Table 1.

Relative roles of etiological factors in the initiation and progression of PDB

Factor Category	Primary Role in Pathogenesis	Mechanism of Contribution	Nature of Role (Trigger / Modifier)
Genetic (SQSTM1, OPTN)	Susceptibility & Initiation	Germline mutations cause inherent dysfunction in osteoclast/osteoblast signaling pathways (NF-κB, autophagy, IFN), lowering the threshold for abnormal remodeling	Necessary Susceptibility Factor & Primary Phenotype Modifier
Genetic (TNFRSF11B, ZNF687)	Phenotype Determination	Specific mutations dictate distinct clinical syndromes (JPD) or complication risks (GCT), guiding disease expression	Primary Phenotype Modifier
Environmental (historical coal, livestock)	Disease Trigger	Provide the external “second hit” that initiates focal osteoclast activation in a genetically primed skeletal site	Primary Trigger
Environmental (pollutants, smoking)	Risk & Severity Modifier	May interact with susceptibility genes (SQSTM1), exacerbating oxidative stress/dysautophagy to modulate lesion onset or aggressiveness	Interacting Trigger & Progression Modifier
Environmental (rural residence, Vit D deficiency)	Population Risk Factor	Associated with increased odds of disease, likely through broad, non-specific mechanisms or confounding	Weak Correlative Modifier
Viral (Measles, RSV)	Not Supported	No serological evidence of causal association; historical links likely coincidental or artefactual	Not a Trigger or Modifier

Abbreviations: Paget’s disease of bone (PDB), Sequestosome1(SQSTM1), Optineurin (OPTN), Nuclear Factor Kappa B (NF-κB), Interferon (IFN), Tumor Necrosis Factor Receptor Superfamily Member 11B (TNFRSF11B), Zinc Finger Protein 687 (ZNF687), Juvenile Paget’s Disease (JPD), Giant Cell Tumor (GGT), Vitamin D (Vit D), Respiratory Syncytial Virus (RSV)