Table 2.

Proposed pathophysiological mechanisms linking PDB to ocular complications

Ocular Complication	Dominant Mechanism	Pathophysiological Process	Key Molecular/Cellular Pathways
Orbital Deformity (Proptosis, Enophthalmos)	Bone Remodeling/ Mechanical	Disordered osteoclastic-osteoblastic activity leads to expansion and deformation of orbital bones, altering orbital volume and anatomy	Dysregulation of osteoclast-osteoblast coupling (RANKL/OPG, SQSTM1/p62, OPTN signal paths)
Ptosis secondary to Orbital GCT	Bone Remodeling/ Mechanical (Mass Effect)	PDB-associated proliferation of osteoclast precursors forms a benign, space-occupying tumor that mechanically compresses the levator palpebrae superioris muscle	Local clonal expansion of osteoclast precursors driven by the systemic PDB milieu; potential role of ZNF687 mutations
Compressive Optic Neuropathy (JPD)	Bone Remodeling/ Mechanical	Craniofacial hyperostosis, particularly of the sphenoid bone, results in stenosis of the bony optic canal, causing direct compression and ischemia of the optic nerve	Uncontrolled osteoblastic bone formation at specific cranial sites
Vascular Optic Neuropathy	Vascular/ Hemodynamic	Hypervascularity of pagetic bone creates a low-resistance shunt (“steal” phenomenon), diverting blood flow from the microvasculature of the optic nerve head and leading to ischemia	VEGF-mediated pathological angiogenesis within pagetic bone; altered local hemodynamics
Orbital & Conjunctival Congestion	Vascular/ Hemodynamic	Increased blood flow and vascular permeability from adjacent active pagetic bone cause venous engorgement and edema in orbital soft tissues and conjunctiva	Inflammatory cytokine release (e.g., IL-6) and angiogenic drive from the bone microenvironment
AS	Metabolic/ Systemic	Systemic dysregulation of mineral homeostasis, due to loss of calcification inhibitors, results in pathological calcification and increased fragility of Bruch’s membrane	Loss-of-function mutations in TNFRSF11B (encoding OPG), a key regulator of extracellular matrix mineralization
Cataract & Maculopathy (Potential Association)	Other/Systemic (Speculative)	A shared systemic milieu of chronic inflammation and oxidative stress may potentially accelerate age-related degenerative processes in the lens and retina	Persistent activation of NF-κB and impairment of the NRF2 antioxidant pathway, as observed in pagetic bone biology

Abbreviations: Paget’s disease of bone (PDB), Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL), Osteoprotegerin (OPG), Sequestosome1 (SQSTM1), Optineurin (OPTN), Giant Cell Tumor (GGT), Zinc Finger Protein 687 (ZNF687), Juvenile Paget’s Disease (JPD), Vascular Endothelial Growth Factor (VEGF), Interleukin-6 (IL-6), Angioid Streak s(AS), Tumor Necrosis Factor Receptor Superfamily Member 11B (TNFRSF11B), Nuclear Factor Kappa B (NF-κB), Nuclear Factor Erythroid 2–Related Factor 2 (NRF2)