Updates on Paget's Disease of Bone

Abstract

Paget's disease of the bone is a prevalent bone disease characterized by disorganized bone remodeling; however, it is comparatively uncommon in East Asian countries, including China, Japan, and Korea. The exact cause still remains unknown. In genetically susceptible individuals, environmental triggers such as paramyxoviral infections are likely to cause the disease. Increased osteoclast activity results in increased bone resorption, which attracts osteoblasts and generates new bone matrix. Fast bone resorption and formation lead to the development of disorganized bone tissue. Increasing serum alkaline phosphatase or unique radiographic lesions may serve as the diagnostic indicators. Common symptoms include bone pain, bowing of the long bones, an enlarged skull, and hearing loss. The diagnosis is frequently confirmed by radiographic and nuclear scintigraphy of the bone. Further, bisphosphonates such as zoledronic acid and pamidronate are effective for its treatment. Moreover, biochemical monitoring is superior to the symptoms as a recurrence indicator. This article discusses the updates of Paget's disease of bone with a clinical case.

Keywords: Bisphosphonates; Genetics; Paget’s disease of bone.

Fig. 1.

Technetium-99m whole-body bone scans of abnormalities in the pelvic bones, cervical vertebrae, T1, T7, T11, L3, and L5/S1 vertebrae, and both tibial bones. (A) Bone mineral densitometry couple with dual-energy X-ray absorptiometry displaying decreased density of the lumbar spine (B) and improvements in bone abnormalities (C) and density (D) following 10 months of zoledronate administration. AP, anterior-posterior; BMD, bone mineral density; YA, young-adult.

Fig. 2.

The hypothesized mechanism of osteoclast activation in sequestosome 1 gene (SQSTM1) mutation. Under normal conditions, the ubiquitin-associated (UBA) domain of p62 (light blue) recruits the deubiquitinating enzyme cylindromatosis (CYLD) to the intracellular domain of the receptor activator of nuclear factor kappa B (RANK) receptor, where it deubiquitinates the tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) (scissors), thereby inhibiting RANK signaling. Certain mutations of the p62 UBA domain (disrupted lines) inhibit the recruitment of CYLD (yellow), thus leading to increased ubiquitination of TRAF6 (light green) and the activation of RANK signaling. RANKL, receptor activator of nuclear factor kappa Β ligand; NF-κB, nuclear factor kappa B.

Fig. 3.

Sanger-sequenced chromatograms for sequestosome 1 gene (SQSTM1) displaying the heterozygous pathogenic variant (c.1237G>T [p.Gly425*]).