MAF identified a patient subgroup that derived benefit from ZOL irrespective of menopausal status.

Investigation of the vertical distribution and speciation of 137Cs in soil profiles at burnt and unburnt forest sites in the Belarusian Exclusion Zone.

The effects of fire events on contaminant radionuclides within soils of the Belarusian Exclusion Zone were investigated. A number of cores were taken from locations known to have been subject to fire events in the past as well as a series of cores from nearby unburnt locations. Both burnt and unburnt cores were analyzed for contaminant radionuclides as well as a range of relevant soil parameters. The distribution of 137Cs between various fractions (reversibly bound, irreversibly bound and insoluble) was analyzed. Results indicate no evidence of enhancement or enrichment of radionuclides within the soil column although this does not negate the possibility that such effects were evident at some point in the past, the fire events at two of the sites having occurred almost ten years earlier. Evidence was present of a persistent effect on how 137Cs was distributed between different fractions of the soil, primarily in relation to the proportions associated with oxides of Fe and Mn and organic matter. The results of the study appear to indicate that the long-term effects of a forest fire on contaminant 137Cs within the soil column are expressed through changes in the physico-chemical forms of the nuclide to a larger extent than simple redistribution of the contaminant within the soil column.

Modelling dispersal of radioactive contaminants in Arctic waters as a result of potential recovery operations on the dumped submarine K-27.

Of the wide variety of dumped objects containing radioactive materials in the Arctic seas, the submarine K-27 constitutes a major risk due to the large amount of highly enriched uranium onboard and its location in shallow waters. As the matter of potential operations involving raising of the submarine have entered the public arena, a priori assessment of the contamination in the Arctic marine environment that could result after a possible accident during such operations is a matter of some interest. The dispersion of contaminants within the Arctic has been assessed using a large scale hydrodynamic model for a series of plausible accident scenarios and locations under different oceanographic regimes. Results indicate that, depending primarily on the nature of a release (i.e. instantaneous or continuous), large areas of the Arctic marine environment will exhibit contamination to varying degrees.

On the divergences in assessment of environmental impacts from ionising radiation following the Fukushima accident.

The accident at the Fukushima-Daiichi Nuclear Power Station on March 11, 2011, led to significant contamination of the surrounding terrestrial and marine environments. Whilst impacts on human health remain the primary concern in the aftermath of such an accident, recent years have seen a significant body of work conducted on the assessment of the accident's impacts on both the terrestrial and marine environment. Such assessments have been undertaken at various levels of biological organisation, for different species, using different methodologies and coming, in many cases, to divergent conclusions as to the effects of the accident on the environment. This article provides an overview of the work conducted in relation to the environmental impacts of the Fukushima accident, critically comparing and contrasting methodologies and results with a view towards finding reasons for discrepancies, should they indeed exist. Based on the outcomes of studies conducted to date, it would appear that in order to avoid the fractured and disparate conclusions drawn in the aftermath of previous accidents, radioactive contaminants and their effects can no longer simply be viewed in isolation with respect to the ecosystems these effects may impact. A combination of laboratory based and field studies with a focus on ecosystem functioning and effects could offer the best opportunities for coherence in the interpretation of the results of studies into the environmental impacts of ionising radiation.

Impacts on the terrestrial environment in case of a hypothetical accident involving the recovery of the dumped Russian submarine K-27.

Objects containing radioactivity have been routinely dumped in Arctic waters near NW Russia up until the 1990s. One of the most radioactive objects in this region, the nuclear submarine K-27, was dumped in Stepogovo Fjord and contained spent nuclear fuel (SNF). Although the two K-27 submarine reactors were mothballed before dumping, concerns about the potential long term risks of contamination remain and plans to retrieve and decommission K-27 exist. In this article, human dose and environmental impact aseessments are presented for two possible future scenarios involving: (1) an ingress of water into a reactor in situ leading to a spontaneous chain reaction (SCR) and (2) an on-board fire when SNF is being removed at the mainland decommissiong site at Gremhika Bay on the Kola Peninsula. Assessments have been completed using conservative assumptions, focusing on possible effects to Norwegian territory. Atmospheric transport and deposition of radioactivity was modelled near field and regionally, using appropriate models, whilst human doses and environmental exposures were modelled using a standard IAEA approach and the ERICA tool, respectively. Results indicate that large areas of Norwegian territory could be affected by fallout from the Gremhika scenario, especially in the north, though at levels two orders of magnitude lower than those observed after the Chernobyl accident. Potential doses, primarily due to ground shine, to a critical group of personnel on-site at Stepogovo resulting from a SCR could require preventative measures based on ICRP recommendations (20-100 mSv). Doses to non-human biota in Norway for the Gremhika scenario would be negligible, typical of background dose rates for terrestrial organisms.

Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: A systematic review and meta-analysis.

AIM: Metformin is the most widely used oral hypoglycaemic drug, but it may lower B12 status, which could have important clinical implications. We undertook a systematic review and meta-analysis of the relationship between metformin use and vitamin B12 deficiency in persons with type 2 diabetes. METHODS: Electronic database searches were undertaken (1st January 1957-1st July 2013) using the Cochrane library, Scopus, CINAHL, Grey literature databases, Pub Med Central, NICE Clinical Guidelines UK, and ongoing clinical trials. Included studies were of any study design, with data from patients with type 2 diabetes of any age or gender, taking any dose or duration of metformin. Planned primary outcomes were serum vitamin B12 levels, % prevalence or incidence of vitamin B12 deficiency and risk of vitamin B12 deficiency. RESULTS: Twenty-six papers were included in the review. Ten out of 17 observational studies showed statistically significantly lower levels of vitamin B12 in patients on metformin than not on metformin. Meta-analysis performed on four trials demonstrated a statistically significant overall mean B12 reducing effect of metformin of 57pmol/L [WMD (fixed)=-0.57 (95% CI: -35 to -79pmol/L)] after 6weeks to 3months of use. CONCLUSION: The evidence from this review demonstrates an association between metformin usage and lower levels of vitamin B12 by 57pmol/L, which leads to frank deficiency or borderline status in some patients with type 2 diabetes. This suggests that it is prudent to monitor B12 levels in these patients who are at increased risk of deficiency.

Synthesis, analysis and biological evaluation of novel indolquinonecryptolepine analogues as potential anti-tumour agents.

A small library of cryptolepine analogues were synthesised incorporating halogens and/or nitrogen containing side chains to optimise their interaction with the sugar-phosphate backbone of DNA to give improved binding, interfering with topoisomerase II hence enhancing cytotoxicity. Cell viability, DNA binding and Topoisomerase II inhibition is discussed for these compounds. Fluorescence microscopy was used to investigate the uptake of the synthesised cryptolepines into the nucleus. We report the synthesis and anti-cancer biological evaluation of nine novel cryptolepine analogues, which have greater cytotoxicity than the parent compound and are important lead compounds in the development of novel potent and selective indoloquinone anti-neoplastic agents.

Temporal genetic stability of Stegomyia aegypti (= Aedes aegypti) populations.

The mosquito Stegomyia aegypti (= Aedes aegypti) (Diptera: Culicidae) is the primary vector of viruses that cause yellow fever, dengue and Chikungunya fever. In the absence of effective vaccines, the reduction of these diseases relies on vector control strategies. The success of these strategies is tightly linked to the population dynamics of target populations. In the present study, 14 collections from St. aegypti populations separated by periods of 1-13 years were analysed to determine their temporal genetic stability. Although temporal structure is discernible in most populations, the degree of temporal differentiation is dependent on the population and does not obscure the geographic structure of the various populations. The results suggest that performing detailed studies in the years prior to and after population reduction- or modification-based control interventions at each target field site may be useful in assessing the probability of success.

A new version of the ERICA tool to facilitate impact assessments of radioactivity on wild plants and animals.

A new version of the ERICA Tool (version 1.2) was released in November 2014; this constitutes the first major update of the Tool since release in 2007. The key features of the update are presented in this article. Of particular note are new transfer databases extracted from an international compilation of concentration ratios (CRwo-media) and the modification of 'extrapolation' approaches used to select transfer data in cases where information is not available. Bayesian updating approaches have been used in some cases to draw on relevant information that would otherwise have been excluded in the process of deriving CRwo-media statistics. All of these efforts have in turn led to the requirement to update Environmental Media Concentration Limits (EMCLs) used in Tier 1 assessments. Some of the significant changes with regard to EMCLs are highlighted.

Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics.

BACKGROUND: Analyses of phase III trials showed that denosumab was superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) irrespective of age, history of SREs, or baseline pain status. This analysis assessed the risk of SREs across additional baseline characteristics. PATIENTS AND METHODS: Patients (N = 5543) from three phase III trials who had breast cancer, prostate cancer, or other solid tumours and one or more bone metastasis were included. Superiority of denosumab versus ZA in reducing risk of first SRE and first and subsequent SREs was assessed in subgroups defined by the Eastern Cooperative Oncology Group performance status (ECOG PS), bone metastasis location, bone metastasis number, visceral metastasis presence/absence, and urinary N-telopeptide (uNTx) level using Cox proportional hazards and Anderson-Gill models. Subgroups except bone metastasis location were also assessed for each solid tumour type. RESULTS: Compared with ZA, denosumab significantly reduced the risk of first SRE across all subgroups (hazard ratio [HR] ranges: ECOG PS, 0.79-0.84; bone metastasis location, 0.78-0.83; bone metastasis number, 0.78-0.84; visceral metastasis presence/absence, 0.80-0.82; uNTx level, 0.73-0.86) and reduced the risk of first and subsequent SREs in all subgroups (HR ranges: ECOG PS, 0.76-0.83; bone metastasis location, 0.78-0.84; bone metastasis number, 0.79-0.81; visceral metastasis presence/absence, 0.79-0.81; uNTx level, 0.74-0.83). Similar results were observed in subgroups across tumour types. CONCLUSION: Denosumab was superior to ZA in preventing SREs in patients with bone metastases from advanced cancer, regardless of ECOG PS, bone metastasis number, baseline visceral metastasis presence/absence, and uNTx level.