Paget disease of bone (PDB, or ostmonostotic or polyostotic skeletal disease. It is characterized by increased bone turnover, which causes normal lamellar bone to be replaced by weak woven bone. The cause of this common yet underdiagnosed skeletal disease is not known. It predominantly affects individuals over the age of 55 and is characterized by localized pain and bony deformities (such as bowing of long bones). Skeletal x-ray, bone scans, and serum alkaline phosphatase are important tests for diagnosing and monitoring the progression of PDB. Treatment is mainly supportive and involves the use of bisphosphonates to inhibit osteoclastic function.rmans) is a slowly progressive
Paget disease of the bone should not be confused with Paget disease of the nipple or , which are named after the same physician.
- Prevalence: second most prevalent skeletal disease after osteoporosis in individuals > 50 years of age 
- Sex: ♂ > ♀ (1.2:1)
- Age of onset: > 55 years 
Epidemiological data refers to the US, unless otherwise specified.
- Idiopathic disease
- Associated with a high rate of bone remodeling: ↑ RANKL-RANK activity → ↑ NF-κB signaling → ↑ osteoclast activity → ↑ osteoblast activity → formation of disorganized (woven) bone
Stages of Paget disease
Bone remodeling in Paget disease occurs in three phases, followed by a quiescent stage: 
- Lytic phase: ↑ number of osteoclasts appear in bone → ↑ osteoclastic activity → ↑ rate of bone resorption
- Mixed lytic and blastic phase: ↑ osteoclastic activity is accompanied by an ↑ number of osteoblasts, which infiltrate the lacunae: → ↑ rate of bone formation with haphazardly laid collagen fibers → formation of abnormal hypervascular woven bone
- Sclerotic phase: Osteoblastic activity overtakes osteoclastic activity, which leads to formation of dense, sclerotic bone.
- Quiescent stage: Both osteoclastic and osteoblastic activity cease (“quiet phase” of the disease).
- Approximately 70–90% of cases are asymptomatic.
- Bone pain, which may be associated with erythema and elevated skin temperature over the affected bones
- Pathological fractures: chalk-stick fractures of long bones 
- Bony deformities; , e.g., bowing of legs (saber shin)
- Skull involvement (in ∼ 40% of cases)
- Cauda equina syndrome, nerve root compression
- Blood work
Urinalysis: ↑ markers of collagen degradation 
- N-telopeptide, C-telopeptide
- See “ .”
- Deformed bones with both sclerotic and osteolytic lesions
Thickened cortical bone
- Coarsened trabeculae; expansion or enlargement of a region of the bone.
- Skull x-ray: thickening of the diploe; osteoporosis circumscripta (cotton wool appearance).
- Vertebral x-ray: thickening of the upper and lower plates of the vertebral body gives rise to a “picture frame” appearance; diffuse enlargement of the vertebrae (ivory vertebra)
- Pelvic x-ray: disruption/fusion of sacroiliac joints; thickened iliopectineal line (brim sign)
- Bone scans (skeletal scintigraphy): to test for additional bony lesions
Osteopetrosis (marble bone disease) 
- Definition: Osteopetrosis is an inherited, diffuse bone disease that results in increased sclerotic appearance of the skeleton on radiological examination.
- Type I osteopetrosis (malignant osteopetrosis): autosomal recessive disease
- Type II osteopetrosis (benign osteopetrosis, Albers-Schonberg disease): autosomal dominant disease
- Carbonic anhydrase II deficiency
- Pathophysiology: mutations → inability of osteoclasts to generate acidic environment in the bone matrix → impaired bone resorption with preserved osteoblastic function → overgrowth of bone with pathological bone composition
- Clinical features
Fibrous dysplasia 
- Description: Fibrous dysplasia is a benign, developmental disorder of bone that causes normal skeletal tissue to be replaced by fibrous tissue.
- Etiology: post-zygotically acquired, somatic, gain-of-function mutation in GNAS1 gene on chromosome 20q
- GNAS1 codes for the α subunit of the Gs protein (Gsα).
- Mutation → constitutive activation of certain Gs-cAMP coupled pathways → inhibition of mesenchymal differentiation into osteoblasts → lack of osteocytes → skeletal lesions composed largely of mesenchymal cells → weak, imperfect bone with fibrous tissue
- Clinical features
- Subtypes and variants (disease phenotype)
- Laboratory tests
- Imaging: x-ray
- Long bones: well-defined, lobulated lesions with a thin cortex and a radiolucent, ground-glass appearance
- Facial bones: radiodense lesions with a leonine appearance
- Pathology: bone biopsy
- The lesions do not heal spontaneously.
- Osteosarcomas occur in < 1% of cases.
- Pathophysiology: postzygotic GNAS gene mutation → impaired Gs-protein signaling → constitutively activated adenylate cyclase → excess production of cAMP 
- Polyostotic fibrous dysplasia
- Café au lait spots with unilateral, ragged edges
- Hormonal abnormalities (at least one)
- Prognosis: The condition is lethal when the mutation affects all cells (i.e., occurs before fertilization), but survivable in patients affected by mosaicism.
The differential diagnoses listed here are not exhaustive.
Medical therapy 
- First-line: bisphosphonates
- Second-line: calcitonin therapy 
- Supportive therapy
Surgical therapy 
- Bone deformities
- Pathological fractures
- Malignant degeneration into osteosarcoma (very rare: < 1% of cases)
- High-output cardiac failure (due to the formation of arteriovenous shunts within the bone, which leads to an increased overall blood flow)
We list the most important complications. The selection is not exhaustive.