The role of exercise in the context of cancer and bone metastases: friend or foe?

Bone metastases represent one of the most feared complications of cancer. Clinically, they are challenging to diagnose, difficult to monitor over time, and complex to manage due to the high risk of skeletal-related complications, which require multidisciplinary expertise and a combination of surgical, pharmacological, and palliative strategies. From the patient perspective, the presence of bone metastases is associated with substantial symptom burden, reduced mobility and independence, impaired quality of life, decreased survival, and significant psychological distress, as their occurrence signals disease progression and incurability. Alongside medical treatments, exercise is increasingly recognized as a key component of supportive cancer care, with demonstrated benefits in physical fitness, treatment-related toxicities, quality of life, and even mortality. However, in patients with bone metastases, safety and feasibility concerns persist due to skeletal fragility and fear of skeletal-related adverse events, particularly in individuals with osteolytic lesions, considered the most vulnerable. Consequently, it remains unclear whether exercise should be viewed as a supportive ally or a potential risk. This doctoral thesis aims to explore the feasibility, safety, and effectiveness of exercise in this population. Chapter 1 introduces the biological mechanisms and clinical complexity of bone metastases and outlines current recommendations for exercise prescription in this setting, addressing the dual perception of exercise as both beneficial and potentially risky. Chapter 2 presents a clinical case report describing the impact of a nine-month structured and individualized exercise program in a patient with non-small cell lung cancer, multiple osteolytic metastases, and previous vertebral fractures. Chapter 3, through a meta-analysis, evaluates whether exercise can counteract or reverse bone loss in individuals with compromised bone health, such as those with osteopenia, osteoporosis, or bone metastases, by examining changes in bone mineral density, bone mineral content, and bone turnover markers. Chapter 4 investigates the feasibility, safety, and preliminary effects of a 12-week supervised or home-based exercise program in patients with various types and locations of bone lesions. Twenty-one participants underwent twice-weekly aerobic and resistance training, followed by participation in a qualitative study (Chapter 5) exploring their experiences, perceived benefits and risks, and perceived facilitators and barriers to inform optimized, individualized exercise prescription. Chapter 6 synthesizes preclinical and clinical evidence on how mechanical loading and exercise-induced muscle signaling influence the tumor-bone microenvironment, providing the rationale for resistance training as a strategy with potential osteogenic and anti-tumorigenic effects. Finally, Chapter 7 presents the protocol of a future randomized clinical trial designed to evaluate the effects of a six-month structured and personalized exercise program, delivered alongside bone-targeting agents, on whole-body skeletal muscle mass and the incidence of skeletal-related events over a 24-month follow-up. Secondary endpoints include body composition, physical fitness, health-related quality of life, cancer-related symptoms (fatigue, bone pain, neuropathy, anxiety, depression), circulating biomarkers of bone turnover and calcium homeostasis, overall survival, and progression-free survival.