Osteoporosis and Skeletal Fragility in non-Metastatic Pheochromocytomas and Paragangliomas: The Adrenergic-Skeletal Axis.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells, characterized by excessive catecholamines secretion. Traditionally, the clinical burden of PPGLs has been attributed to cardiovascular, neurological and metabolic complications, including hypertension, arrhythmias, insulin resistance, and increased cardiovascular mortality. However, growing evidence suggests that chronic catecholamine excess may also exert clinically relevant effects on skeletal health. Over the last decade, few clinical studies have demonstrated increased bone turnover, reduced bone mineral density (BMD), impaired trabecular bone quality, and a higher prevalence of vertebral fractures (VFs) in patients with PPGLs. These clinical manifestations are supported by a strong biological rationale, as bone tissue is richly innervated by sympathetic fibers and expresses functional adrenergic receptors (AR) that modulate bone remodeling. Although skeletal involvement remains underrecognized in routine clinical practice, the accumulating evidence suggests that PPGLs may be associated with an adverse skeletal phenotype with increased skeletal fragility. This review summarizes current knowledge regarding the pathophysiological mechanisms, clinical features, and management implications of PPGL-induced bone loss. Crucially, it explores the distinct impacts of catecholamine secretion profiles and discusses the emerging, yet speculative, role of genetic backgrounds-specifically VHL and SDHx mutations-as novel modulators of the skeletal phenotype. Furthermore, this work aims to raise awareness among clinicians involved in PPGLs management in order to implement early screening and prevention strategies.