Background Prostate cancer (PCa) patients are at increased fracture risk due to the need for androgen deprivation therapy (ADT) and progressive bone metastases. Previous meta-analyses of randomised controlled trials suggest that androgen receptor pathway inhibitors (ARPIs) increase fracture risk. Objective We assessed the impact of abiraterone-based treatment intensification on fracture-related hospitalisation (FRH) within the STAMPEDE trial platform. Design, setting and participants We performed a secondary analysis of two STAMPEDE trials in patients with high-risk non-metastatic (M0) or metastatic (M1) disease. Interventions Patients were allocated to either standard of care (SOC) or SOC plus abiraterone with prednisolone (AAP) or, in a later comparison, SOC+AAP with enzalutamide (Enza). Outcome measurements and statistical analysis A prespecified coding framework within Hospital Episode Statistics (HES) identified FRHs. Flexible parametric competing-risk models estimated 5-year cumulative incidence of FRH and sub-distribution hazard ratios (SDHR), with death as a competing risk. Outcome measurements and statistical analysis Between Nov 2011 and Mar 2016, 3893 patients were randomised to the STAMPEDE AAP±Enza trials. Linked HES data were available for 3102 patients in England. In M1 disease, 5-year FRH incidence was significantly lower with SOC + AAP than SOC alone (22% vs 30%; SDHR 0.77, 95%CI 0.59-0.99; p = 0.04) and with SOC + AAP + Enza than SOC alone (28% vs 38%; SDHR 0.69, 95%CI 0.54-0.88; p = 0.002). No significant difference was observed in M0 patients. Limitations include potential under-estimation of total fracture burden by exclusion of non-hospitalised fractures, lack of baseline assessment of fracture risk including bone mineral density, and longitudinal use of bone-protective therapy. Conclusions Abiraterone-based treatment intensification did not increase FRH compared to SOC alone. In M1 disease, abiraterone reduced rather than augmented fracture risk, most plausibly reflecting improved metastatic bone disease control.

Introduction Comorbidity impacts breast cancer treatment decisions, toxicity and overall survival. Use of biological therapies has rapidly expanded, with multiple new agents adopted in the past 10 years, including a range of human epidermal growth factor receptor 2 (HER2) targeting agents, cyclin-dependent kinase (CDK)4/6 inhibitors, antibody-drug conjugates, and PARP inhibitors. There has been no review assessing the influence of comorbidity on rates of drug use, toxicity, or overall outcomes. This scoping review has evaluated how comorbidity affects the prescribing, toxicity, and outcomes of biologics in breast cancer. Materials and methods Using the Joanna Briggs Institute methodology for scoping reviews, all original research articles published since 2000, assessing the influence of comorbidity on use, toxicity and outcomes with biologics in breast cancer, were included. Results A total of 58 studies were included. Comorbidity assessment was heterogeneous: formal comorbidity indices were used in 18/58 studies (predominantly the Charlson Comorbidity Index, used in some form in 15/58), specific conditions as a proxy for comorbidity in 30/58, symptom burden in 3/58 and other measures in 7/58. Over half of the studies (33/58) assessed trastuzumab; we excluded 29 of these as they focused on comorbidities in relation to trastuzumab-related cardiotoxicity, which has been reviewed in existing systematic reviews. A further 4 of the 33 trastuzumab studies were retained as they also discussed biologic prescribing patterns. The remaining 29 studies assessed other anti-HER2 agents (15/29), CDK4/6 inhibitors (9/29), bevacizumab (2/29), everolimus (1/29), or multiple agents (2/29). There were no studies focused on PARP inhibitors or immunotherapies. The influence of comorbidity varied depending on the comorbidity measure used, outcome assessed, and biologic agent. Increasing comorbidity showed trends towards monotherapy prescribing (4/13) and reduced biologic initiation (6/13). Findings regarding toxicity (13/58), treatment interruption/discontinuation (7/58), and survival (6/58) were mixed. Discussion Comorbidity significantly impacts biological agent use in breast cancer, with reduced prescribing observed in patients with comorbidities. Effects on survival, toxicity, and treatment discontinuation remain heterogeneous and inconclusive. Focused research examining biologic use in specific patient subgroups with comorbidities is needed. Older age and frailty should also be explored.

BACKGROUND:Men with prostate cancer (PC) are at increased risk of fragility fractures due to age, the disease itself, and cancer treatment, such as androgen-deprivation therapy. Despite the burden of fragility fractures on individuals and the healthcare systems, preventative measures are poorly implemented for this patient population. AIM:This study aims to explore osteoporosis knowledge, health beliefs, and self-efficacy among men with PC, and how these factors differ across socioeconomic groups. Findings will inform a tailored, integrated bone health intervention for men with PC. METHOD:A cross-sectional survey was conducted across eight general practices in an urban city in the UK from November 2024 to January 2025. Data collected included sociodemographic information; osteoporosis risk factors; and three validated questionnaires: FOOQ & MOKQ, OHBS, and OSES. Data were analysed using SPSS. RESULTS:Of 516 eligible men,197 responded (38.2% response rate). Participants demonstrated low osteoporosis knowledge (mean scores: 48.2% FOOQ, 33.5% MOKQ), yet showed moderate motivation and belief in the benefits of exercise and calcium. Self-efficacy scores were moderate (OSE-exercise: 69.6; OSE-calcium: 71.4). Men with older age, lower education, and greater deprivation tend to have poorer knowledge and more barriers to exercise. In addition, 19.6% reported falls in the previous 12 months. CONCLUSION:Men with PC have limited understanding of osteoporosis despite increased risk. Our findings highlight the need for a tailored, person-centred intervention co-produced with patients, to support bone health self-management with practical guidance, and integrated into the primary care pathway for PC.

Phantom calibration is currently the gold standard for calibrating CT scans and for calculating material properties of dense tissues for computational models. However, in Oncology departments and low-resource settings, it is not routine to include a calibration phantom within the scanning protocol. Therefore, retrospective scan datasets are challenging to calibrate for biomechanical investigations, precluding detailed measurements of material and mechanical properties. In this study, we compared the results from a phantomless calibration technique, where the density within each scan was independently calibrated based on known tissue densities captured within each scan (e.g., air), with those from a traditional inline phantom calibration. To do so we used scans from a cohort of healthy volunteers from the control arm of a clinical trial dataset (ANTELOPE) in which inline calibration phantoms were included. We found that, when selecting air and the aorta as regions for calibration within individual CT scans, a strong individual-specific correlation existed between bone mineral density measured in the phantomless and phantom calibrations. This indicates that the phantomless calibration method can be a useful and reliable tool for quantifying the densitometric material properties of healthy human vertebrae, and provides the opportunity for further analysis of spinal CT scans in either retrospective datasets or in low-resource clinical settings.

Background: Women with hormone-responsive breast cancer who receive adjuvant endocrine treatment with aromatase inhibitors (AI) are known to be at higher fracture risk due to a marked increase in bone resorption. In 2017, several interdisciplinary cancer and bone societies involved in the management of women with AI-associated bone loss (AIBL) published a joint position statement comprising evidence-based recommendations and a practical management algorithm for the assessment of fracture risk and optimal treatment of this patient population. Patients and methods: In order to provide updated recommendations that reflect recent advances in the assessment and management of AIBL since publication of the 2017 joint position statement, a systematic literature review was undertaken to identify relevant studies for analysis, including systematic reviews and meta-analyses. Individual trials identified were assessed for their level of evidence based on design, size, follow-up, and evaluation of safety, as well as the impact of bone directed treatments on breast cancer outcomes. Results: New evidence was combined with the existing recommendations to provide an updated joint position statement regarding fracture risk assessment and implementation of bone-directed therapy. Conclusion: Current published literature, including recent clinical trial reports, systematic reviews and meta-analyses, continue to affirm the high risk of fractures in women with breast cancer who are receiving adjuvant AI treatment, a risk which has been observed to increase with the commonly used approach of extended duration AI therapy (>5 years). Risk factors for fracture and risk assessment in this patient population as well as the most suitable treatment modalities have been updated. Finally, the influence of bone protective treatments on breast cancer outcomes such as incidence of bone metastasis and breast cancer related overall survival have been included.

Purpose. Increased CD73 expression has been associated with progression in various cancer types. Results of the AZURE and other trials suggest that, in postmenopausal breast cancer patients, adjuvant bisphosphonates inhibit bone relapses and prolong overall survival. Based on these findings, adjuvant bisphosphonates (typically zoledronic acid) are standard-of-care in postmenopausal patients with high-risk early breast cancer. However, biomarkers are needed for improved patient selection. The aim of this study was to investigate the association of primary tumor CD73 expression with later development of bone metastases. Methods. To determine whether CD73 levels correlated with tumor parameters (hormone receptor status, tumor stage and grade), patient outcomes (bone metastases and survival) or other patient characteristics (menopausal status, chemotherapy or statin use), we analyzed primary breast tumor CD73 expression immunohistochemically in tumor microarray samples from the AZURE (BIG01/04) trial. Results. In the AZURE control arm, high CD73 score are significantly prognostic for overall survival (p-value = 0.03, HR = 1.87, 95% CI = 1.06–3.29), disease-free survival (p-value = 0.06, HR = 1.66, 95% CI = 0.982–2.8) and time to first metastasis to bone (p-value = 0.04, HR = 2.23, 95% CI = 1.04–4.81), as compared with low CD73 scores. However, high CD73 score did not display an association with time to non-bone metastasis or first recurrence to a non-skeletal site. In the zoledronate arm, high CD73 score did not have association with patient outcomes, first metastasis to bone, nor with bone recurrence at any time (distant recurrence, including skeletal) or first non-skeletal recurrence. In multivariate testing, CD73 had no significant association with age, ER status, tumor stage, histological grade, menopausal status, chemotherapy or statin use in either arm. Conclusions. High CD73 expression is associated with development of bone metastases. Zoledronate counteracts this effect. These results suggest that CD73 expression might serve as a biomarker for adjuvant zoledronic acid use.

Purpose of review Skeletal metastases occur in approximately 80% of advanced breast, 70% of advanced prostate, and 30% of lung cancers, and place patients at increased risk of skeletal related events (SRE). Bone modifying agents (BMAs) have been shown to prevent or delay SRE development. Our objective was to summarize the role of these agents in the management of these three cancers. Recent findings Total 52 studies met our inclusion criteria. These highlighted the benefit of BMAs in reducing SREs in metastatic breast and castrate resistant prostate cancer (mCRPC), with less clear impact on reducing SRE in lung cancer, or on improving progression-free and overall survival due to significant heterogeneity in trial design and outcomes. Benefits in SRE reduction occurred with bisphosphonates and denosumab, however when compared, denosumab was superior. Denosumab however is not more cost effective, and multiple trials support potential de-escalation to either 12 weekly dosing or other reduced duration. Summary There is a large body of evidence to support the role of BMAs in reducing SREs in metastatic breast and mCRPC. Impact on survival outcomes is heterogeneous, and future large database trials would be helpful in identifying which subgroups of patients truly have survival benefit from BMAs.

Prostate cancer bone metastases are commonly treated with radium-223 (Ra-223); however, patients ultimately experience relapse. These metastases are currently incurable and there is an unmet need to improve the efficacy of Ra-223 treatment regimens. Ra-223 causes DNA strand breaks within tumor cells that are in close proximity to bone. We hypothesized that relapse is partly due to Ra-223-induced activation of DNA damage-response pathways; therefore, inhibiting DNA repair pathways with ATM inhibitors (ATMi), currently in clinical trials for other cancers, would radiosensitize bone metastases, increasing anti-tumor efficacy of Ra-223. To test this hypothesis, 2 mouse models of prostate cancer bone metastasis were administered 20 mg/kg/d ATMi on day 2, 7 or 10 and Ra-223 treatment (50 kBq/kg/wk or 300 kBq/kg/wk) commenced 24 h after first ATMi treatment. The 300 kBq/kg Ra-223 reduced PC3 prostate cancer bone metastases by 60.9%-87.4% compared with placebo. Radiosensitization with either the ATMi AZD0156 or AZD1390 prior to 300 kBq/kg Ra-223 treatment further reduced bone metastasis by 94.1% and 88.7%, respectively, whereas combining AZD1390 with 50 kBq/kg synergistically reduced tumor size and the number of mice with tumors in bone by 50% compared with Ra-223 alone. Treating early-stage RM1 prostate cancer bone metastasis with a combination of AZD1390 and 50 kBq/kg Ra-223 had no additional benefits compared with Ra-223 alone. However, delaying treatment to mimic overt bone metastases resulted in a 50% reduction in bone metastasis when ATMi was added prior to Ra-223 compared with Ra-223 alone. Notably, adding ATMi prior to Ra-223 did not exacerbate Ra-223-induced adverse effects on the bone. Instead, this treatment combination increased subsets of anti-tumor immune cells. Taken together, our data suggest that ATMi may be an effective radiosensitizer for increasing efficacy of Ra-223 in prostate cancer bone metastases, reducing Ra-223-induced adverse effects on bone.

INTRODUCTION:Physiological age-related bone loss is common, with 50% of women aged ≥80 having osteoporosis. Bone loss is exacerbated in women receiving aromatase inhibitors (AIs) for early breast cancer (EBC), increasing fracture risk. This study explored the management of bone-health in older women (≥70 years) with EBC and factors influencing clinical decision-making. MATERIALS AND METHODS:This was a sub-study of a larger United Kingdom multicentre observational study into practice variation and outcomes in older women (≥70) with EBC (Age Gap study). Participants were aged ≥70 years with EBC; data were collected on health status, treatments, and outcomes. This sub-study focused on patients recruited at five hospitals, where more detailed data on bone health and management were collected for women with ER + ve (oestrogen receptor positive) cancers who received adjuvant or primary endocrine therapy treatment. We aimed to determine factors influencing treatment selection and outcomes in this age group. RESULTS:The main Age Gap study recruited between 2013 and 2018. In this sub-study, 565 patients had ER + ve cancers, of whom 529 (93.6%) received AIs and 26 (4.6%) tamoxifen. The median age of participants was 77 years (70-98 years). A baseline dual energy x-ray absorptiometry (DEXA) scan was performed in only 354/529 (67%) of the AI group. Bisphosphonates were prescribed for 226/529 (43%). Baseline DEXA scans were more likely to be requested if patients were fit for surgery and were < 80 years old. Of those scanned (n = 354), 148 (42%) were osteopenic and 64 (18%) osteoporotic. Bisphosphonate prescription was associated with younger age (<80 years old) (p = 0.02). From recruitment to 2022, fractures were diagnosed in 23% of participants (122/529), of whom only 38% (46/122) had received prior bisphosphonates. Frailty or prefrailty (Rockwood scale) were present in 94% (431/461), but there was no correlation between frailty and baseline hip (r2 = 0.0098) or spine (r2 = 0.00007) T-scores. Rates of DEXA scanning varied between centres from 36% to 76% (p < 0.001) for unknown reasons. DISCUSSION:Age and general health influenced bone-health management decision-making, but there was considerable variation between centres, highlighting the need for standardised bone-health care for older women with EBC.

4531 Background: The STAR trial (ISRCTN06473203) was a phase 2/3 randomised controlled non-inferiority trial (N=920) which assessed whether treatment breaks from tyrosine kinase inhibitors (TKIs, oral sunitinib/pazopanib) could be safely used in locally advanced/metastatic renal cell carcinoma (RCC). We aimed to determine if it was possible to obtain a frailty index (FI) which could be linked to toxicity and clinical outcomes from routinely collected large trial data, using the STAR trial as an example. Methods: We developed the FI using Rockwood’s accumulation of deficits methodology. STAR data was initially searched for variables measuring baseline health problems and functional limitations. Variables were excluded if there was a significant proportion of missing values (>10%); if too rare or too common (<1%, >80%); or if significantly correlated with another variable ( r >0.95). Variables were coded from 0 (no deficit) to 1 (full deficit); these were summed then divided by the number of variables assessed to give the FI. Frailty thresholds were adopted in line with the literature: Not Frail (FI≤0.08); Pre-Frail (FI 0.08-0.24); Frail (FI≥0.25). Results: Of 57 variables screened, 35 variables remained for inclusion in the FI. 50 participants missing >20% of FI variables were excluded, leaving n=870. FI scores ranged from 0 to 0.43 (median 0.15, IQR 0.10-0.22). Kaplan-Meier survival analysis showed a statistically significant difference by FI for overall survival (OS) (FI≥0.25: HR 2.48, p<0.001, 95% CI 1.89-3.26). In multivariate Cox proportional hazards regression, FI remained a statistically significant risk factor for OS (HR 1.41, P=0.047, 95% CI 1.00-1.99); other statistically significant variables included age group, sites of metastatic disease, IMDC and MOTZER scores. Toxicity was assessed over the first 6 months, while all participants were treated with continuous TKIs. The most common severe toxicities (G3+) were hypertension (200/870), hepatobiliary disorders (97/870) and fatigue (63/870). Time free of severe toxicity was statistically significantly shorter for frail participants. Conclusions: Amongst STAR trial participants with advanced/metastatic RCC treated with TKIs, frailty was a statistically significant risk factor for poorer survival and for shorter time to severe toxicity. It is noted that the eligibility criteria for STAR included a baseline PS of ECOG 0-1 which will have excluded many frailer patients. This data shows that it is feasible to use routinely collected trial data to create a clinically meaningful FI and this approach could be applied to other trial datasets. Clinical trial information: ISRCTN06473203 . Toxicity-free survival, by frailty group. Toxicity FI group HR p-value 95% CI Severe toxicity (G3+) Intermediate 1.00 0.960 0.83-1.21 Frail 1.28 0.025 1.03-1.59 All toxicity (G1+) Intermediate 1.11 0.031 1.01-1.22 Frail 1.08 0.201 0.96-1.20

Some current prostate cancer (PCa) treatment regimens are known to have adverse effects on bone, for example androgen deprivation therapy (ADT), and on cardiovascular health, for example ADT and antiandrogen therapy. Strengthened recommendations for the practical assessment and management of bone and cardiovascular health in men with PCa are needed. This review aims to provide practical guidance for healthcare providers along the continuum of patient care on the management of bone and cardiovascular health in men with PCa undergoing ADT and antiandrogen therapy based on real-world evidence. Evidence was identified by searching PubMed for publications that reported the effects of PCa treatment on bone or cardiovascular health in a real-world setting and were published between January 2017 and August 2023. Review articles were excluded. The evidence identified indicates that ADT decreases bone mineral density (BMD) and increases the risk of osteoporosis and fractures. Bone-protecting agents (BPAs) are effective at improving bone health in patients undergoing ADT and antiandrogen therapy at all stages of the PCa pathway. Despite this, the use and timing of initiation of BPAs are variable. Furthermore, real-world studies have confirmed an association between ADT and cardiovascular risk. As survival outcomes improve, maintenance of bone and cardiovascular health is increasingly important in men with PCa. Risk is a continuous variable that must be assessed throughout the continuum of PCa treatment. Therefore, all men starting ADT should be assessed for bone and cardiovascular risk. Lifestyle adjustments, dietary supplementation and pharmacological intervention may be advised.

Androgen deprivation therapy (ADT) for localised and metastatic prostate cancer (PCa) is known to improve survival in patients but has been associated with negative long-term impacts on the skeleton, including decreased bone mineral density (BMD) and increased fracture risk. Generally, dual-enery X-ray absorptiometry (DXA) measurements of areal BMD (aBMD) of vertebrae are used clinically to assess bone health. However, a prediction of vertebral bone strength requires information that aBMD cannot provide, such as geometry and volumetric BMD (vBMD). This study aims to investigate the effect of ADT on the densitometric (aBMD, trabecular vBMD, integral vBMD) and mechanical integrity (failure load and failure strength) of vertebrae, using a combination of DXA, quantitative computed tomography (QCT) and finite element (FE) modelling. For the FE analyses, 3D models were reconstructed from QCT images of 26 ADT treated patients, and their matched controls, collected as part of the ANTELOPE clinical trial. The ADT treated group experienced significantly decreased trabecular and integral vBMD (trabecular vBMD: -18 %, p < 0.001, integral vBMD: -11 %, p < 0.001) compared to control patients that showed no significant temporal changes (trabecular vBMD p = 0.037, integral vBMD p = 0.56). A similar trend was seen in the ADT treated group for the failure load and failure strength, where a decrease of 14 % was observed (p < 0.001). When comparing the proficiency in predicting the mechanical properties from densitometric properties, the integral vBMD performed best in the pooled data (r = 0.86-0.87, p < 0.001) closely followed by trabecular vBMD (r = 0.73-0.75, p < 0.001) with aBMD having a much weaker predictive ability (r = 0.19-0.21, p < 0.01). In conclusion, ADT significantly reduced both the densitometric properties and the mechanical strength of vertebrae. A stronger relationship between both trabecular vBMD and integral vBMD with the mechanical properties than the aBMD was observed, suggesting that such clinical measurements could improve predictions of fracture risk in prostate cancer patients treated with ADT.

Background UK national clinical guidance recommends that men with prostate cancer on androgen deprivation therapy are offered twice weekly supervised aerobic and resistance exercise to address iatrogenic harm caused by treatment. Very few NHS trusts have established adequate provision of such services. Furthermore, interventions fail to demonstrate sustained behaviour change. The STAMINA lifestyle intervention offers a system-level change to clinical care delivery addressing barriers to long-term behaviour change and implementation of new prostate cancer care pathways. This trial aims to establish whether STAMINA is clinically and cost-effective in improving cancer-specific quality of life and/or reducing fatigue compared to optimised usual care. The process evaluation aims to inform the interpretation of results and, if the intervention is shown to benefit patients, to inform the implementation of the intervention into the NHS. Methods Men with prostate cancer on androgen deprivation therapy (n = 697) will be identified from a minimum of 12 UK NHS trusts to participate in a multi-centre, two-arm, individually randomised controlled trial. Consenting men will have a 'safety to exercise' check and be randomly allocated (5:4) to the STAMINA lifestyle intervention (n = 384) or optimised usual care (n = 313). Outcomes will be collected at baseline, 3-, 6- and 12-month post-randomisation. The two primary outcomes are cancer-specific quality of life and fatigue. The parallel process evaluation will follow a mixed-methods approach to explore recruitment and aspects of the intervention including, reach, fidelity, acceptability, and implementation. An economic evaluation will estimate the cost-effectiveness of the STAMINA lifestyle intervention versus optimised usual care and a discrete choice experiment will explore patient preferences. Discussion The STAMINA lifestyle intervention has the potential to improve quality of life and reduce fatigue in men on androgen deprivation therapy for prostate cancer. Embedding supervised exercise into prostate cancer care may also support long-term positive behaviour change and reduce adverse events caused by treatment. Findings will inform future clinical care and could provide a blueprint for the integration of supervised exercise and behavioural support into other cancer and/or clinical services. Trial registration ISRCTN 46385239, registered on 30/07/2020. Cancer Research UK 17002, retrospectively registered on 24/08/2022.

Introduction Bone metastases negatively affect prognosis in patients with advanced renal cell carcinoma (aRCC). We conducted a systematic literature review to identify clinical trial publications including patients with aRCC with and without bone metastases. Methods The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta‑Analyses (PRISMA) guidelines and registered with PROSPERO (CRD42022355436). MEDLINE and Embase databases were searched (September 2, 2022) to identify publications reporting efficacy and safety outcomes for patients with/without bone metastasis from clinical trials of systemic RCC therapies. Risk of bias was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results Of 526 publications screened, 19 were eligible: seven (from five studies) reported phase 3 trials, six reported phase 2 trials, one reported phase 1b/2 trials, and five were pooled analyses. Five publications reported moderate-quality evidence, while 14 were graded as low- or very low-quality evidence, suggesting a high potential for uncertainty. Five studies reported benefits of investigational therapies versus comparators in patients with and without bone metastases; these studies included cabozantinib, nivolumab, cabozantinib plus nivolumab, and lenvatinib plus pembrolizumab treatment arms. Data were also available for nivolumab plus ipilimumab. Bone metastases were consistently associated with poor prognosis in patients with aRCC. Preliminary data support the hypothesis that therapies targeting pathways implicated in the development of bone metastases may be beneficial, and warrant further investigation. However, data to support treatment decision-making are lacking. Conclusion Our findings highlight the need for clinical data to assist in defining the optimal treatment for patients with aRCC and bone metastasis.

Purpose Androgen deprivation therapy (ADT) is a mainstay of treatment of prostate cancer (PCa) and is associated with increased risk of osteoporosis and fragility fractures. Despite international guidelines to mitigate fracture risk, osteoporosis is under-diagnosed and under-treated due to poor implementation. This scoping review aims to synthesise knowledge surrounding the implementation of guidelines and strategies to inform health service interventions to reduce fracture risk in men with PCa taking ADT. Method Four databases and additional literature were searched from January 2000 to January 2023. Studies which provided evidence influencing the implementation of guidelines were included. The i-PARIHS (Promoting Action on Research Implementation in Health Services) framework was used to inform the narrative synthesis. Results Of the 1229 studies identified, 9 studies met the inclusion criteria. Overall, an improvement in fracture risk assessment was observed across heterogeneous study designs and outcome measures. Six studies were from Canadian. Two studies involved family physicians or a community healthcare programme. Two studies incorporated patient or specialist surveys. One utilised an implementation framework. Barriers included lack of knowledge for both patients and clinicians, time constraints, unsupportive organisational structures and challenges in transferring patient care from specialists to primary care. Effective strategies included education, novel care pathways using a multidisciplinary approach and incorporating existing services, point-of-care interventions, and bespoke clinics. Conclusion Guideline implementation requires contextualisation and innovation to address barriers and enablers. Implications for Cancer Survivors Whilst specialist cancer care is expected, primary care clinicians can play an important role in management of complications from long-term cancer treatment induced bone loss. Futurestudies should incorporate both patient and clinician perspectives and co-design interventions in primary care.

Background Androgen deprivation therapy (ADT) is a front-line treatment for prostate cancer. In some men, their tumors can become refractory leading to the development of castration-resistant prostate cancer (CRPC). This causes tumors to regrow and metastasize, despite ongoing treatment, and impacts negatively on patient survival. ADT is known to stimulate the accumulation of immunosuppressive cells like protumoral tumor-associated macrophages (TAMs), myeloid-derived suppressor cells and regulatory T cells in prostate tumors, as well as hypofunctional T cells. Protumoral TAMs have been shown to accumulate around tumor blood vessels during chemotherapy and radiotherapy in other forms of cancer, where they drive tumor relapse. Our aim was to see whether such perivascular (PV) TAMs also accumulate in ADT-treated prostate tumors prior to CRPC, and, if so, whether selectively inducing them to express a potent immunostimulant, interferon beta (IFNβ), would stimulate antitumor immunity and delay CRPC.Methods We used multiplex immunofluorescence to assess the effects of ADT on the distribution and activation status of TAMs, CD8+T cells, CD4+T cells and NK cells in mouse and/or human prostate tumors. We then used antibody-coated, lipid nanoparticles (LNPs) to selectively target a STING agonist, 2′3′-cGAMP (cGAMP), to PV TAMs in mouse prostate tumors during ADT.Results TAMs accumulated at high density around blood vessels in response to ADT and expressed markers of a protumoral phenotype including folate receptor-beta (FR-β), MRC1 (CD206), CD169 and VISTA. Additionally, higher numbers of inactive (PD-1-) CD8+T cells and reduced numbers of active (CD69+) NK cells were present in these PV tumor areas. LNPs coated with an antibody to FR-β selectively delivered cGAMP to PV TAMs in ADT-treated tumors, where they activated STING and upregulated the expression of IFNβ. This resulted in a marked increase in the density of active CD8+T cells (along with CD4+T cells and NK cells) in PV tumor areas, and significantly delayed the onset of CRPC. Antibody depletion of CD8+T cells during LNP administration demonstrated the essential role of these cells in delay in CRPC induced by LNPs.Conclusion Together, our data indicate that targeting a STING agonist to PV TAMs could be used to extend the treatment window for ADT in prostate cancer.