Bone health impairment in childhood cancer : from preclinical studies to clinical insights

Survival outcomes in childhood cancer have significantly improved over recent decades. While this is a remarkable achievement, it has also led to a growing number of survivors who face a great risk of long-term morbidities. Among the various contributing factors, therapeutic interventions frequently cause skeletal morbidities, mediated through systemic endocrine disruptions or direct cellular impact. These deleterious effects manifest as longitudinal bone growth suppression, lower bone mineral density and susceptibility to fractures. The prevalence of these burdensome conditions underscores the need for heightened awareness and identification of novel therapeutic approaches to safeguard skeletal health in childhood cancer.

This thesis aims to investigate the effects of the novel inhibitor venetoclax on bone tissue, explore potential bone growth-rescuing strategies in preclinical models and finally, provide a comprehensive summary of the available evidence on bone mineral density in survivors of childhood cancer.

In paper I, we demonstrated that venetoclax, a BCL-2 inhibitor effective in various cancer types, suppressed longitudinal bone growth in different experimental models. In paper II, we expanded our studies to a neuroblastoma cancer model where venetoclax impaired longitudinal bone growth. We also showed that co-treatment with the mitochondrial peptide humanin protected fetal rat metatarsal bones cultured ex vivo against venetoclax-induced bone growth retardation. In paper III, we explored the potential for lithium chloride to prevent dexamethasone-induced bone growth suppression. We also performed RNA sequencing to investigate potential genes and pathways that contribute to the observed effects. In paper IV, we performed a systematic review and meta-analysis of published studies that reported BMD data in childhood cancer survivors.

Overall, the present thesis evolves from an initial focus on preclinical investigations into the side effects of a novel antineoplastic drug and the exploration of potential growth-rescuing therapies, advancing toward a clinical outlook, aiming to provide a systematic overview of BMD status in survivors of childhood cancer.

List of scientific papers

I. Lilly Velentza, Malin Wickström, Per Kogner, Claes Ohlsson, Farasat Zaman #, Lars Sävendahl #. Pharmacological inhibition of BCL-2 with the FDA-approved drug venetoclax impairs longitudinal bone growth. Scientific Reports. 2023 May 17;13(1):8054. # Denotes equal last-author contribution
https://doi.org/10.1038/s41598-023-34965-4

II. Lilly Velentza, Malin Wickström, Per Kogner, Claes Ohlsson, Farasat Zaman #, Lars Sävendahl #. Humanin Treatment Protects Against Venetoclax-Induced Bone Growth Retardation in Ex Vivo Cultured Rat Bones. Journal of the Endocrine Society. 2024 Jan 25;8(3):bvae009. # Denotes equal last-author contribution
https://doi.org/10.1210/jendso/bvae009

III. Ondrej Soucek, Ondrej Cinek, Lilly Velentza, Valerij Semjonov, Martin Bezdicka, Farasat Zaman #, Lars Sävendahl #. Lithium rescues cultured rat metatarsals from dexamethasone-induced growth failure. Pediatric Research. 2024 Apr 29. # Denotes equal last-author contribution
https://doi.org/10.1038/s41390-024-03192-6

IV. Lilly Velentza, Panagiotis Filis, Mari Wilhelmsson, Per Kogner, Nikolas Herold #, Lars Sävendahl #. Bone mineral density in survivors of childhood cancer: A meta-analysis PEDIATRICS. #Denotes equal last-author contribution. [Accepted]