Cancer Treatment and Bone Health

Considerable advances in oncology over recent decades have led to improved survival, while raising concerns about long-term consequences of anticancer treatments. In patients with breast or prostate malignancies, bone health is a major issue due to the high risk of bone metastases and the frequent prolonged use of hormone therapies that alter physiological bone turnover, leading to increased fracture risk. Thus, the onset of cancer treatment-induced bone loss (CTIBL) should be considered by clinicians and recent guidelines should be routinely applied to these patients. In particular, baseline and periodic follow-up evaluations of bone health parameters enable the identification of patients at high risk of osteoporosis and fractures, which can be prevented by the use of bone-targeting agents (BTAs), calcium and vitamin D supplementation and modifications of lifestyle. This review will focus upon the pathophysiology of breast and prostate cancer treatment-induced bone loss and the most recent evidence about effective preventive and therapeutic strategies

Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Prostate cancer and bone health

Introduction Both prostate cancer (PC) and its treatment have important effects on bone and body composition. Three distinct mechanisms affect bone; androgen deprivation therapy (ADT); use of chemotherapy and systemic glucocorticoids (GC), and bone metastases (BM). Work undertaken in this thesis investigates the effect of ADT on bone density, microarchitecture, strength, physical performance, frailty, biomarkers of bone turnover and body composition. The second section explores the role of biomarkers in predicting the development of PC BM. Methods The ANTELOPE trial recruited men receiving ADT or ADT and chemotherapy/GC for PC, and healthy controls. A comprehensive bone health assessment was undertaken at baseline and 12 months to identify changes associated with ADT. The biomarker discovery project applied proteomic methods to PC cell lines to quantify the expression of CAPG, GIPC1 and DOCK4 proteins and sought to relate expression to their predicted metastatic potential. Results ADT was associated with loss of bone density at all skeletal sites. There was significant loss of volumetric density at the radius, along with microarchitectural deterioration and reduced bone strength and stiffness. ADT increased bone turnover, and led to sarcopenic obesity with marked effects in upper limb composition. Frailty increased and physical performance and strength deteriorated in association with ADT. The biomarkers GIPC1 and DOCK4 showed differential expression across PC cell lines and may have a role in the early stages of metastasis, but do not appear to predict BM development. Conclusions ADT has profound effects on bone density, structure, strength and body composition, and has important effects on frailty and physical performance. Assessment of bone health is an unmet need in this population and must be incorporated into clinical practice to reduce risk of fractures and their associated morbidity and mortality. Studies should explore the effects of bone targeted therapies on density and microstructure in order to select the most appropriate treatment for this population. Proteomic techniques allow the identification of predictive biomarkers of BM in PC, and further work should explore GIPC1 and DOCK4 in PC cell lines and tissue models

Medical Prevention and Treatment of Bone Metastases.

The presence of metastatic bone disease is a devastating complication that has signifcant impact on morbidity and mortality in cancer patients. Although the type, incidence, and consequences of bone metastases (BM) may vary between primary cancer sites, all patients with BM require consideration as to how both their primary tumour and their bone disease should be managed in terms of avoiding complications and maximizing both quality of life and survival. This chapter will describe normal bone turnover, the pathophysiology of BM, and the most common clinical sequelae. We will then explain the current evidence for the prevention and treatment of BM for the most osteotropic tumours (breast, prostate, lung, and renal)

Setting Research Priorities in Partnership with Patients to Provide Patient-centred Urological Cancer Care.

There is a well-documented discrepancy in prioritisation of research agendas between patients and researchers. Patient involvement in urological research from the outset is critical for well-prioritised research.Ni

Efficacy, immunogenicity, and safety of a next-generation mRNA-1283 COVID-19 vaccine compared with the mRNA-1273 vaccine (NextCOVE): results from a phase 3, randomised, observer-blind, active-controlled trial

Background: mRNA-1283 is an investigational, next-generation COVID-19 vaccine that encodes only the immunodominant regions of the SARS-CoV-2 spike protein—the receptor-binding domain (RBD) and the N-terminal domain rather than the full-length spike used in currently authorised mRNA vaccines. We evaluated the relative vaccine efficacy (rVE), immunogenicity, and safety of mRNA-1283 compared to the first-generation vaccine (mRNA-1273). Methods: This randomised, observer-masked, active-controlled, phase 3 trial (NextCOVE) was conducted in individuals (aged ≥12 years) with no evidence of SARS-CoV-2 infection within 90 days of screening in the USA, the UK, and Canada. Participants were randomly assigned in a 1:1 ratio to receive one 10 μg dose of the bivalent formulation of mRNA-1283 (original plus omicron BA.4/BA.5) or 50 μg of the bivalent mRNA-1273, encoding the same variants. Randomisation was stratified by age (12–17 years, 18–64 years, and ≥65 years). Primary objectives comparing mRNA-1283 with mRNA-1273 were non-inferior rVE to prevent a first event of COVID-19 from 14 days after study injection to the end of follow-up (assessed in the per-protocol set for efficacy, with non-inferiority declared when the lower bound of the α-adjusted two-sided CI for rVE was greater than –10%), non-inferior immunogenicity at day 29 (assessed in the per-protocol immunogenicity subset, with non-inferiority declared when the lower bounds of the CIs for the geometric mean concentration ratios [GMRs] of neutralising antibodies against SARS-CoV-2 D614G and omicron BA.4/BA.5 were &gt;0·667 and the lower bounds of the 95% CI seroresponse rate differences for the two variants were greater than –10%), and safety (assessed in the safety set, which included all participants who received a vaccination). The trial is registered at ClinicalTrials.gov (NCT05815498) and is complete. Findings: Between March 28 and Aug 23, 2023, we screened 13 054 individuals for eligibility and randomly allocated 11 454 participants (5728 to mRNA-1283 and 5726 to mRNA-1273). 1177 confirmed COVID-19 events occurred up to Jan 31, 2024 (560 [9·9%] of 5679 in mRNA1283.222 and 617 [10·8%] of 5687 in mRNA-1273.222). The median age of participants at enrolment was 56 years (IQR 38–66). Of the 11 417 participants who received a vaccine, 6200 (54·3%) were female and 5217 (45·7%) were male; 9381 (82·2%) were White; and 1510 (13·2%) were Hispanic or Latino. Of the total cohort, 992 (8·7%) participants were aged 12–17 years, 7151 (62·6%) were aged 18–64 years, and 3274 (28·7%) were 65 years and older; in addition, 6857 participants (60·1%) were 50 years and older. The rVE point estimate was 9·3% (99·4% CI –6·6 to 22·8; p=0·0005). The GMR was 1·3 (95% CI 1·2 to 1·5) for BA.4/BA.5 and 1·2 (1·1 to 1·4) for D614G. The day-29 seroresponse rate difference was 14·4% (95% CI 9·3 to 19·4) for BA.4/BA.5 and 10·7% (6·0 to 15·4) for D614G. Local and systemic adverse reactions were similar between mRNA-1283 and mRNA-1273; mRNA-1283 was associated with fewer injection-site pain reactions than mRNA-1273 (3905 [68·5%] of 5701 vs 4419 [77·5%] of 5705, respectively). The frequency of unsolicited adverse events, serious adverse events, and medically attended adverse events were similar between groups during the first 28 days after injection. One event of sudden death occurred in a participant with underlying cardiovascular disease in the mRNA-1273 group; it was reported as related to vaccination due to its temporal association. Interpretation: mRNA-1283 was well-tolerated. The rVE and immunogenicity non-inferiority criteria were met, with higher antibody responses for mRNA-1283 versus mRNA-1273. The potential clinical benefit of mRNA-1283 versus mRNA-1273 needs to be confirmed in post-marketing evaluation. Funding: Moderna.</p